阅读说明：本技术 一种制备磺胺类化合物的工艺 (Process for preparing sulfonamide compound ) 是由 郭明 温剑锋 陆惠荣 冯建鹏 张晶 金明 曹钱磊 于 2020-01-03 设计创作，主要内容包括：本发明涉及一种制备磺胺类化合物的工艺,所述磺胺类化合物是Bcl-2/Bcl-xL的抑制剂,包括化合物(3R)-1-(3-(4-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-4-甲磺酰基-5-甲基-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)-苯氨基磺酰)-2-三氟甲磺酰基-苯胺基)-4-苯硫基-丁基)-哌啶-4-羧酸3-膦酸基丙酯。本发明还涉及用于制备所述磺胺类化合物的中间体及其制备方法。(The present invention relates to a process for the preparation of sulfonamides, which are inhibitors of Bcl-2/Bcl-x L, including the compound (3R) -3-phosphonopropyl 1- (3- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylaminosulfonyl) -2-trifluoromethanesulfonyl-anilino) -4-thiophenyl-butyl) -piperidine-4-carboxylate, to intermediates useful in the preparation of said sulfonamides and to processes for their preparation.)

1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I)

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluorine, chlorine, C1-C4 alkyl, more preferably methyl, propylAn isopropyl group,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

the method comprises the following steps:

1) hydrolyzing the compound of formula 1 to produce a compound of formula 2,

2) carrying out condensation reaction on the compound shown in the formula 2 and the compound shown in the formula 3 to generate a compound shown in the formula 4,

wherein R is₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

wherein R is₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

3) allowing the compound of formula 4 to form a compound of formula 5

Wherein TMS represents trimethylsilyl;

4) allowing the compound of formula 5 to form a compound of formula (I);

wherein the radicals in the various compounds have the same meaning as the radicals described in formula (I).

2. The method of claim 1, comprising one or more of the following features:

step 1) carrying out a hydrolysis reaction in the presence of a base, preferably a hydroxide, preferably sodium hydroxide, in a solvent, preferably a polar solvent, preferably water and tetrahydrofuran;

step 2) carrying out a condensation reaction in the presence of a condensing agent, preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), and a catalyst, preferably 4-Dimethylaminopyridine (DMAP), in a polar organic solvent, more preferably dichloromethane;

step 3) is carried out in a polar solvent, preferably Acetonitrile (ACN), in the presence of a trialkylbromine, preferably trimethylbromosilane or triethylbromosilane, more preferably trimethylbromosilane (TMSBr);

step 4) is carried out in a polar solvent, preferably water and Acetonitrile (ACN), more preferably water and acetonitrile in a volume ratio v/v of 1/6 to 1/2;

step 4) is carried out in the presence of bicarbonate and an acid, preferably ammonium bicarbonate and trifluoroacetic acid and/or phosphoric acid.

3. A process according to any one of claims 1 to 2, wherein the compound of formula 1 is prepared by:

1') reacting a compound of formula 1' with a compound of formula 2 'to produce a compound of formula 3',

2') reacting the compound of formula 3' with the compound of formula 4 'to produce the compound of formula 5',

3') reacting the compound of formula 5' with a compound of formula 6 'to produce a compound of formula 7',

4') reacting the compound of formula 7' to form a compound of formula 8',

5') reacting the compound of formula 8' to form a compound of formula 9',

6') allowing the compound of formula 9' to form a compound of formula 10',

7') allowing the compound of formula 10' to form a compound of formula 11',

8') reacting the compound of formula 11' with a compound of formula 12 'to form a compound of formula 13',

9') allowing the compound of formula 13' to form a compound of formula 14',

10') reacting the compound of formula 14' with a compound of formula 15 'to produce a compound of formula 16',

11') reacting the compound of formula 16' with the compound of formula 17' to produce the compound of formula 1,

wherein the radicals in the various compounds have the same meaning as the radicals mentioned in claim 1.

4. A method according to claim 3, comprising one or more of the following features:

step 1') is carried out in an organic solvent, preferably toluene, in the presence of a base, preferably an organic base, more preferably piperidine and an organic acid, preferably a monohydric organic acid containing from 1 to 4 carbons, more preferably acetic acid;

step 2') on a catalyst, e.g.And basic conditions, such as the presence of an organic base, such as an amine, such as a trialkylamine, such as tri-C1-C4 alkylamine, preferably triethylamine;

step 3') is carried out in the presence of an organic acid, preferably a monobasic organic acid containing from 1 to 4 carbons, more preferably acetic acid, and/or in the presence of an organic base, preferably an alkylamine, more preferably a C1-C4 alkylamine, in an organic solvent, preferably an alcohol, more preferably a C1-C4 alcohol;

step 4') is carried out in the presence of a base, preferably a hydroxide, more preferably sodium hydroxide, in a polar solvent, preferably dioxane and/or ethanol and/or water;

step 5') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of an organic acid, preferably trifluoroacetic acid;

in step 6'), the compounds of the formula 9' are reacted withReaction, preferably in the presence of a coupling ligand, preferably proline orIn the presence of a ketone iodide and/or potassium carbonate;

step 6') is carried out at 120. + -. 5 ℃;

step 7') is carried out in an organic solvent, preferably dimethylformamide, in the presence of N-iodosuccinimide;

step 8') is carried out in an organic solvent, preferably dimethyl sulfoxide, in the presence of a metal iodide, preferably cuprous iodide L-proline, under basic conditions, preferably a hydroxide, more preferably a metal hydroxide, further preferably sodium hydroxide;

step 8') is carried out at 100. + -. 5 ℃;

step 9') is carried out in an organic solvent, preferably a polar organic solvent, more preferably methanol or tetrahydrofuran, in the presence of hydrogen, a catalyst, preferably raney nickel or palladium on carbon;

step 10') is carried out in an organic solvent, preferably a polar organic solvent, more preferably tetrahydrofuran or methanol and a polar solvent, preferably dichloromethane, in the presence of basic conditions, preferably an organic base, further preferably pyridine;

step 11') is carried out in a polar organic solvent, more preferably dichloromethane, or in a polar solvent, preferably DMF, in the presence of basic conditions, preferably an organic base, further preferably diisopropylethylamine.

5. The process according to claim 3, wherein the preparation of the compound of formula 17' comprises the steps of:

1') allowing the compound of formula 1' to form a compound of formula 2',

formula 1 ", v ═ n-1, n is as defined above,

2') allowing the compound of formula 2' to form a compound of formula 3',

3') allowing the compound of formula 3' to form a compound of formula 4',

4') allowing the compound of formula 4' to form a compound of formula 5',

5') allowing the compound of formula 5' to form a compound of formula 6',

6') reacting the compound of formula 6' with the compound of formula 7 'to produce the compound of formula 8',

7 ") allowing the compound of formula 8" to form a compound of formula 17';

wherein the radicals in the various compounds have the same meaning as the radicals mentioned in claim 1.

6. The method of claim 5, comprising one or more of the following features:

step 1 ") comprises the following steps:

(a) the compound of formula 1 "is reacted in the presence of isobutyl chloroformate, N-methylmorpholine and/or in ethylene glycol dimethyl ether,

(b) further reacting with an aqueous solution of sodium borohydride;

step 2 ") is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of diphenyl disulfide, a trialkylphosphine, preferably a tri-C1-C4 alkylphosphine, more preferably tributylphosphine;

step 3 ") is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of an organic acid, preferably trifluoroacetic acid;

step 4 ") comprises the following steps:

(c) the compound of formula 4 "is reacted in the presence of isobutyl chloroformate, N-methylmorpholine and/or in ethylene glycol dimethyl ether,

(d) further reacting with an aqueous solution of sodium borohydride; step 5 ") is carried out in the presence of oxalyl chloride, dimethyl sulfoxide, diisopropylethylamine, and/or in dichloromethane;

step 6 ") is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of sodium triacetoxyborohydride;

step 7 ") is carried out in the presence of diethylamine in a polar solvent, preferably acetonitrile.

7. A process according to any one of claims 1 to 6, wherein the compound of formula 3 is prepared by:

1') hydrolyzing the compound of formula 1', to produce a compound of formula 3,

unless otherwise defined, R herein₇Is an alkyl radical, preferably a C1-C4 alkaneEthyl is particularly preferred, w ═ 1,2,3, 4 or 5.

8. The process according to claim 7, wherein step 1 "') is carried out in the presence of a catalyst, preferably lithium borohydride, in a polar organic solvent, more preferably dichloromethane.

9. The process according to any one of claims 1 to 8, wherein the preparation of the compound of formula 3 comprises the steps of:

1') reacting the compound of formula 1' to produce a compound of formula 2',

m is 1,2,3, 4 or 5;

2') reacting the compound of formula 2' to produce a compound of formula 3',

3') reacting the compound of formula 3' to produce the compound of formula 3.

10. The method of claim 9, comprising one or more of the following features:

step 1 "") is carried out in the presence of a catalyst, such as PPTS, in the presence of DHP and in an organic solvent, such as dichloromethane or MTBE;

step 2 'Compound of formula 2' with P (OEt)₃Or PO (OEt)₂Reacting to generate a compound shown as a formula 3';

step 3') is carried out in the presence of an ion exchange resin, preferably Amberlite, more preferably Amberlite (10%), in the presence of an organic solvent, e.g. a polar organic solvent, e.g. a C1-C4 alcohol, and/or in the presence of PPTS and/or TFA, and/or in the presence of Dowex 10%, and/or in the presence of Ambrlyst-1510%.

11. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I)

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluoro, chloro, C1-C4 alkyl, more preferably H, methyl, propyl, isopropyl, most preferably H,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

the method comprises the following steps:

(1) the compound of formula (1) and the compound of formula (2) are subjected to condensation reaction to generate the compound of formula (3)

R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

(2) allowing the compound of formula (3) to produce a compound of formula (4),

(3) allowing the compound of formula (4) to produce a compound of formula (I);

wherein the radicals in the various compounds have the same meaning as the radicals described in formula (I).

12. The method of claim 11, comprising one or more of the following features:

step (1) is carried out in a polar solvent, preferably DMF, ethyl acetate or Dichloromethane (DCM), in the presence of basic conditions, preferably an organic base, further preferably diisopropylethylamine;

step (2) is carried out in the presence of a trialkylbromine, preferably of trimethylbromosilane or triethylbromosilane, more preferably of trimethylbromosilane, and/or in acetonitrile, preferably in an amount of from 20 to 5 equivalents, preferably from 15 to 5 equivalents, with respect to the compound of formula (3);

the step (3) comprises the following steps:

a) reacting the compound of formula (2) in a polar organic solvent, more preferably acetonitrile or dichloromethane, with an ammonia-alcohol solution, preferably an ammonia-C1-C4 alcohol solution, more preferably an ammonia-methanol solution, to give crude 1;

b) dissolving crude product 1 in an organic solvent, preferably methyltetrahydrofuran, preferably 2-methyltetrahydrofuran, washing with aqueous ammonium bicarbonate, preferably 5% aqueous ammonium bicarbonate, to give crude product 2,

c) crude 2 is treated with an organic solvent, preferably methyltetrahydrofuran, preferably 2-methyltetrahydrofuran, and an organic solvent, preferably an ether, more preferably methyl tert-butyl ether.

13. A process according to any one of claims 11 to 12, wherein the preparation of the compound of formula (1) comprises the steps of:

(1') allowing the compound of formula (1') to produce a compound of formula (2'),

(2') allowing the compound of formula (2') to produce a compound of formula (1);

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

14. The method of claim 13, comprising one or more of the following features:

in step (1'), reacting the compound of formula (1') with a metal, more preferably a metal powder, more preferably iron powder, in a polar organic solvent, more preferably ethanol;

in the step (2'), reacting the compound of formula (2') with the compound of formula 15' in the presence of an organic solvent, preferably tetrahydrofuran, toluene and dichloromethane, more preferably dichloromethane, in basic conditions, preferably an organic base, further preferably triethylamine, diisopropylethylamine, pyridine hydrochloride, triethylamine hydrochloride, more preferably triethylamine hydrochloride, at a temperature ranging from room temperature to a solvent reflux temperature;

in step (2'), the compound of formula 15' is preferably used in an amount of 2.0 to 1.5 equivalents with respect to the compound of formula (2'), and the base is preferably used in an amount of 1.5 to 5 equivalents with respect to the compound of formula (2').

In the step (2'), adding the compound of the formula (2') into a polar organic solvent, more preferably dichloromethane, then adding triethylamine hydrochloride, controlling the internal temperature to be 10-15 ℃, dropping the polar organic solvent, more preferably dichloromethane solution of the compound of the formula 15' into the reaction system, and stirring at room temperature for 1.0 hour; heating and refluxing for 10 hours;

in step (2'), the organic phases are preferably in succession

With HCl solution, H₂Washing with sodium chloride solution, filtering, and concentrating(ii) a Obtaining a crude product; dissolving the crude product in an organic solvent, preferably ethyl acetate, dichloromethane, tetrahydrofuran, methanol or ethanol, heating to the boiling point of the organic solvent +/-5 ℃, dropwise adding n-heptane, methyl tert-butyl ether or water, and stirring; cooling to room temperature, filtering, and washing a filter cake with n-heptane.

15. The method according to any one of claims 11 to 14,

wherein the preparation of the compound of formula (1') comprises the steps of:

(1') allowing the compound of formula (1') to produce a compound of formula (2'),

(2') allowing the compound of formula (2') to produce a compound of formula (3 '),

(3 ') allowing the compound of formula (3 ') to produce a compound of formula (4 '),

(4 ') allowing the compound of formula (4 ') to produce a compound of formula (5 '),

(5 ') allowing the compound of formula (5 ') to produce a compound of formula (6 '),

(6 ') subjecting the compound of formula (6') to a condensation reaction with the compound of formula (7 ') to produce a compound of formula (8'),

(7 ') allowing the compound of formula (8 ') to produce a compound of formula (9 '),

(8 ') allowing the compound of formula (9 ') to produce a compound of formula (10 '),

(9 ') allowing the compound of formula (10 ') to produce a compound of formula (1 ');

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

16. The method of claim 15, comprising one or more of the following features:

step (1') in CBr₄In the presence of/PPh 3 in a polar organic solvent, more preferably dichloromethane, at 0-30 ℃;

step (2 ") is carried out in the presence of lithium diisopropylamide (L DA) at-85 to-70 ℃ in a solvent, preferably a polar solvent, more preferably tetrahydrofuran;

step (3') is carried out in the presence of a lithium reagent, preferably L DA, at-85 to-70 ℃ in a solvent, preferably a polar solvent, more preferably tetrahydrofuran;

step (4 ") is carried out in the presence of dimethyldisulfide (MeSSMe) in a solvent, preferably a polar solvent, more preferably tetrahydrofuran;

the steps (2 ") to (4") are carried out in a one-pot process;

step (5') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of an oxidizing agent, preferably m-chloroperoxybenzoic acid (mCPBA), at 0-30 ℃;

step (6') is carried out in acetic anhydride at a temperature of 100 to 110 ℃;

in step (7 '), the compound of formula (8 ') is reacted with the compound of formula (11 '),

preferably, after adding the phosphine ligand and the palladium catalyst, preferably R-BINAP and Pd (OAc)2, to the organic solvent, preferably toluene, the reaction is carried out by raising the temperature to 50 ℃ and stirring;

step (8') is preferably carried out in a solvent, preferably a polar solvent, preferably ethanol, in the presence of CH3 COCl;

in step (9 '), it is preferred that the compound of formula (10 ') is reacted with the compound of formula (12 ')The reaction is carried out in dimethyl sulfoxide in the presence of potassium carbonate at a temperature of 55 to 65 ℃ and preferably 80 to 110 ℃.

17. A method according to claim 15 or 16, comprising one or more of the following features:

the preparation of the compound of formula (7 ") comprises the following steps:

(1') subjecting the compound of formula (1') to produce a compound of formula (2'),

(2') subjecting the compound of formula (2') to produce a compound of formula (3 '),

(3 '") subjecting the compound of formula (3'") to produce a compound of formula (7 ");

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

18. The method of claim 17, comprising one or more of the following features:

step (1') in SOCl₂In a solvent, preferably a polar solvent, preferably methanol;

step (2') in NaBH (OAc)₃In a solvent, preferably acetone/dichloromethane;

step (3') is carried out in the presence of AcCl, DIPEA/DMA;

step (4 "') is carried out in the presence of a base, preferably L iOH, in a solvent, preferably a polar solvent, preferably water and tetrahydrofuran.

19. A method according to any one of claims 11 to 18, including one or more of the following features:

the preparation of the compound of formula (2) comprises the following steps:

(1') reacting the compound of formula (1') to produce a compound of formula (2'),

(2') reacting the compound of formula (2') with the compound of formula (3 ') to produce the compound of formula (4'),

(3 ') reacting the compound of formula (4') to produce a compound of formula (2);

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

20. The method of claim 19, comprising one or more of the following features:

step (1 "") is carried out in the presence of a base, preferably a hydroxide, more preferably sodium hydroxide, in a solvent, preferably a polar solvent, more preferably water and tetrahydrofuran;

step (2') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of a condensing agent, preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), and a catalyst, preferably 4-Dimethylaminopyridine (DMAP);

step (3 ') is carried out in a polar organic solvent, more preferably dichloromethane, under acidic conditions and/or in the presence of TBDMSOTf, and/or said TBDMSOTf is used in an amount ranging from 1 to 3eq with respect to formula (4');

in the step (3'), after the reaction is stopped, the reaction system is supplied with H₂O extraction, combining aqueous phases, DCM, aqueous phase saturated NaHCO₃Adjusting the pH value to 8; stirring for 0.5 hour; the aqueous phase was extracted with DCM; the organic phases were combined with 8% Na₂CO₃And (6) washing.

21. A method according to claim 19 or 20, comprising one or more of the following features:

the preparation of the compound of formula (1 "") comprises the following steps:

(1') reacting the compound of formula (1') to produce a compound of formula (2'),

(2') reacting the compound of formula (2') to produce a compound of formula (3 '),

(3 ') reacting the compound of formula (3') with the compound of formula (4 ') to produce a compound of formula (5'),

(4 ') reacting the compound of formula (5 ') to produce a compound of formula (6 '),

u is 1,2,3 or 4,

(5 ') reacting the compound of formula (6 ') to produce a compound of formula (7 '),

(6 ') reacting the compound of formula (7 ') to produce a compound of formula (8 '),

(7 ') reacting the compound of formula (8') with the compound of formula (9 ') to produce a compound of formula (10'),

(8 ') reacting the compound of formula (10 ') to produce a compound of formula (11 '),

(9 ') reacting the compound of formula (11 ') to produce a compound of formula (1 ');

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

22. The method of claim 21, comprising one or more of the following features:

step (1') is carried out in PhSH, NaOEt, EtOH at 50-55 ℃;

step (2') at H₂SO₄In MeTHF, under reflux;

step (3') is carried out in the presence of PPTS, Dean-s tark, MeTHF, reflux;

step (4') is carried out in THF, preferably at 20-25 ℃, in the presence of methyl bromoacetate, Zn, DIBA L-H;

step (5') is carried out in the presence of Red-Al in an organic solvent, preferably toluene;

step (6') is carried out in the presence of MsCl, TEA;

step (8') is carried out in the presence of HCl in a solvent, preferably a polar solvent, preferably methanol;

step (9') is carried out in (Boc)₂O/K₂CO₃In the presence of a solvent, preferably DCM/H₂In O.

23. A process according to any one of claims 11 to 22, wherein the compound of formula (1 "") is prepared by:

(a ') reacting a compound of formula (a') with a compound of formula (b ') to produce a compound of formula (c'),

u is 1,2,3 or 4,

(b ') allowing the compound of formula (c ') to produce a compound of formula (d '),

(c ') allowing the compound of formula (d ') to produce a compound of formula (e '),

(d ') allowing the compound of formula (e ') to produce a compound of formula (f '),

wherein t is n-1, n is as defined above,

(e ') reacting the compound of formula (f') with the compound of formula (g ') to produce a compound of formula (1'),

(ii) when u is 1, directly reacting the compound of formula (d ') with the compound of formula (g') to produce a compound of formula (1 "");

wherein the radicals in the various compounds have the same meaning as the radicals described in claim 11.

24. The method of claim 23, comprising one or more of the following features:

step (a') at pd₂(dba)₃And/or DIPEA, and/or xantphos in an organic solvent, preferably 1, 4-dioxane;

step (b') is carried out in the presence of DIBA L H in an organic solvent, preferably toluene;

in step (c '), the compound of formula (d') is reacted with MeOH₂PPh₃A Cl reaction, said reaction being carried out at-85 ℃ to Room Temperature (RT);

step (d') is carried out in the presence of an organic acid, preferably HCl, more preferably 2M HCl, at room temperature;

step (e') in NaBH (OAc)₃In the presence of oxygen at room temperature.

25. A method according to any one of claims 11 to 24, wherein

In the compounds of the formula (I), R₅Substituted in the meta position, R₄Substituted in the para position, R₆Is hydrogen.

26. The method according to any one of claims 1 to 25, wherein the compound of formula (I) is a compound having the following structural formula

27. A process for the preparation of a compound of formula II,

wherein:

R₆selected from H, halogen, alkyl, preferably fluorine, chlorine, C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

the method comprises the following steps:

(a ') allowing the compound of formula (a ') to produce a compound of formula (b '),

(b ') allowing the compound of formula (b ') to produce a compound of formula (c ')

(c ') allowing the compound of formula (c ') to produce a compound of formula (d '),

(d ') allowing the compound of formula (d ') to produce a compound of formula (e '),

(e ') allowing the compound of formula (e ') to produce a compound of formula (f '),

(f ') allowing the compound of formula (f ') to produce a compound of formula (g '),

(g ') reacting the compound of formula (g') with the compound of formula (h ') to produce a compound of formula (c'),

28. the method of claim 27, comprising one or more of the following features:

step (a') is carried out in ClCO₂iBu, and/or NMM, and/or NaBH₄In the presence of THF and/or H₂O, carried out at-20 to-40 ℃;

step (b') at pH₂S2, and/or Bu3P in an organic solvent, preferably toluene, at 10-25 ℃, preferably for 3 hours (h);

step (c ") is carried out in the presence of TFA, and/or in DCM at 25 ℃ for preferably 24-36 h;

step (d') in ClCO₂iBu, and/or NMM, and/or NaBH₄In the presence of THF, and/or H₂O at-20 to-40 ℃, preferably for 12 h;

step (e') comprises the step of reacting in ACN in the presence of NHEt2, further comprising reacting in (Boc)2O, and/or Na₂CO₃In the presence ofA step of reaction at 25 ℃, preferably reaction for 12 hours;

step (f') in SO₃Py, and/or TEA, and/or in DMSO and/or DCM at 5-25 ℃, preferably for 12 h;

step (g') in NaBH (OAc)₃And/or in DCM at 0-25 c, preferably for 12 h.

29. A method according to claim 19 or 20, comprising one or more of the following features:

replacing the compound of formula (1 "") of claim 19 with a compound of formula II to prepare a compound of formula (2 "").

30. A process for preparing a compound of formula 2, the process comprising the steps of:

1) hydrolyzing the compound of formula 1 to produce a compound of formula 2,

wherein the radicals in the various compounds have the same meaning as the radicals mentioned in claim 1.

31. The process according to claim 30, step 1) being carried out in a solvent in the presence of a base, preferably the base is a hydroxide, preferably sodium hydroxide, and the solvent is a polar solvent, preferably water and tetrahydrofuran.

32. The compounds of the formulae 1,2, 1') to 3'), the formulae II,

and compounds having the structural formula

All intermediates mentioned in the synthesis of compounds 1-08A, including compounds 1-05C;

wherein the radicals in the various compounds have the same meaning as the radicals mentioned in claim 1.

33. Use of a compound according to claim 30 for the preparation of a compound of formula (I).

Technical Field

The present invention relates to a process for the preparation of sulfonamides which are inhibitors of Bcl-2/Bcl-x L, including the compounds of formula (I) described below, especially 3-phosphonopropyl (3R) -1- (3- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylaminosulfonyl) -2-trifluoromethanesulfonyl-anilino) -4-thiophenyl-butyl) -piperidine-4-carboxylate, to intermediates used in the preparation of said sulfonamides and to processes for their preparation.

Background

The compound (3R) -1- (3- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylamino sulfonyl) -2-trifluoromethanesulfonyl-anilino) -4-phenylthio-butyl) -piperidine-4-carboxylic acid 3-phosphonopropyl ester (hereinafter referred to as compound 1) is a sulfonamide compound that can be used as a Bcl-2/Bcl-x L inhibitor, having the formula

Compound 1 is a potential Bcl-2 and/or Bcl-x L inhibitor (see WO 2014113413). the compound is effective in inducing apoptosis in cancer cells and has a mechanism of action that is highly consistent with targeting Bcl-2 and Bcl-x L, and the compound can treat a variety of cancers.

Patent WO2014113413 (hereinafter referred to as patent 1) discloses a method for preparing compound 1, which involves three column chromatography purifications, one-time preparation liquid phase purification and freeze-drying operation, and has the disadvantages of high cost, long period, low total yield and limitation of batch production capacity. Is not suitable for commercial production. Therefore, there is an urgent need for a method for preparing compound 1 suitable for industrial scale-up, which can reduce or eliminate column chromatography purification, liquid phase purification and lyophilization, reduce cost, shorten cycle time, improve yield, and improve mass productivity, to solve the technical problems in the prior art.

Summary of The Invention

The object of the present invention is to provide a process for the preparation of sulfonamides, including compounds of formula (I), especially compound 1. The present inventors have surprisingly found that by using two specific preparative methods (i.e., method I and method II described below), column chromatography purification may or may not be employed, liquid phase purification and lyophilization operations may or may not be employed, resulting in reduced cost, shorter cycle time, higher yield, and higher batch throughput.

Specifically, the present invention relates, in a first aspect, to a process for producing a compound of the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as process I),

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluoro, chloro, C1-C4 alkyl, more preferably H, methyl, propyl, isopropyl, most preferably H,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl;

the method comprises the following steps:

1) hydrolyzing the compound of formula 1 to produce a compound of formula 2,

2) carrying out condensation reaction on the compound shown in the formula 2 and the compound shown in the formula 3 to generate a compound shown in the formula 4,

unless otherwise indicated, R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

unless otherwise indicated, R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

3) allowing the compound of formula 4 to form a compound of formula 5

Wherein TMS represents a trimethylsilyl group,

4) allowing the compound of formula 5 to produce a compound of formula (I).

Another aspect of the present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as process II),

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluoro, chloro, C1-C4 alkyl, more preferably H, methyl, propyl, isopropyl, most preferably H,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

the method comprises the following steps:

(1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3),

unless otherwise indicated, R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

unless otherwise indicated, R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl,

(2) allowing the compound of formula (3) to produce a compound of formula (4),

(3) allowing the compound of formula (4) to produce a compound of formula (I).

In a further aspect the present invention also relates to intermediate compounds involved in the above preparation processes, to a process for the preparation of said intermediates, and to the use of said intermediate compounds for the preparation of compounds of formula (I).

Definition of

The term "about" as used herein means ± 20%, preferably ± 15%, more preferably ± 10%, even more preferably ± 5%, most preferably ± 2% of the numerical value modified by the term, and thus the range of the term "about" can be clearly determined according to the modified numerical value by one of ordinary skill in the art.

iPr is isopropyl;

DCM refers to dichloromethane;

THF means tetrahydrofuran;

eq refers to the molar ratio;

m is molar concentration;

IPC refers to monitoring in the production process;

t L C refers to thin layer chromatography;

DMF means dimethylformamide;

SM refers to the raw material;

Raney-Ni refers to Raney nickel;

AcCl refers to acetyl chloride;

DIPEA refers to diisopropylethylamine;

fmoc refers to fluorenylmethoxycarbonyl;

tBu refers to tert-butyl;

ph means phenyl;

ACN refers to acetonitrile;

TMS represents trimethylsilyl;

TMSBr represents trimethylbromosilane;

EDCI refers to 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride;

DCM refers to dichloromethane;

DMPAO refers to [ (2, 6-xylyl) amino ] (oxy) acetic acid

MeTHF means methyltetrahydrofuran;

PPTS refers to pyridinium p-toluenesulfonate;

Dean-Stark refers to the Dean-Stark apparatus (also known as a Dean-Stark receiver or Dean-Stark distiller);

Red-Al refers to Red aluminum;

MsCl refers to methylsulfonyl chloride;

TEA refers to triethylamine;

xanthphos means 4,5-bis (diphenylphosphino) -9, 9-dimethylxanthene;

RT means room temperature;

DIBA L H refers to diisobutylaluminum hydride;

MTBE refers to methyl tert-butyl ether;

DHP is 3, 4-dihydro-2H-pyran;

TBDMSOTf refers to tert-butyldimethylsilyl trifluoromethanesulfonate;

a good solvent generally refers to a solvent that is well soluble in a substance, and conversely, a poor solvent for the substance.

Detailed Description

The first aspect of the present invention relates to a process for producing a compound having the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as process I),

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluorine, chlorine, C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

the method comprises the following steps:

1) hydrolyzing the compound of formula 1 to produce a compound of formula 2,

2) carrying out condensation reaction on the compound shown in the formula 2 and the compound shown in the formula 3 to generate a compound shown in the formula 4,

wherein R7 is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

unless otherwise indicated, R₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

3) allowing the compound of formula 4 to form a compound of formula 5

4) Allowing the compound of formula 5 to produce a compound of formula (I).

In some embodiments, step 1) is carried out in the presence of a base in a solvent, preferably the base is a hydroxide, preferably sodium hydroxide, and the solvent is a polar solvent, preferably water and tetrahydrofuran.

In some embodiments, step 2) is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of a condensing agent, preferably 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI), and a catalyst, preferably 4-Dimethylaminopyridine (DMAP).

In some embodiments, step 3) is carried out in a polar solvent, preferably Acetonitrile (ACN), in the presence of a trialkylbromine, preferably trimethylbromosilane or triethylbromosilane, more preferably trimethylbromosilane (TMSBr).

In some embodiments, step 4) is performed in a polar solvent, preferably water and Acetonitrile (ACN), more preferably water and acetonitrile in a volume ratio v/v of 1/6 to 1/2.

In some embodiments, step 4) is performed in the presence of bicarbonate and an acid, preferably ammonium bicarbonate and trifluoroacetic acid and/or phosphoric acid.

Compared with Dicyclohexylcarbodiimide (DCC) and Diisopropylcarbodiimide (DIC), the method I and the step 2) of the invention have the advantages that byproducts generated by EDCI are easy to remove, and the yield is improved.

The diethyl phosphonate used in step 2) of the method I can be a commercially available product, and the commercially available product of the diethyl phosphonate is cheaper and more easily obtained than the commercially available product of the dimethyl phosphonate, so that the production cost can be greatly reduced.

The ACN adopted in the step 3) of the method I can be used as a solvent to carry out reaction at a higher temperature (60 ℃), so that the reaction time can be effectively shortened, and the generation risk of impurities can be reduced.

In some embodiments, the preparation of the compound of formula 1 comprises the steps of:

1') reacting a compound of formula 1' with a compound of formula 2 'to produce a compound of formula 3',

2') reacting the compound of formula 3' with the compound of formula 4 'to produce the compound of formula 5',

3') reacting the compound of formula 5' with a compound of formula 6 'to produce a compound of formula 7',

4') reacting the compound of formula 7' to form a compound of formula 8',

5') reacting the compound of formula 8' to form a compound of formula 9',

6') allowing the compound of formula 9' to form a compound of formula 10',

7') allowing the compound of formula 10' to form a compound of formula 11',

8') reacting the compound of formula 11' with a compound of formula 12 'to form a compound of formula 13',

9') allowing the compound of formula 13' to form a compound of formula 14',

10') reacting the compound of formula 14' with a compound of formula 15 'to produce a compound of formula 16',

11') reacting the compound of formula 16' with the compound of formula 17' to produce the compound of formula 1,

in some embodiments, step 1') is carried out in an organic solvent, preferably toluene, in the presence of a base, preferably an organic base, more preferably piperidine, or an organic acid, preferably a monohydric organic acid containing 1-4 carbons, more preferably acetic acid.

In some embodiments, step 2') is carried out over a catalyst, e.g.

In the presence of basic conditions, such as organic bases, for example amines, such as trialkylamines, for example tri-C1-C4-alkylamines, preferably triethylamine.

In some embodiments, step 3') is carried out in an organic solvent, preferably an alcohol, more preferably a C1-C4 alcohol, in the presence of an organic acid, preferably a monobasic organic acid containing 144 carbons, more preferably acetic acid, or in the presence of an organic base, preferably an alkylamine, more preferably a C1-C4 alkylamine.

In some embodiments, step 4') is performed in the presence of a base, preferably a hydroxide, more preferably sodium hydroxide, and/or in a polar solvent, preferably dioxane and/or ethanol and/or water.

In some embodiments, step 5') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of an organic acid, preferably trifluoroacetic acid.

In some embodiments, in step 6'),

compounds of formula 9' andthe reaction is carried out in the presence of a catalyst,

preferably in the presence of a coupling ligand, preferably proline orCarrying out a reaction in the presence of a catalyst;

and/or in the presence of an iodinated sulfinol and/or potassium carbonate;

in some embodiments, step 6') is performed at 120 ± 5 ℃.

In the above process of the present invention, step 6') allows the compound of formula 9' to produce the compound of formula 10', wherein the reaction temperature, the coupling ligand, is used, while the reaction conversion rate is increased, and the production of dechlorinated by-products can be effectively controlled. Specifically, the use of DMPAO as the coupling ligand increased the yield by 15% to 20%.

In some embodiments, step 7') is performed in an organic solvent, preferably dimethylformamide, in the presence of N-iodosuccinimide.

In some embodiments, step 8') is performed in an organic solvent, preferably dimethyl sulfoxide, in the presence of a metal iodide, preferably cuprous iodide L-proline, under basic conditions, preferably hydroxide, more preferably metal hydroxide, further preferably sodium hydroxide;

in some embodiments, step 8') is performed at 100 ± 5 ℃.

In the above process of the present invention, the reaction temperature used in step 8') is increased to increase the conversion rate of the reaction and to control the formation of dechlorinated by-products.

In some embodiments, step 9') is carried out in an organic solvent, preferably a polar organic solvent, more preferably methanol or tetrahydrofuran, in the presence of hydrogen, a catalyst, preferably raney nickel or palladium on carbon.

In some embodiments, step 10') is performed in an organic solvent, preferably a polar organic solvent, more preferably tetrahydrofuran or methanol, or a polar solvent, preferably dichloromethane, in the presence of basic conditions, preferably an organic base, further preferably pyridine.

In some embodiments, step 11') is carried out under basic conditions, preferably in the presence of an organic base, further preferably diisopropylethylamine, and/or in a polar solvent organic solvent, preferably dichloromethane or DMF.

In some embodiments, the preparation of a compound of formula 17' comprises the steps of:

1') allowing the compound of formula 1' to form a compound of formula 2',

formula 1 ", v ═ n-1, n is as defined above,

2') allowing the compound of formula 2' to form a compound of formula 3',

3') allowing the compound of formula 3' to form a compound of formula 4',

4') allowing the compound of formula 4' to form a compound of formula 5',

5') allowing the compound of formula 5' to form a compound of formula 6',

6') reacting the compound of formula 6' with the compound of formula 7 'to produce the compound of formula 8',

7') allowing the compound of formula 8' to form a compound of formula 17 '.

In some embodiments, step 1 ") comprises the steps of:

(a) the compound of formula 1 "is reacted in the presence of isobutyl chloroformate, N-methylmorpholine and/or in ethylene glycol dimethyl ether,

(b) further reacted with an aqueous solution of sodium borohydride.

In some embodiments, step 2 ") is carried out in the presence of diphenyl disulfide, a trialkylphosphine, preferably a tri C1-C4 alkylphosphine, more preferably tributylphosphine, in a polar organic solvent, more preferably dichloromethane.

In some embodiments, step 3 ") is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of an organic acid, preferably trifluoroacetic acid.

In some embodiments, step 4 ") comprises the steps of:

(a) the compound of formula 4 "is reacted in the presence of isobutyl chloroformate, N-methylmorpholine and/or in ethylene glycol dimethyl ether,

(b) further reacted with an aqueous solution of sodium borohydride. In some embodiments, step 5 ") is performed in the presence of oxalyl chloride, dimethyl sulfoxide, diisopropylethylamine, and/or in dichloromethane.

In some embodiments, step 6 ") is performed in the presence of sodium triacetoxyborohydride in a polar organic solvent, more preferably dichloromethane.

In some embodiments, step 7 ") is performed in the presence of diethylamine, and/or in a polar solvent, preferably acetonitrile.

In some embodiments, the compounds of formula 15' are commercially available or are prepared according to methods known in the art.

In some embodiments, the preparation of the compound of formula 3 comprises the steps of:

1') reacting the compound of formula 1') to produce a compound of formula 3,

unless otherwise defined, herein R7 is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, and w ═ 1,2,3, 4, or 5.

In some embodiments, step 1 "') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of a catalyst, preferably lithium borohydride.

In some embodiments, the preparation of the compound of formula 3 comprises the steps of:

1') reacting the compound of formula 1' to produce a compound of formula 2', wherein m is 1,2,3, 4 or 5,

2') reacting the compound of formula 2' to produce a compound of formula 3',

3') reacting the compound of formula 3' to produce the compound of formula 3.

In some embodiments, step 1 "") is performed in the presence of a catalyst, such as PPTS, in the presence of DHP, in an organic solvent, such as dichloromethane or MTBE.

In some embodiments, step 2'), the compound of formula 2' is reacted with P (OEt)₃Or PO (OEt)₂Reacting to generate the compound shown in the formula 3'.

In some embodiments, step 3') is performed in the presence of an ion exchange resin, preferably Amberlite, more preferably Amberlite (10%), in the presence of an organic solvent, e.g., a polar organic solvent, e.g., a C1-C4 alcohol, and/or in the presence of PPTS and/or TFA, and/or in the presence of Dowex (preferably 10%), and/or in the presence of ambrlyt-15 (preferably 10%).

The foregoing embodiments may optionally be combined.

Another aspect of the present invention relates to a process for preparing a compound of the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter referred to as process II),

wherein the content of the first and second substances,

R₁is SO₂R'，

R₂Is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₃is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

R₄is a halogen, preferably fluorine, chlorine,

R₅is a halogen, preferably fluorine, chlorine,

R₆selected from H, halogen, alkyl, preferably fluoro, chloro, C1-C4 alkyl, more preferably H, methyl, propyl, isopropyl, most preferably H,

y is

Q is C (═ O) O (C)_1-5Alkylene), preferably C (═ O) O (C)₃An alkylene group),

R_bis hydrogen or alkyl, preferably C1-C4 alkyl, more preferably methyl, propyl, isopropyl,

n, r and s are independently 1,2,3, 4,5 or 6, preferably, r and s are both 2 and n is 3,4 or 5, more preferably, n, r and s are all 2,

r' is an alkyl group, preferably a C1-C4 alkyl group, more preferably methyl, propyl, isopropyl,

the method comprises the following steps:

(1) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3)

Unless otherwise defined, R herein₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

unless otherwise defined, R herein₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, m is 1,2,3, 4 or 5,

(2) allowing the compound of formula (3) to produce a compound of formula (4),

(3) allowing the compound of formula (4) to produce a compound of formula (I).

Wherein, unless otherwise defined, the radicals and variables in the above formulae (1) to (3) are as defined above for the corresponding radicals of the compounds of the formula (I).

In some embodiments, step (1) is carried out under basic conditions, preferably in the presence of an organic base, further preferably diisopropylethylamine, and/or in a polar solvent, preferably DMF, ethyl acetate or Dichloromethane (DCM).

In the method II of the present invention, the side reaction of the formula (3) with the compound of formula 2 in the method I is avoided in the step (1), a high conversion rate is achieved, and the generation of impurities is effectively controlled; meanwhile, the hydrolysis step of the compound of formula 2 in the method I is omitted, and the generation of sulfonic acid ester hydrolysis byproducts in the step is avoided.

In some embodiments, step (2) is carried out in the presence of a trialkylbromine silane, preferably trimethylbromosilane or triethylbromosilane (more preferably trimethylbromosilane), and/or in acetonitrile; the trialkyl bromosilane is preferably used in an amount of 20 to 5 equivalents, more preferably 15 to 5 equivalents, relative to the compound of formula (3).

In some embodiments, step (3) comprises the steps of:

a) the compound of formula (2) is reacted with ammonium bicarbonate, aqueous ammonia or an ammonia-alcohol solution (preferably an ammonia-C1-C4 alcohol solution, more preferably an ammonia-methanol solution) in a polar organic solvent, more preferably acetonitrile or dichloromethane, to give crude 1.

b) Crude product 1 is treated with an extraction system comprising a polar organic solvent, preferably methyltetrahydrofuran or dichloromethane, and an aqueous salt solution, e.g. an aqueous carbonate solution, preferably an aqueous ammonium bicarbonate solution, further preferably an aqueous 5% ammonium bicarbonate solution, which is washed to give crude product 2.

c) The crude product 2 is treated with a benign organic solvent, preferably dichloromethane and/or methyltetrahydrofuran (more preferably 2-methyltetrahydrofuran), and a poor organic solvent, preferably ethers, more preferably isopropyl ether and/or methyl t-butyl ether.

In some embodiments, the preparation of the compound of formula (1) comprises the steps of:

(1') allowing the compound of formula (1') to produce a compound of formula (2'),

(2') allowing the compound of formula (2') to produce a compound of formula (1).

In some embodiments, in step (1'), the compound of formula (1') is reacted with a metal, further preferably a metal powder, more preferably iron powder, in a polar organic solvent, more preferably ethanol.

In some embodiments, in step (2'), the compound of formula (2') is reacted with the compound of formula 15' in the presence of basic conditions, preferably an organic base, further preferably triethylamine, diisopropylethylamine, pyridine hydrochloride, triethylamine hydrochloride, more preferably triethylamine hydrochloride, in an organic solvent, preferably tetrahydrofuran, toluene and dichloromethane, more preferably dichloromethane, at a temperature ranging from room temperature to the reflux temperature of the solvent.

In some embodiments, in step (2'), the compound of formula 15' is used in an amount of 2.0 to 1.5 equivalents relative to the compound of formula (2'), and the base is used in an amount of 1.5 to 5 equivalents relative to the compound of formula (2').

In some embodiments, in step (2'), the compound of formula (2') is added to a polar organic solvent, more preferably dichloromethane, followed by addition of triethylamine hydrochloride, and a solution of the compound of formula 15' in the polar organic solvent, more preferably dichloromethane, is dropped into the reaction system; heating and refluxing to react.

In some embodiments, in step (2'), the organic phase is preferably successively treated with aqueous HCl (preferably 1N HCl), H₂Washing with sodium chloride solution (preferably 10% sodium chloride solution), and/or filtering, and/or concentrating; obtaining a crude product;and/or treating the crude product with a good-crystallizing solvent comprising a polar organic solvent, preferably ethyl acetate, dichloromethane, tetrahydrofuran, methanol or ethanol, and a poor solvent comprising heptane, n-heptane, methyl-tert-butyl ether or water.

In some embodiments, the preparation of the compound of formula (1') comprises the steps of:

(1') allowing the compound of formula (1') to produce a compound of formula (2'),

(2') allowing the compound of formula (2') to produce a compound of formula (3 '),

(3 ') allowing the compound of formula (3 ') to produce a compound of formula (4 '),

(4 ') allowing the compound of formula (4 ') to produce a compound of formula (5 '),

(5 ') allowing the compound of formula (5 ') to produce a compound of formula (6 '),

(6 ') reacting the compound of formula (6') with the compound of formula (7 ') to produce the compound of formula (8'),

(7 ') allowing the compound of formula (8 ') to produce a compound of formula (9 '),

(8 ') allowing the compound of formula (9 ') to produce a compound of formula (10 '),

(9 ') allowing the compound of formula (10 ') to produce a compound of formula (1 ').

In some embodiments, step (1 ") is at CBr₄/PPh₃In a polar organic solvent, more preferably dichloromethane, and/or at 0-30 ℃.

In some embodiments, step (2 ") is carried out in the presence of lithium diisopropylamide (L DA), at-85 to-70 ℃, in a solvent, preferably a polar solvent, more preferably tetrahydrofuran.

In some embodiments, step (3 ") is carried out in the presence of a lithium reagent, preferably L DA, at-85 to-70 ℃, in a solvent, preferably a polar solvent, more preferably tetrahydrofuran.

In some embodiments, step (4 ") is carried out in the presence of dimethyldisulfide (mesme) in a solvent, preferably a polar solvent, more preferably tetrahydrofuran.

In some embodiments, steps (2 ") through (4") are performed in a one-pot process.

In some embodiments, step (5 ") is performed in the presence of an oxidizing agent, preferably m-chloroperoxybenzoic acid (mCPBA), at 0-30 ℃ in a polar organic solvent, more preferably dichloromethane.

In some embodiments, step (6 ") is carried out in acetic anhydride and at a temperature of 100 to 110 ℃.

In some embodiments, in step (7 "), the compound of formula (8") is reacted with the compound of formula (11 "),

preferably, a phosphine ligand and a palladium catalyst, preferably R- (+) -1,1 '-binaphthyl-2, 2' -diphenylphosphine (R-BINAP) and Pd (OAc)₂Adding organic solvent, preferably toluene, heating to 40-60 deg.C, and stirring; sequentially adding a compound of formula (8 '), a compound of formula (11'), water and sodium tert-butoxide; after the addition, the temperature is raised to 100 to 110 ℃, and/or the reaction is carried out under reflux.

In some embodiments, step (8 ") is under acidic conditions, preferably CH₃In the presence of COCl in a solvent, preferably a polar solvent, preferably ethanol, it is preferred to add the compound of formula (9 ") to a mixed solution of dichloromethane and absolute ethanol.

In some embodiments, in step (9 "), the compound of formula (10") is reacted with the compound of formula (12 ″)

The reaction is preferably carried out under basic conditions, preferably in the presence of potassium carbonate, in a polar solvent, preferably dimethyl sulfoxide, at a temperature of 55 to 65 ℃.

In some embodiments, the preparation of the compound of formula (7 ") comprises the steps of:

(1') subjecting the compound of formula (1') to produce a compound of formula (2'),

(2') subjecting the compound of formula (2') to produce a compound of formula (3 '),

(3 ') subjecting the compound of formula (3 ') to produce a compound of formula (7 ').

In some embodiments, the step(1') in SOCl₂In a solvent, preferably a polar solvent, preferably methanol.

In some embodiments, step (2') is performed in NaBH (OAc)₃In a solvent, preferably acetone/dichloromethane.

In some embodiments, step (3') is performed in the presence of AcCl, DIPEA/DMA.

In some embodiments, step (4 "') is carried out in the presence of a base, preferably L iOH, in a solvent, preferably a polar solvent, preferably water and tetrahydrofuran.

In some embodiments, the preparation of the compound of formula (2) comprises the steps of:

(1') reacting the compound of formula (1') to produce a compound of formula (2'),

(2') reacting the compound of formula (2') with the compound of formula (3 ') to produce the compound of formula (4'),

(3 ') reacting the compound of formula (4') to produce the compound of formula (2).

In some embodiments, step (1 "") is carried out in the presence of a base, preferably a hydroxide, more preferably sodium hydroxide, in a solvent, preferably a polar solvent, more preferably water and tetrahydrofuran.

In some embodiments, step (2 "") is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of a condensing agent, preferably EDCI, and a catalyst, preferably DMAP.

In some embodiments, step (3 "") is carried out under acidic conditions and/or in the presence of tert-butyldimethylsilyl triflate (TBDMSOTf), preferably in an amount of 1-6eq, more preferably 1-3 eq, relative to formula (4 ""), in a polar organic solvent, more preferably dichloromethane.

In some embodiments, in step (3'), after the reaction is stopped, the reaction system is treated with H₂O extraction, combining the aqueous phases and adding saturated NaHCO₃Adjusting the pH value to 8; and/or the aqueous phase was extracted with DCM.

In step (3') of the method II, the Boc removing reagent and the post-treatment mode are adopted to ensure that the ester group is not influenced during Boc removal, and byproducts introduced by the Boc removing reagent can be effectively removed.

In some embodiments, the preparation of the compound of formula (1 "") comprises the steps of:

(1') reacting the compound of formula (1') to produce a compound of formula (2'),

(2') reacting the compound of formula (2') to produce a compound of formula (3 '),

(3 ') reacting the compound of formula (3') with the compound of formula (4 ') to produce a compound of formula (5'),

(4 ') reacting the compound of formula (5 ') to produce a compound of formula (6 '),

formula (6'), u ═ 1,2,3, or 4,

(5 ') reacting the compound of formula (6 ') to produce a compound of formula (7 '),

(6 ') reacting the compound of formula (7 ') to produce a compound of formula (8 '),

(7 ') reacting the compound of formula (8') with the compound of formula (9 ') to produce a compound of formula (10'),

(8 ') reacting the compound of formula (10 ') to produce a compound of formula (11 '),

(9 ') the compound of formula (11 ') is reacted to produce the compound of formula (1 ').

In some embodiments, step (1 ""') is performed in PhSH, NaOEt, EtOH, and/or at 45-60 ℃.

In some embodiments, step (2 ""') is at H₂SO₄In MeTHF, and/or under reflux.

In some embodiments, step (3 ""') is performed in the presence of PPTS, Dean-stark, MeTHF, reflux.

In some embodiments, step (4 ""') is performed in THF in the presence of methyl bromoacetate, Zn, DIBA L-H.

In some embodiments, step (5') is carried out in the presence of Red-Al in an organic solvent, preferably toluene.

In some embodiments, step (6 ""') is performed in the presence of MsCl, TEA.

In some embodiments, step (8 ""') is carried out in the presence of HCl in a solvent, preferably a polar solvent, preferably methanol.

In some embodiments, step (9 ""') is performed at (Boc)₂O/K₂CO₃In the presence of a solvent, preferably DCM/H₂In O.

In some embodiments, the preparation of the compound of formula (1 "") comprises the steps of:

(a ') reacting a compound of formula (a') with a compound of formula (b ') to produce a compound of formula (c'),

formula (a'), u ═ 1,2,3, or 4,

(b ') allowing the compound of formula (c ') to produce a compound of formula (d '),

(c ') allowing the compound of formula (d ') to produce a compound of formula (e '),

(d ') allowing the compound of formula (e ') to produce a compound of formula (f '),

wherein t is n-1, n is as defined above,

(e ') reacting the compound of formula (f') with the compound of formula (g ') to produce a compound of formula (1'),

when u is 1, the compound of formula (d ') is directly reacted with the compound of formula (g') to produce the compound of formula (1 "").

In some embodiments, step (a') is carried out over a palladium catalyst, preferably tris (dibenzylideneacetone) dipalladium pd₂(dba)₃And/or DIPEA, and/or xantphos in an organic solvent, preferably 1, 4-dioxane.

In some embodiments, step (b') is carried out in the presence of a reducing agent, preferably DIBA L H, in an organic solvent, preferably toluene.

In some embodiments, in step (c '), the compound of formula (d') is reacted with MeOCH₂PPh₃A Cl reaction, and/or the reaction is carried out at-85 ℃ to Room Temperature (RT).

In some embodiments, step (d') is performed under acidic conditions, preferably in the presence of HCl, more preferably 2M HCl, at room temperature.

In some embodiments, step (e') is performed in a reducing agent, preferably NaBH (OAc)₃In the presence of oxygen at room temperature.

In some embodiments, the preparation of a compound of formula (3 "") comprises the steps of:

1') reacting the compound of formula 1') to produce a compound of formula (3 '),

unless otherwise defined, R herein₇Is alkyl, preferably C1-C4 alkyl, particularly preferably ethyl, w ═ 1,2,3, 4 or 5.

In some embodiments, step 1 "') is carried out in a polar organic solvent, more preferably dichloromethane, in the presence of a catalyst, preferably lithium borohydride.

In some embodiments, the preparation of the compound of formula (3 "") comprises the steps of:

1') reacting the compound of formula 1' to produce a compound of formula 2', m is 1,2,3, 4 or 5,

2') reacting the compound of formula 2' to produce a compound of formula 3',

3') reacting the compound of formula 3' to produce a compound of formula (3 ').

In some embodiments, step 1 "") is performed in the presence of a catalyst, such as PPTS, in the presence of DHP, in an organic solvent, such as dichloromethane or MTBE.

In some embodiments, step 2'), the compound of formula 2' is reacted with P (OEt)₃Or PO (OEt)₂The reaction yielded a compound of formula (3 "") ".

In some embodiments, step 3') is performed in the presence of an ion exchange resin, preferably Amberlite, more preferably Amberlite (10%), in the presence of an organic solvent, e.g., a polar organic solvent, e.g., a C1-C4 alcohol, and/or in the presence of PPTS and/or TFA, and/or in the presence of Dowex (preferably 10%), and/or in the presence of ambrlyt-15 (preferably 10%).

The foregoing embodiments may optionally be combined.

In some embodiments of said compounds of formula (I) as referred to in the preceding preparation processes I and II, R₅Substituted in the meta position, R₄Substituted in the para position, R₆Is hydrogen.

In some embodiments of the compounds of formula (I) referred to in the foregoing preparative methods I and II, the compound of formula (I) is a compound having the following structural formula

In another aspect the invention relates to a process for the preparation of a compound of formula II,

the method comprises the following steps:

(a ') allowing the compound of formula (a ') to produce a compound of formula (b '),

f is 0,1, 2,3 or 4

The compound of formula (a'),

(b ') allowing the compound of formula (b ') to produce a compound of formula (c ')

(c ') allowing the compound of formula (c ') to produce a compound of formula (d '),

(d ') allowing the compound of formula (d ') to produce a compound of formula (e '),

(e ') allowing the compound of formula (e ') to produce a compound of formula (f '),

(f ') allowing the compound of formula (f ') to produce a compound of formula (g '),

(g ') reacting the compound of formula (g') with the compound of formula (h ') to produce a compound of formula (c'),

in some embodiments, step (a ") is performed in a ClCO system₂ ⁱBu, and/or NMM, and/or NaBH₄In the presence of THF and/or H₂O, and/or at-20 to-40 ℃.

In some embodiments, step (b ") is at pH₂S₂And/or Bu3P in an organic solvent, preferably toluene.

In some embodiments, step (c ") is performed under ester hydrolysis conditions, preferably in the presence of TFA, and/or in DCM.

In some embodiments, step (d ") is performed in a ClCO₂ ⁱBu, and/or NMM, and/or NaBH₄In the presence of THF and/or H₂O, and/or-20 to-40 ℃.

In some embodiments, step (e ") is under basic conditions, preferably NHEt₂And in the presence of (C) and (Boc)₂O, and/or Na₂CO₃In the presence of (a).

In some embodiments, step (f ") is under oxidizing conditions, preferably SO₃Py, and/or TEA in DMSO and/or DCM.

In some embodiments, step (g') is performed using NaBH (OAc)₃In DCM at 0-25 ℃.

The compound of formula II may be used in place of the compound of formula (1 "") to prepare the compound of formula (2 "").

In another aspect, the present invention also relates to a process for preparing a compound of formula 2, said process comprising the steps of:

1) hydrolyzing the compound of formula 1 to produce a compound of formula 2,

in some embodiments, step 1) is carried out in the presence of a base in a solvent, preferably the base is a hydroxide, preferably sodium hydroxide, and the solvent is a polar solvent, preferably water and tetrahydrofuran.

In another aspect, the present invention also relates to the compounds of formulae 1,2, 1') to 3'), formula II, above, and having the following structural formula

The compounds are useful as intermediates in the preparation of compounds of formula (I).

In a further aspect the present invention relates to the use of any one of the intermediate compounds described above in the preparation of a compound of formula (I).

The invention has the beneficial effects that:

the present invention provides an excellent process for the preparation of compounds of formula (I), in particular, compound 1. Particularly, the method II avoids high performance liquid preparation and freeze-drying operation, further shortens the preparation time, improves the yield, and is more suitable for expanded production. In particular, the method II of the invention can avoid high performance liquid phase preparation, simultaneously ensure that all key indexes of the compound of the formula (I) meet the requirements, and realize the production of more than kilogram level. The ratio of reaction materials, the selection and the dosage of alkali, the selection of solvent, the reaction temperature and the dropping speed are easier to control, and the post-treatment method improves the yield and the product purity. The reaction conditions of the invention can realize higher conversion rate under mild reaction conditions and can effectively control the generation of key impurities.

Detailed Description

The present invention is further illustrated by the following specific preparation examples and effect experiments, however, it should be understood that these examples and effect experiments are only for illustrative purposes in more detail and are not to be construed as limiting the present invention in any way.

Preparation example 1:

this example prepared compound 1 by a specific method corresponding to method I, which included the following:

the synthesis process of the compound 1 is as follows:

the first step is as follows: preparation of Compounds 1-12A

At room temperature, compound 1-11A (566g) was dissolved in tetrahydrofuran, and a pre-prepared aqueous solution of sodium hydroxide was added; stirring at room temperature, monitoring by IPC (monitoring in the production process), dropwise adding 1N hydrochloric acid aqueous solution into the reaction system when the raw materials disappear, and adjusting the pH value to 1-2; followed by extraction with dichloromethane; combining organic phases, adding anhydrous magnesium sulfate and drying; filtering, washing a filter cake with dichloromethane, and concentrating the filtrate under reduced pressure to dryness; vacuum drying to obtain compound 1-12A. The yield is 90-110%.

The second step is that: preparation of Compounds 1-13A

Compounds 1-12A (567g) were dissolved in dichloromethane at room temperature and compound 023(474g), DMAP, EDCI were added sequentially; stirring the reaction solution for 3 +/-0.5 hours under the protection of nitrogen, monitoring by IPC, diluting the reaction solution with dichloromethane when the raw materials disappear, and washing an organic phase with water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution once respectively; drying with anhydrous magnesium sulfate; filtering, washing a filter cake with dichloromethane, and concentrating the filtrate under reduced pressure to dryness; carrying out column chromatography on the obtained crude product; concentrating the eluate; vacuum drying to obtain compound 1-13A. The yield is 60-80%.

The third step: preparation of Compounds 1-14A

Dissolving a compound 1-13A (404g) in an acetonitrile solution at room temperature, protecting a reaction system by using nitrogen, dropwise adding trimethyl bromosilane, and heating the system to 60 +/-2 ℃ after the addition is finished; stirring for about 1 hour under heat preservation; and (4) monitoring by IPC until the raw materials disappear, directly concentrating the reaction solution to dryness, and drying in vacuum to obtain the compounds 1-14A. The yield is 100-120%.

The fourth step: preparation of Compound 1

Compound 1-14A was dissolved in a mixture of acetonitrile and purified water (v/v ═ 8/2) at a concentration of about 50mg/ml, the sample was purified using a hplc, the product was collected, concentrated, a small amount of acetonitrile was added, the supernatant was dissolved, the product was enriched using a hplc, and the solvent was removed by lyophilization to give compound 1. The yield is 50-80%.

¹H NMR(400MHz,DMSO-d₆)9.88(s,1H),7.80(d,J＝2.2Hz,1H),7.66(dd,J＝9.3,2.3Hz,1H),7.43-7.34(m,2H),7.30-7.25(m,4H),7.25-7.14(m,3H),6.99(d,J＝9.6Hz,1H),6.93(d,J＝8.9Hz,2H),6.90-6.80(m,3H),6.63-6.46(m,2H),6.41-6.33(m,1H),4.42-4.22(m,1H),4.06(t,J＝6.4Hz,3H),3.30(ddd,J＝45.4,14.0,5.8Hz,2H),3.10(dd,J＝18.6,5.2Hz,8H),2.93(s,4H),2.67(s,4H),2.39(d,J＝30.5Hz,3H),2.14(d,J＝37.4Hz,2H),1.97(d,J＝10.3Hz,1H),1.78(s,5H),1.63(s,2H),1.49(dt,J＝16.7,7.8Hz,2H),1.35(d,J＝7.0Hz,6H).

The compounds 1 to 11A involved in the present invention are preferably synthesized according to the following methods:

the synthesis process of the compound 1-11A is as follows:

the first step is as follows: preparation of Compounds 1-01A

Adding the material compounds 1-k01(500g), ethyl acetoacetate (354g), piperidine (16m L) and acetic acid (50m L) into toluene (1.8L), heating and refluxing, removing water generated in the reaction, tracking the reaction by T L C (thin layer chromatography) until the compound 1-k01 disappears, cooling the reaction system to room temperature, diluting with ethyl acetate, washing an organic phase, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain a brownish red oily substance, and directly using the crude compound 1-01A in the next reaction.

The second step is that: preparation of Compounds 1-02A

Adding the crude compound 1-01A (1560g) obtained in the first step into absolute ethyl alcohol (8L), sequentially adding a compound 1-k02(696g), triethylamine (1000g) and 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazole bromide (187g), introducing nitrogen, heating the system to 70 +/-2 ℃, keeping the temperature and stirring, carrying out T L C tracking reaction until the compound 1-01A disappears, cooling the reaction system to room temperature, concentrating, diluting with ethyl acetate, washing an organic phase, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain a brownish red oily substance, and directly using the crude compound 1-02A in the next step.

The third step: preparation of Compounds 1-03A

Adding the crude product compound 1-02A (2256g) obtained in the second step into methanol (12.6L), sequentially adding isopropylamine (4.34L) and acetic acid (2.86L), introducing nitrogen, heating the system to 50 +/-2 ℃, keeping the temperature and stirring, tracking the reaction by T L C until the compound 1-02A disappears, cooling the reaction system to room temperature, concentrating under reduced pressure, diluting with ethyl acetate, washing an organic phase, drying with anhydrous magnesium sulfate, and performing column chromatography on the crude product with a petroleum ether and ethyl acetate system to obtain a white solid compound 1-03A (the yield in the previous three steps is about 40%) (yield in the previous three steps)

The fourth step: preparation of Compound 1-04B

Adding a compound 1-03A (2440g) into a mixed solution of 1, 4-dioxane (12.2L), ethanol (12.2L) and water (12.2L), adding sodium hydroxide (8Kg), heating to reflux, keeping the temperature and stirring, tracking the reaction by T L C until the compound 1-03A disappears, cooling the reaction system to room temperature, concentrating under reduced pressure, adjusting the pH value to 1-2, separating out a large amount of solids, filtering, washing a filter cake with water, and drying the solids in vacuum to obtain a white solid compound 1-04B which is directly used for the next reaction (yield: 95%)

The fifth step: preparation of Compounds 1-05B

Adding the compound 1-04B (2164g) into a mixed solution of dichloromethane (3.1L) and trifluoroacetic acid (9.3L), introducing nitrogen, stirring at room temperature, tracking the reaction at T L C until the compound 1-05B disappears, adding dichloromethane (3L) for dilution, adding water (6L), stirring for 0.5 hour, standing for layering, extracting an aqueous phase with dichloromethane, combining organic phases, washing, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain the compound 1-05B, and directly using the compound 1-05B in the next reaction (yield: 95%)

And a sixth step: preparation of Compound 1-06A

Adding a compound 1-05B (320g) into dimethyl sulfoxide (3.2L), sequentially adding 1- (nitrophenyl) piperazine (489g), cuprous iodide (74g), 2, 6-dimethylphenylcarbamoyl formic acid (152g) and potassium carbonate (434g), heating the reaction system to 120 +/-5 ℃ under the protection of nitrogen, keeping the temperature and stirring, detecting T L C to react, cooling the reaction system to room temperature, adding a saturated ammonium chloride solution to quench the reaction, extracting the water phase with ethyl acetate for multiple times, combining the organic phases, washing with anhydrous magnesium sulfate, drying the crude product, performing column chromatography on the crude product by using petroleum ether, ethyl acetate and dichloromethane to obtain a yellow solid compound 1-06 A. (yield: -55%)

The seventh step: preparation of Compounds 1-07A

Adding compound 1-06A (673g) into N, N-dimethylformamide (7.5L), introducing nitrogen, cooling the system to 0 +/-5 ℃, adding iodosuccinimide (341g), stopping cooling, stirring the system at room temperature in a dark place, carrying out tracking reaction at T L C until the compound 1-06A disappears, concentrating the reaction solution to dryness, adding crude product into a mixed solution of petroleum ether and ethyl acetate (v/v ═ 3/1) (1.5L), stirring at room temperature, filtering, washing a filter cake with a mixed solution of petroleum ether and ethyl acetate (v/v ═ 3/1), and drying in vacuum to obtain a yellow solid compound 1-07A which is directly used for the next reaction (yield: -95%)

Eighth step: preparation of Compounds 1-08A

Adding a compound 1-07A (300g) into dimethyl sulfoxide (3L), sequentially adding sodium methanesulfinate (464g), cuprous iodide (52g), L-proline (52g) and sodium hydroxide (36g), protecting a reaction system with nitrogen, heating to 100 +/-5 ℃, keeping the temperature and stirring, detecting a reaction by T L C, allowing most of raw materials to react, cooling the reaction system to room temperature, adding a saturated ammonium chloride solution to quench the reaction, extracting a water phase with ethyl acetate for multiple times, combining organic phases, washing, drying with anhydrous magnesium sulfate, and performing column chromatography on a crude product by using petroleum ether, ethyl acetate and dichloromethane to obtain a yellow solid compound 1-08 A. (yield: 55%) (

Ninth and tenth steps: preparation of Compounds 1-09A, Compounds 1-10A

Adding a compound 1-08A (120g) into tetrahydrofuran (1.2L), adding raney nickel (180g) under a stirring state, performing hydrogen replacement, stirring the reaction at room temperature under a hydrogenation condition, tracking the reaction by T L C until the compound 1-08A disappears, stopping the reaction, filtering to remove raney nickel, and directly using the filtrate for subsequent reaction;

adding compound 011(96g) into dichloromethane (1L), cooling the system to-5 +/-5 ℃, adding pyridine (40m L), slowly dropwise adding the filtrate obtained in the ninth step, stirring, carrying out T L C tracking reaction until compound 1-09A disappears, adding dichloromethane (3L), washing the organic phase twice with water, drying over anhydrous magnesium sulfate, carrying out column chromatography on the crude product with petroleum ether, ethyl acetate and dichloromethane system, and obtaining light yellow solid compound 1-10A (the yield of the two steps is about 70%)

The eleventh step: preparation of Compounds 1-11A

Adding a compound 1-10A (487g) into N, N-dimethylformamide (6L), adding a compound 020(207g) and diisopropylethylamine (285m L), introducing nitrogen, stirring at room temperature, carrying out tracking reaction by T L C until the compound 1-10A disappears, directly concentrating the reaction liquid to dryness, and carrying out column chromatography on a crude product by using a dichloromethane and methanol system to obtain a light yellow solid compound 1-11A (the yield is about 90%)

¹H NMR(400MHz,DMSO-d₆)9.76(s,1H),7.83(d,J＝2.2Hz,1H),7.60(dd,J＝9.3,2.3Hz,1H),7.38(d,J＝8.5Hz,2H),7.34-7.14(m,7H),7.01-6.80(m,6H),6.65-6.50(m,2H),6.47-6.31(m,1H),4.34(q,J＝7.0Hz,1H),4.06(s,1H),3.59(s,3H),3.43-3.22(m,2H),3.19-3.00(m,8H),2.90(s,3H),2.68(s,4H),2.33-2.14(m,3H),1.91(t,J＝11.0Hz,2H),1.74(dq,J＝30.4,14.7,13.0Hz,4H),1.56-1.27(m,8H).

Compound 020 can be synthesized by the following steps:

the first step is as follows: preparation of Compound 020-02A

Adding a compound 020-01A (100.0g) and N-methylmorpholine (27.0g) into ethylene glycol dimethyl ether (300m L), introducing nitrogen, cooling the system to-8 +/-2 ℃, dropwise adding isobutyl chloroformate (36.5g), stirring, carrying out T L C tracking reaction until the compound 020-01A disappears, filtering the reaction solution, introducing nitrogen, dropwise adding a mixed solution of sodium borohydride (13.5g) and water (160m L), heating to room temperature after dropwise adding, stirring, diluting the reaction system with water, extracting with ethyl acetate, combining organic phases, washing, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain a product 020-02A, and directly using the product in the next step for synthesis.

The second step is that: preparation of Compound 020-03A

Compound 020-02A (96.6g), tributyl phosphate (108.2g), diphenyl disulfide (116.8g) were added to dichloromethane (650m L), nitrogen was bubbled through, stirring was carried out at room temperature, the reaction was followed by T L C until compound 020-02A disappeared, the reaction was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and used directly in the next reaction.

The third step: preparation of Compound 020-04A

And transferring the compound 020-03A obtained in the second step into another reaction vessel, introducing nitrogen, dropwise adding trifluoroacetic acid (148g), stirring at room temperature, tracking the reaction by T L C until the compound 020-03A disappears, washing the reaction liquid with water, standing for layering, extracting an aqueous phase with dichloromethane, combining organic phases, drying over anhydrous magnesium sulfate, filtering and concentrating, washing with ethyl acetate/n-hexane (v/v ═ 1/6), and drying the solid in vacuum to obtain the compound 020-04A (yield of the previous three steps is: -55%).

The fourth step: preparation of Compound 020-05A

Adding a compound 020-04A (60g) and N-methylmorpholine (15.4g) into ethylene glycol dimethyl ether (240m L), introducing nitrogen, cooling the system to minus 8 +/-2 ℃, dropwise adding isobutyl chloroformate (20.7g), stirring, carrying out T L C tracking reaction until the compound 020-04A disappears, filtering the reaction solution, introducing nitrogen, cooling the system to minus 15 +/-2 ℃, dropwise adding a water (100m L) solution of sodium borohydride (7.8g), stirring for 45 +/-15 minutes, diluting the reaction system with water, extracting with ethyl acetate, combining organic phases, washing, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain a product 020-05A, which is directly used for next synthesis (yield: 90%).

The fifth step: preparation of Compounds 020-06A

Oxalyl chloride (49.6g) is added into dichloromethane (600m L), nitrogen is introduced, the system is cooled to-60 +/-5 ℃, a mixed solution of dimethyl sulfoxide (50.9g) dissolved in dichloromethane (240ml) is dropwise added into the reaction system, stirring is carried out at the constant temperature for 1.0 hour, then a mixed solution of a compound 020-05A (54.7g) dissolved in dichloromethane (360m L) is dropwise added into the reaction system, stirring is carried out at the constant temperature for 1.5 hours, the temperature is kept to-60 +/-5 ℃, diisopropylethylamine (101.2g) is dropwise added, the temperature is raised to room temperature, the reaction system is diluted with water, stirring is carried out at the room temperature for 24 hours, standing and layering are carried out, an aqueous phase is extracted by dichloromethane, an organic phase is combined, washing is carried out, anhydrous magnesium sulfate is dried, filtration and concentration are carried out, and a crude product is subjected to column chromatography by using petroleum ether and ethyl acetate.

And a sixth step: preparation of Compounds 020-07A

Adding a compound 020-06A (26.6g) and methyl 4-piperidinecarboxylate (9.9g) into dichloromethane (500m L), introducing nitrogen, stirring at room temperature for 2.0 hours, then adding sodium triacetoxyborohydride (26.5g) into the reaction system, stirring at room temperature, tracking the reaction by T L C until the compound 020-06A disappears, diluting the reaction system with water, standing for layering, extracting an aqueous phase with dichloromethane, combining organic phases, washing, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain a compound 020-07A, and directly using a crude product for next synthesis.

The seventh step: preparation of Compound 020

Adding a compound 020-07A (37.6g) and diethylamine (114m L) into acetonitrile (360m L), introducing nitrogen, stirring at room temperature, carrying out tracking reaction by T L C until the compound 020-07A disappears, concentrating a reaction solution to dryness, carrying out column chromatography on a crude product by using a dichloromethane and methanol system to obtain an oily product compound 020 (the two-step yield is about 50%)

¹H NMR (400MHz, chloroform-d) 7.35(dd, J ═ 8.3,1.3Hz,2H),7.26(dd, J ═ 8.5,6.9Hz,2H),7.21-7.07(m,1H),3.66(s,3H),3.11(dd, J ═ 13.1,4.3Hz,1H),2.97(tt, J ═ 8.4,4.5Hz,1H),2.85(dd, J ═ 22.2,11.4Hz,2H),2.74(dd, J ═ 13.2,8.3Hz, ddh), 2.39(dd, J ═ 20.0,12.6,7.5,5.5Hz,2H),2.27(tt, J ═ 11.1,4.0, 1H), 99.1H, 1-1H), 1.27 (tt, J ═ 11.1, 1.0, 1H), 1H.62(m,9H),1.61-1.47(m,1H).

Compound 011 of the present invention can be synthesized by the following steps:

the synthesis process comprises the following steps:

first step preparation of Compound 011-B1

The temperature is controlled to be minus 25 +/-5 ℃, trifluoroiodomethane (100g) is introduced into N, N-dimethylformamide (225m L), 1 '-dimethyl-4, 4' -dichloropyridine (4.37g) and 2-fluorobenzothiophenol (43.6g) are added into a reaction system under the protection of nitrogen, triethylamine (48.2g) is added dropwise, the temperature is raised to room temperature after the dropwise addition is finished, the mixture is stirred for 24 hours, water (800m L) is added, the reaction liquid is extracted by diethyl ether, organic phases are combined, washed, dried by anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain an oily product compound 011-B1, and the yield is 85%.

Second step preparation of Compound 001

Adding a compound 011-B1(56g) into a mixed solution of carbon tetrachloride (170m L), acetonitrile (170m L) and water (340m L), adding sodium periodate (183g) and ruthenium trichloride hydrate (0.59g), stirring at room temperature, carrying out T L C tracking reaction until the compound 011-B1 disappears, adding dichloromethane (300m L), filtering the solution, adjusting the pH value of the filtrate to 7-8, standing for layering, extracting a water phase with dichloromethane, combining organic phases, washing, drying with anhydrous magnesium sulfate, carrying out column chromatography on a crude product with petroleum ether and ethyl acetate systems to obtain an oily product compound 001, wherein the yield is about 90%.

(third step) preparation of Compound 011

Adding a compound 001(4g) into chlorosulfonic acid (4m L), introducing nitrogen, heating the system to 120 +/-5 ℃, keeping the temperature and stirring for 24 hours, cooling the system to room temperature, slowly pouring the reaction solution into a mixed system of ice (40m L) and ethyl acetate (25m L) under a stirring state, standing for layering, extracting an aqueous phase by using ethyl acetate, combining organic phases, washing, drying by using anhydrous magnesium sulfate, filtering and concentrating to obtain an oily product compound 011 with the yield of about 60%.

Compound 011:¹h NMR (400MHz, chloroform-d) 8.71(dd, J ═ 5.8,2.5Hz,1H),8.54(ddd, J ═ 8.9,4.1,2.5Hz,1H),7.68(t, J ═ 8.7Hz,1H).

The compound 023 to which the present invention relates can be prepared by the following steps:

adding 023-01A (132g) into dichloromethane (1.4L) at room temperature, introducing nitrogen, adding lithium borohydride (18.1g) in portions, stirring, tracing the reaction by T L C until the compound 023-01A disappears, slowly adding saturated aqueous sodium carbonate (400m L), stirring for 30 minutes, standing for layering, extracting an aqueous phase by dichloromethane, combining organic phases, washing, drying by anhydrous magnesium sulfate, filtering and concentrating, and performing column chromatography on a crude product by dichloromethane and methanol system to obtain an oily product 023 with the yield of about 50%.

Compound 023:¹H NMR(400MHz,DMSO-d₆)4.53(t,J＝5.3Hz,1H),3.98(dqd,J＝8.1,7.0,3.8Hz,4H),3.50-3.36(m,2H),1.80-1.50(m,4H),1.23(t,J＝7.0Hz,6H).

the compound 023 relating to the present invention can also be prepared by the following steps:

the synthesis process comprises the following steps:

first step for preparing Compound 023-02B

Adding 023-01B (8.00Kg) into MTBE (24.0L) under stirring, cooling to-20-10 ℃, dropwise adding DHP (5.33Kg), heating to 5 ℃ after adding, reacting, tracking T L C until the reaction is finished, washing the reaction liquid with water and saturated sodium chloride solution respectively, drying with anhydrous sodium sulfate, filtering, concentrating, and obtaining the crude product with the yield of 93 percent.

Second step for preparing Compound 023-03B

Adding 023-01B (10.00Kg) into triethyl phosphite (22.3Kg), heating to 165-180 deg.C, reacting while maintaining the temperature (removing triethyl phosphate by azeotropy), T L C tracing the reaction until the reaction is finished, directly concentrating the reaction liquid to dryness, and distilling the crude product under reduced pressure to obtain the pure compound 023-03B with a yield of 76%.

023 preparation of Compound

Adding compound 023-03B (10.00Kg) and ion exchange resin (1.0Kg) into ethanol (30.0L) under stirring, controlling the temperature to 55 ℃ for reaction, monitoring the reaction by GC (gas chromatography) until the reaction is finished, filtering, concentrating the filtrate, and performing column chromatography on the crude product to obtain the compound 023 with the yield of 38%.

Compound 023:¹H NMR(400MHz,DMSO-d₆)4.53(t,J＝5.3Hz,1H),3.98(dqd,J＝8.1,7.0,3.8Hz,4H),3.50-3.36(m,2H),1.80-1.50(m,4H),1.23(t,J＝7.0Hz,6H).

preparation example 2:

this example prepares compound 1, which corresponds to method II. Taking the compound 024 and the compounds 1-10A as starting materials to prepare the compound 1.

The synthesis process is described as follows:

the first step is as follows: preparation of Compounds 1-13A

Adding 1-10A (1.60Kg) into dichloromethane (32Kg) under stirring, adding 024(1.18Kg) and N, N-diisopropylethylamine (0.70Kg), and stirring at room temperature for 24 hours under nitrogen protection; IPC monitors the reaction to the end, stops the reaction and washes; directly concentrating the organic phase to dryness; the crude product was subjected to column chromatography (dichloromethane/methanol eluent) to give light yellow solid compounds 1-13A. (yield: 75%).

The second step is that: preparation of Compounds 1-14A

Adding the compound 1-13A (877g) into acetonitrile (7.5Kg) under the stirring state, and protecting the reaction system by using nitrogen; trimethyl bromosilane (502g) is quickly added dropwise; heating to 60 +/-2 ℃; stirring for 60 minutes under heat preservation; IPC monitors the reaction to the end; cooling; directly decompressing and concentrating the reaction liquid to be dry; adding acetonitrile, and concentrating to dryness; adding dichloromethane, and concentrating to dryness to obtain compound 1-14A. The yield thereof was found to be 110%.

The third step: preparation of Compound 1

Adding 1-14A (1.02Kg) into dichloromethane (20Kg) under stirring at room temperature, dropwise adding ammonia-methanol solution (2.0 mol/L) (1.44Kg), stirring for 45 min, directly transferring the reaction solution to a rotary evaporator to concentrate to dryness, dissolving the crude product in 2-methyltetrahydrofuran (suspension), dissolving the organic phase in 5% ammonium bicarbonate water solution (washing; transferring the organic phase to the rotary evaporator to concentrate to dryness), adding 2-methyltetrahydrofuran (8.6Kg × 3) to the rotary evaporator to concentrate to dryness, dissolving the crude product in 2-methyltetrahydrofuran (7.5Kg), introducing nitrogen, adding methyl tert-butyl ether (23Kg) to the reaction kettle, dropwise adding the solution of the crude product in 2-methyltetrahydrofuran to the reaction kettle, stirring for 45 min, filtering, washing the filter cake with methyl tert-butyl ether, and vacuum drying to obtain the compound 1 with yield of 80%.

¹H NMR(400MHz,DMSO-d₆)7.79(d,J＝2.1Hz,1H),7.66(d,J＝9.0Hz,1H),7.37(d,J＝8.0Hz,2H),7.30-7.16(m,7H),6.99(d,J＝9.4Hz,1H),6.93(d,J＝8.5Hz,2H),6.86(t,J＝10.9Hz,3H),6.61-6.49(m,2H),6.37(d,J＝9.2Hz,1H),4.33(p,J＝7.0Hz,1H),4.06(s,3H),3.35(d,J＝11.8Hz,2H),3.10(d,J＝20.2Hz,8H),2.89(s,4H),2.67(s,4H),2.38(d,J＝28.3Hz,3H),2.16(s,2H),1.96(s,1H),1.78(s,5H),1.69-1.43(m,4H),1.34(d,J＝7.0Hz,6H).

The intermediate compound 1n2 and the intermediate compound 1-08A related to the invention can be synthesized by the following method:

the synthesis process of compound 1n2 is described as follows:

the first step is as follows: preparation of Compound 1n2-01

Adding parachlorophenylglycine (300g) into methanol (3.0Kg) under the protection of nitrogen; controlling the temperature to be 0-10 ℃, and dropwise adding thionyl chloride (384 g); after the addition, heating to 55-65 ℃, keeping the temperature and stirring for 1-2 hours, and monitoring by IPC until the reaction is finished; directly concentrating the reaction solution to dryness; dissolving the crude product in dichloromethane (3.2Kg), and alkalizing the crude product by using 8% ammonium bicarbonate solution (4.8Kg) until the pH value is 7-8; standing for layering, and extracting a water phase with dichloromethane; the organic phases are combined and washed with 25% sodium chloride solution; drying with anhydrous magnesium sulfate; filtering and concentrating; the crude compound 1n2-01 was used directly in the next reaction.

The second step is that: preparation of Compound 1n2-02

Adding compound 1n2-01(323g) and acetone (112g) into dichloromethane (3.9Kg) at room temperature under the protection of nitrogen; sodium triacetoxyborohydride (681g) was added in portions; reacting for 16-20 hours, and monitoring by IPC until the reaction is finished; dripping water (2.4 Kg); after the addition, stirring for 20-40 minutes, standing and layering; washing the organic phase; drying with anhydrous magnesium sulfate; filtering and concentrating; the crude compound 1n2-02 was used directly in the next reaction.

The third step: preparation of Compound 1n2-03

Under the protection of nitrogen, adding the compound 1N2-02(386g) into N, N-dimethylacetamide (3.7 Kg); controlling the temperature to be 0-10 ℃, and dropwise adding acetyl chloride (251g) and diisopropylethylamine (811g) in sequence; after the addition, heating to 35-45 ℃, reacting for 2-4 hours, and monitoring by IPC until the reaction is finished; concentrating; to the concentrate was added dichloromethane (4.3 Kg); washing the organic phase; drying with anhydrous magnesium sulfate; filtering and concentrating; adding ethyl acetate (448g) and n-heptane (2.38g) into the concentrate, and stirring at room temperature for 3-5 hours; filtering and washing a filter cake; vacuum drying to obtain compound 1n 2-03. Yield: the yield of the three steps is 90 percent.

The fourth step: preparation of Compound 1n2

Adding compound 1n2-03(396g) into a mixture of tetrahydrofuran (5.6Kg) and water (2.1Kg) at room temperature under the protection of nitrogen; lithium hydroxide monohydrate (170g) was added in portions; reacting for 16-18 hours, and monitoring by IPC until the reaction is finished; 1N hydrochloric acid (3.0Kg) was added; adding ethyl acetate (6.8Kg), stirring for 20-40 minutes, and standing for layering; extracting the aqueous phase with ethyl acetate; combining the organic phases and washing the organic phases with 25% sodium chloride solution; drying with anhydrous magnesium sulfate; filtering, and washing a filter cake with n-heptane; vacuum drying to obtain compound 1n 2. Yield: -80%.

The synthesis process of the compound 1-08A is described as follows:

the first step is as follows: preparation of Compound 1n1

Under the protection of nitrogen, 3-bromo-5-fluorobenzaldehyde (400g) and triphenylphosphine (1.3Kg) are added into dichloromethane (4.7 Kg); controlling the temperature to be 0-10 ℃, and dropwise adding a prepared dichloromethane (1.2Kg) solution of carbon tetrabromide (817 g); stirring for 2-4 hours at room temperature, and monitoring by IPC until the reaction is finished; adding 8% sodium bicarbonate solution (2Kg) into the reaction system, standing and layering; washing the organic phase; drying with anhydrous magnesium sulfate; filtering, and washing a filter cake with n-heptane; filtering and concentrating to obtain the product which is directly used for the next reaction. Yield: 85 percent.

The second step is that: preparation of Compounds 1-01C

Under the protection of nitrogen, compound 1n1(270g) was added to tetrahydrofuran (2.4 Kg); cooling to-85-70 ℃, and dropwise adding a prepared tetrahydrofuran (2.0Kg) solution of lithium diisopropylamide (976 g); IPC monitoring till the conversion of the raw materials is complete; controlling the temperature to be-85 to-70 ℃, and dropwise adding a prepared tetrahydrofuran (890g) solution of dimethyl disulfide (248 g); in the dropping process, IPC monitors the conversion rate of the intermediate compound 1n1-01 and the compound 1n 01-02; adding 20% ammonium chloride solution (2.0Kg) into the reaction system, standing and layering; the aqueous phase was extracted with ethyl acetate (1.35 Kg); combining organic phases and washing; drying with anhydrous magnesium sulfate; filtering and concentrating; and distilling under reduced pressure to obtain the product. Yield: -55%.

¹H NMR (400MHz, chloroform-d) 7.35(s,1H),7.20(dt, J ═ 8.3,2.1Hz,1H),7.08-7.01(m,1H),2.51(s,3H).

The third step: preparation of Compounds 1-02C

Adding the compound 1-01C (212g) into dichloromethane (2.6Kg) under the protection of nitrogen; controlling the temperature to be 0-10 ℃, and dropwise adding a prepared dichloromethane (9.8Kg) solution of m-chloroperoxybenzoic acid (522 g); stirring for 2-3 hours at room temperature, and monitoring by IPC until the reaction is finished; filtering, and washing a filter cake by using dichloromethane; slowly adding 10% sodium thiosulfate solution (3.7Kg) into the filtrate, standing and layering; washing the organic phase; drying with anhydrous magnesium sulfate; filtering and concentrating to obtain a crude product which is directly used for the next reaction. Yield: -100%. Nuclear magnetic data for compounds 1-02C are as follows:

¹h NMR (400MHz, chloroform-d) 7.59-7.55(m,1H),7.45(ddd, J ═ 8.0,2.4,1.7Hz,1H),7.30-7.25(m,1H),3.33(s, 3H).

The fourth step: preparation of Compounds 1-03C

Adding the compound 1-02C (207g) and the compound 1n2(242g) into acetic anhydride (3.8Kg) under the protection of nitrogen; controlling the temperature to be 100-110 ℃, stirring for 2-3 hours, and monitoring by IPC until the reaction is finished; cooling to 50-60 ℃, and directly concentrating the reaction solution to dryness; dissolving the crude product in ethyl acetate (4.1Kg), and washing; drying with anhydrous magnesium sulfate; filtering, washing filter cake, vacuum drying to obtain compound 1-03C. Yield: -95%.

The fifth step: preparation of Compounds 1-04C

Under the protection of nitrogen, R-BINAP (1.5g), Pd (OAc)₂(0.15g) was added to toluene (348 g); after the addition, the temperature is raised to 50 ℃ and the mixture is stirred for 0.5 hour; successively, compound 1-03C (20g), Boc-piperazine (7.7g), water (1.0g), and sodium tert-butoxide (6.0g) were added; after the addition, heating to 100-110 ℃, refluxing for 3-5 hours, and monitoring by IPC until the reaction is finished; cooling to room temperature, adding 20% ammonium chloride solution (200g) and active carbon (20g), and stirring for 0.5 hr; filtering, standing the filtrate for layering; washing the organic phase; filtering, washing the filter cake, and vacuum drying to obtain the compound 1-04C. Yield: -75%.

Nuclear magnetic data for compounds 1-04C are as follows:

¹h NMR (400MHz, chloroform-d) 7.27(d, J ═ 8.2Hz,2H),7.07(d, J ═ 8.2Hz,2H),6.65(t, J ═ 1.8Hz,1H),6.40(dt, J ═ 11.9,2.4Hz,1H),6.35-6.25(m,1H),4.38(H, J ═ 7.1Hz,1H),3.51(t, J ═ 5.1Hz,4H),3.04(t, J ═ 5.2Hz,4H),2.75(d, J ═ 9.0Hz,6H),1.45(d, J ═ 16.0Hz, 15H).

And a sixth step: preparation of Compounds 1-05C

Under the protection of nitrogen, adding the compound 1-04C (17g) into a mixed solution of dichloromethane (157g) and absolute ethyl alcohol (94 g); controlling the temperature to be 0-10 ℃, and dropwise adding acetyl chloride (23 g); after the addition, heating to room temperature, stirring for 4-6 hours, and monitoring by IPC until the reaction is finished; adding activated carbon (1.7g), and stirring for 1-2 hours; filtering and concentrating; isopropanol (80g) was added; heating to 55-65 ℃, and stirring for 1-3 hours; cooling to room temperature, and crystallizing; filtering and washing a filter cake; vacuum drying to obtain compound 1-05C. Yield: -95%.

Nuclear magnetic data for compounds 1-05C are as follows:

¹h NMR (400MHz, chloroform-d) 9.57(s,1H),7.28(d, J ═ 8.2Hz,2H),7.07(d, J ═ 8.1Hz,2H),6.72(s,1H),6.42(d, J ═ 11.3Hz,1H),6.30(d, J ═ 8.9Hz,1H),4.39(p, J ═ 7.1Hz,1H),3.61-3.17(m,8H),2.74(d, J ═ 7.7Hz,6H),1.44(d, J ═ 7.1Hz, 6H).

The seventh step: preparation of Compounds 1-08A

Under the protection of nitrogen, adding compound 1-05C (14g), 4-nitrofluorobenzene (4.5g) and potassium carbonate (11g) into dimethyl sulfoxide (154g) in sequence; controlling the temperature to be 55-65 ℃, stirring for 4-6 hours, and monitoring by IPC until the reaction is finished; activated charcoal (1.4g) was added; controlling the temperature to be 55-65 ℃, and stirring for 1-2 hours; filtering, and washing a filter cake by using dimethyl sulfoxide; water (77g) was added dropwise to the filtrate at room temperature; stirring for 1-3 hours after the addition; filtering; dissolving the wet product in dichloromethane, and washing; directly concentrating the organic phase to dryness; to the crude was added ethyl acetate (25g), n-heptane (57 g); controlling the temperature to be 55-65 ℃, and stirring for 1-3 hours; cooling to room temperature, and crystallizing for 1-2 hours; filtering and washing a filter cake; vacuum drying to obtain compound 1-08A. Yield: 85 percent.

Synthesis of Compounds 1-10A

The synthesis process is described as follows:

the first step is as follows: preparation of Compound 1-09A

Adding 1-08A (1.6Kg) and 0.7Kg of iron powder into 6.6Kg of ethanol under stirring; adding 2.1Kg of prepared ammonium chloride aqueous solution into a reaction kettle; heating to reflux, and refluxing overnight; cooling to 40 plus or minus 2 ℃, adding dichloromethane (8.2Kg), and stirring for 0.5 hour; filtering, and washing a filter cake by using dichloromethane; combining the filtrates, and concentrating under reduced pressure in batches to remove most of the organic solvent; filtering, and washing a filter cake with ethanol; drying at 35 +/-2 ℃ in vacuum to obtain a compound 1-09A, wherein the yield is as follows: 93 percent.

The second step is that: preparation of Compounds 1-10A

Compound 011(1.6Kg) was added to dichloromethane (14.7Kg) at room temperature under stirring; adding triethylamine hydrochloride (1.0Kg) under the protection of nitrogen; dissolving the compound 1-09A (1.4Kg) in dichloromethane (27.8Kg) and dripping into a reaction system; after the dropwise addition, stirring for 1.0 hour under heat preservation; refluxing for 10 hours; washing the organic phase; filtering and concentrating; dissolving the crude product in ethyl acetate (3.2Kg), passing through a silica gel column, and washing with ethyl acetate for 5 times; concentrating the ethyl acetate to dryness; dissolving the solid in dichloromethane (9.8Kg), controlling the temperature to be 35 +/-2 ℃, dissolving the solid clearly, dripping n-heptane (5.1Kg) to separate out the solid, and stirring for 0.5 hour; cooling to room temperature, filtering, and washing a filter cake; vacuum drying to obtain the compound 1-10A yield: 91 percent.

¹H NMR(400MHz,DMSO-d₆)10.12(s,1H),8.33-8.11(m,2H),7.99-7.78(m,1H),7.38(d,J＝8.5Hz,2H),7.28(d,J＝8.1Hz,2H),7.01-6.65(m,4H),6.63-6.45(m,2H),6.43-6.29(m,1H),4.33(p,J＝7.1Hz,1H),3.13(q,J＝5.9Hz,8H),2.90(s,3H),2.67(s,3H),1.35(d,J＝6.9Hz,6H)。

The intermediate compound 024-01 of the present invention can be synthesized by the following method:

the first step is as follows: preparation of Compounds 020-01B

Adding sodium ethoxide (41.05kg) into an ethanol (165.5kg) solution, obviously releasing heat, cooling to room temperature, dropwise adding thiophenol (66.98kg), heating to 50-55 ℃, dropwise adding bromoacetal (100kg), heating after the addition, refluxing and stirring for 1 hour, measuring a sample (petroleum ether: ethyl acetate: 50:1) at T L C, basically finishing the reaction, cooling a reaction solution to 15-20 ℃, dropwise adding water (149.6kg), distilling the ethanol under reduced pressure after the addition is finished (the water bath temperature is 50-55 ℃), adding methyltetrahydrofuran (161.05kg) after the evaporation is finished, stirring for 30 minutes, separating, and directly using an organic phase in the next step.

The second step is that: preparation of Compounds 020-02B

Adding concentrated sulfuric acid (50.15kg) into water (600.65kg), dropwise adding a methyl tetrahydrofuran solution containing a compound 020-01B, heating to reflux after the addition is finished, keeping the temperature for 2 hours, detecting by T L C, standing after the reaction is basically finished, separating an upper organic phase, and directly using the upper organic phase in the next step.

The third step: preparation of Compounds 020-03B

Adding p-toluenesulfonic acid pyridinium (20kg) into methyltetrahydrofuran (75kg), adding S-tert-butylsulfinamide (60kg), stirring for 30 minutes, dropwise adding a methyltetrahydrofuran solution (300L) containing a compound 020-02B, heating to 80-85 ℃ after the addition, refluxing for more than 5 hours, detecting by T L C, after the reaction is finished, cooling to room temperature, adding water (100kg) and toluene (87kg), stirring for 30 minutes, separating liquid, washing an organic phase, drying with anhydrous sodium sulfate, filtering, and concentrating a mother liquor under reduced pressure to obtain 101.5kg of a crude compound 020-4 (yield is 78%).

The fourth step: preparation of Compounds 020-04B

Under the protection of nitrogen, adding zinc powder (77.87kg) into tetrahydrofuran (200kg), heating the system to 30-35 ℃, dropwise adding methyl bromoacetate (6.03kg), dropwise adding diisobutyl lithium hydride (35.16L) after the addition is finished, heating to 50-55 ℃, dropwise adding methyl bromoacetate (96.96kg), keeping the temperature for more than 1 hour between 50-55 ℃, cooling to room temperature, dropwise adding a tetrahydrofuran (100kg) solution of a compound 020-03B (100.05kg), stirring for 1 hour after the dropwise addition is finished, detecting by T L C, after the reaction is basically finished, dropwise adding 25% saline (30kg), a 10% citric acid aqueous solution (320kg) and 25% saline (163kg), adding toluene (180kg), stirring for 30 minutes, separating out an aqueous phase, extracting the toluene, combining organic phases, concentrating under reduced pressure to be dry, collecting crude products of n-hexane, ethyl acetate (4: 1 to 3; 1, concentrating under reduced pressure to be dry to obtain a compound yield of 020-5(55.8kg), and performing column chromatography on the crude products.

The fifth step: preparation of Compounds 020-05B

Adding toluene (290kg) and red aluminum (77L) into a reaction kettle, cooling to 0-5 ℃ under the protection of nitrogen, dropwise adding a toluene (100kg) solution of a compound 020-04B (55kg), stirring for 30 minutes after dropwise adding, then heating to room temperature, stirring for 1 hour, detecting by T L C, adding a 10% NaOH aqueous solution after reaction is finished, stirring for 1 hour, extracting an aqueous phase with toluene, combining organic phases, washing, adding anhydrous sodium sulfate, drying, filtering, and directly using a mother solution in the next step.

And a sixth step: preparation of Compounds 020-06B

Adding TEA (33.66kg) into a toluene solution (about 600L) containing the compounds 020-05B, cooling to 0 ℃ under the protection of nitrogen, dropwise adding methylsulfonyl chloride (28.66kg), stirring for 1 hour, detecting by T L C, finishing the reaction, adding water (200kg) into an organic phase, stirring for half an hour, separating liquid, adding saturated saline water for washing, adding sodium sulfate into the organic phase for drying, filtering, and directly using a mother liquor (600L) containing the compounds 020-06B in the next step.

The seventh step: preparation of Compounds 020-07B

Potassium carbonate (69.02kg) and piperidine-4-carboxylic acid methyl ester (35.75kg) were added to a toluene solution (600L) containing compound 020-06B, and the mixture was stirred at room temperature overnight, water (300kg) was added to the organic phase, the mixture was stirred for half an hour, liquid separation was performed, the organic phase was washed with water, the organic phase was evaporated under reduced pressure, and column chromatography (n-hexane: ethyl acetate: 3:1 column chromatography) was performed to obtain compound 020-07B (25.55kg, 36%).

Eighth step: preparation of Compound 020

Adding methanol (45kg) and a compound 020-07B (25kg) into a reaction kettle, adding a 1.5N methanol solution (117L) of hydrochloric acid at room temperature, stirring for 1 hour, monitoring by a T L C, after the reaction is finished, concentrating under reduced pressure to be dry, adding water (100kg) and ethyl acetate (150kg), adjusting the pH value to be 9-10, separating, adding ethyl acetate into an aqueous phase for extraction, combining organic phases, stirring and drying anhydrous sodium sulfate, filtering the organic phases, and evaporating to dryness under reduced pressure to obtain a crude compound 020 product (12.5kg, 66%).

Adding the crude compound 020 to (122kg) acetone, adding L-p-dimethylbenzyltartaric acid (24.85kg) at room temperature, stirring for 1 hour at room temperature, filtering, leaching with a small amount of acetone, drying (40-45 ℃) to obtain a salt, adding water (100kg), regulating the pH value to be 9-10 at room temperature, adding ethyl acetate into an aqueous phase for extraction, combining organic phases, adding anhydrous sodium sulfate, stirring and drying, filtering the organic phase, and evaporating to dryness under reduced pressure to obtain 8.75kg compound 020 (71%).

The ninth step: preparation of Compound 024-01

Adding potassium carbonate (4.88kg) and water (22kg) into a reaction kettle, stirring to dissolve the mixture, adding dichloromethane (29kg) and a compound 020(8.7kg), adding BOC-anhydride (Boc)2O (5.89kg) at room temperature, stirring for 1 hour at room temperature, monitoring by T L C, standing for liquid separation after the reaction is finished, extracting an aqueous phase by dichloromethane (20kg), combining organic phases, washing by using water, adding anhydrous sodium sulfate into the organic phase, stirring and drying, filtering the organic phase, evaporating the organic phase under reduced pressure, adding tetrahydrofuran, and evaporating to dryness under reduced pressure again to obtain a compound 024-01(10.27kg, 90%).

¹H NMR(400MHz,DMSO-d₆)7.42-7.24(m,4H),7.21-7.10(m,1H),6.90(d,J＝8.4Hz,1H),3.60(s,4H),3.11-2.92(m,2H),2.76(s,2H),2.37-2.19(m,3H),1.91(s,2H),1.82-1.45(m,6H),1.37(s,9H).

Intermediate compound 024-01 of the present invention can also be synthesized by the following method:

the first step is as follows: preparation of Compounds 020-01C

The flask was charged with 30g of N-Boc cysteine methyl ester, 24.02g of bromobenzene, pd₂(dba)₃₍Tris (dibenzylideneacetone) dipalladium₎5.80g of xanthphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, i.e. 9,9-Dimethyl-4,5-bis (diphenylphosphino) xanthene)7.38g, DIPEA 49.4g, 1, 4-dioxane 400ml, evacuation, nitrogen substitution, temperature rise to 90 ℃ reaction, T L C for monitoring the completion of the reaction of the raw materials, cooling to room temperature, and addition of 300ml of H₂Stirring, filtering, extracting the filtrate twice with DCM 150M L, combining the organic phases, washing with saturated sodium chloride, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product 66.5g, and performing column chromatography to obtain pure product 31.6g with yield 79%.

The second step is that: preparation of Compounds 020-02C

5g of compound 020-01C (1eq) and 100ml of toluene are added into a flask, the temperature is reduced to-78 ℃, 32.1ml of 1.5M toluene solution of DIBA L H is started to be dripped, T L C is used for monitoring the completion of the reaction after the dripping is finished, 20ml of anhydrous methanol is dripped at the temperature of-78 ℃ for quenching, the mixture is stirred for 30min, the mixture is heated to room temperature, diatomite is filtered, the filtrate is concentrated under reduced pressure, and 3.87g of oily substance is obtained and is directly used for the next reaction.

The third step: preparation of Compounds 020-03C

7.32g of Compound n3(2.0eq), THF60ml were charged in a flask, evacuated and replaced with nitrogen three times, and the temperature was lowered to-78 ℃. 26.7ml of 1M (Me) are initially added dropwise₃Si)₂NK (2.5eq) is added dropwise, stirring is carried out for 30min, the temperature is slowly raised to 0 ℃, 30ml of THF solution of 3.0g of crude compound 020-02C is added dropwise, the reaction is stirred at 0 ℃, T L C monitors that no raw material is left in the reaction, water is added for quenching, EA 40ml of × 3 is used for extraction, saturated saline solution is used for washing, magnesium sulfate is used for drying, filtering is carried out, filtrate is concentrated, and column chromatography is carried out, so that 0.5g of target product is obtained, and the yield of two steps is 10%.

The fourth step: preparation of Compounds 020-04C

0.35g of the compound 020-03C (1.0eq) and 7ml of acetone (20v) were added to the flask, the mixture was stirred at room temperature, 0.85ml of 2N Cl (1.5eq) and T L C were added dropwise to monitor the progress of the reaction, the reaction was completed in about 2.5 hours, the pH was adjusted to 7 with saturated sodium bicarbonate, EA20ml × 3 was extracted, the extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the filtrate was concentrated and dried to give an oil with a yield of 0.33g and 100%.

The fifth step: preparation of Compound 024-01

0.30g of the compound 020-04C and 7.5ml of DCM are added into a 50ml three-necked flask, the mixture is stirred and dissolved, 0.17g of the compound n4(1.2eq) is added, the mixture is stirred at room temperature for 1h, 0.43g of sodium borohydride acetate (2.0eq) is added for reaction at room temperature overnight, the reaction is monitored to be complete by T L C, water is added for quenching, liquid separation is carried out, an aqueous phase is extracted by DCM, saturated saline is washed, magnesium sulfate is dried, and the oily substance is filtered to obtain 0.5g of oily substance, and column chromatography (DCM: MEOH 100:1) is carried out to obtain 0.35g of the target product, wherein the yield is 82%, the purity is 99.

The intermediate compound 024-k related to the invention can be synthesized by the following method:

preparation of Compound 020-02A

Adding THF (9L) into a compound 020-01A (3000g) and NMM (885g) to obtain a solution 1, adding THF (19L) into a reaction kettle, adding ClCOOiBu (1195g) under stirring, cooling a reaction system to-35 ℃, dropwise adding the solution 1, reacting at-40 ℃ for 1h after dropwise adding, filtering under reduced pressure, washing a filter cake with THF, using a filtrate for later use, adding THF (11L) into another reaction kettle, stirring, cooling dry glacial ethanol to-40 ℃, starting dropwise adding a solution mixed by sodium borohydride (522g) and water (5.5L) at-35 ℃, controlling the temperature to-40-30 ℃, generating a large amount of gas, stirring for 1h after the addition is finished, detecting that the reaction is complete, reducing the temperature to-45 ℃, adding a solution prepared by 2kg of ammonium chloride and 10L water, quenching the reaction system, demixing, separating an organic phase, concentrating to obtain a yellow oily substance, adding n-heptane, concentrating, drying to obtain 8.6% of white solid, and obtaining a yield of 62.88% of 97.97%.

Preparation of Compounds 020-03A and 04A

Adding toluene (12L) into a reaction kettle, adding the compound 020-02A (25.3kg) and Ph2S2(22.5kg,14.5mol and 1.6eq) under stirring, cooling to-5 ℃, dropwise adding Bu3P (24kg,117.76mol and 1.85eq) for reacting for 7h, pouring the reaction mixture into ice water for quenching, adding DCM for extraction, separating out an organic phase, transferring the organic phase into another reaction kettle, adding TFA (40L), raising the internal temperature to room temperature, reacting for 36h, supplementing TFA (20L) for reaction, detecting the completion of the reaction, adding water (150L), separating out an aqueous phase, extracting the aqueous phase with DCM, combining the organic phases, adding n-heptane, separating out a solid, and drying to obtain 24.7kg of a white solid with a yield of 88% in two steps.

Preparation of Compound 020-05A

Adding 020-04A (24.7kg), THF (72L) and NMM (8.1kg) into a glass kettle to obtain a solution 1, adding THF (180L) into a 1000L stainless steel reaction kettle, adding ClCOOiBu (10.8kg) under stirring, cooling to-35 ℃, adding the solution 1, reacting at-30 ℃ for 1h after dropwise addition is finished, filtering under reduced pressure to obtain a filtrate 1, adding THF into the stainless steel reaction kettle, cooling liquid nitrogen to-50 ℃ under stirring, adding a solution formed by mixing sodium borohydride (4200g) and water (40L) at-50 ℃, starting dropwise adding the filtrate, adding sodium borohydride (2600g) after the addition is finished, discharging a large amount of gas, naturally raising the temperature to room temperature, carrying out IPC detection to show that the reaction is complete, adding an ammonium chloride aqueous solution, quenching the reaction, adding water and EA, extracting, separating, adding n-heptane into an organic phase, filtering, and drying the obtained solid to obtain 22kg of white solid with the yield of 92%.

Preparation of Compounds 020-06D

Adding 020-05A (22kg), ACN (60L) and diethylamine (60L) into a glass kettle, stirring for 12 hours, removing acetonitrile and diethylamine from a reaction solution through rotary evaporation and desolventizing, transferring the residue into an extraction kettle, adding water and dichloromethane, stirring, adjusting the pH to 1 with hydrochloric acid, separating an organic phase, extracting with water to obtain an aqueous phase, adjusting the pH to 7-8 with a 5% NaOH solution, adding sodium carbonate, adjusting the system to be alkaline, cooling to 10 ℃, adding water and THF, dropwise adding (BOC)2O (12.5kg,57.2mol,1.1eq), naturally stirring for 12 hours, adding water and EA, adding n-heptane into the organic phase, separating out a solid, drying the solid to obtain 10kg of white solid, and obtaining the yield of 64%.

Preparation of Compounds 020-07D

Adding 020-06D (10.0kg), DMSO (13.13kg) and triethylamine (17.01kg) into a glass kettle, cooling to below 20 ℃, adding pyridine sulfur trioxide (16.05kg), stirring at room temperature, adding ice water after the HP L C detection reaction is finished, stirring and quenching, extracting to separate an organic phase, washing the organic phase with water, and concentrating to obtain 11.4kg brown oily matter, wherein the yield of a crude product is 114%.

Preparation of compound 024-k

Adding a compound 020-07D (11.4kg), DCM (35L) and piperidine-4-methyl formate (5.29kg) into a glass kettle, cooling to below 5 ℃, adding sodium triacetoxyborohydride (16.4kg), stirring for 12h, adding piperidine-4-methyl formate (200g,1.39mol,0.03eq), sodium triacetoxyborohydride (600g,2.68mol,0.06eq) after IPC detection reaction is finished, adding ice water, stirring and quenching, extracting and separating out an organic phase, concentrating to obtain 14.8kg of brown oily matter with a crude product yield of 100.3%, adding 14.8kg of the crude product and acetone into the glass kettle, heating to 40-50 ℃, adding anhydrous oxalic acid (0 g,34.55mol,1eq) at one time, stirring for 2h at 40-50 ℃, precipitating a white solid, performing suction filtration, and drying the obtained solid, wherein the yield is 10kg of white powder and 56%.

Analytical data for compound 024-k is as follows:

1H NMR(400MHz,DMSO-d6)7.33(dt,J＝15.1,7.4Hz,4H),7.25-7.13(m,1H),6.99(d,J＝8.5Hz,1H),3.63(s,4H),3.29(s,2H),3.15-2.75(m,6H),2.63(s,1H),2.00(d,J＝11.7Hz,3H),1.93-1.67(m,3H),1.38(s,9H).13C NMR(101MHz,DMSO-d6)173.98,164.96,129.50,128.73,126.23,78.47,53.64,52.22,51.08,50.85,48.54,38.01,37.68,28.65,28.40,28.25,25.52。

intermediate compound 024 of the present invention can be synthesized by the following method:

the first step is as follows: preparation of Compound 024-02

024-01(1.2Kg) was added to THF (8.0Kg) with stirring; NaOH (0.46Kg) was dissolved in H₂O (3.3Kg), added into the reaction system, stirred overnight at room temperature; adjusting the pH value of the reaction system to 3-4; extracting with DCM; combining the organic phases, concentrating to remove most of the solvent; adding DCM for dilution, and washing with saturated saline water; standing, separating, drying the organic phase with MgSO4, filtering, concentrating, dissolving the crude product in DCM, and directly carrying out the subsequent reaction.

The second step is that: preparation of Compound 024-03

024-02(1.2Kg) was added to DCM (12.5Kg) with stirring, DMAP (0.70Kg), EDCI (1.1Kg) and compound 023(0.65Kg) were added in sequence under nitrogen protection, stirred at room temperature for 4 hours, the reaction was stopped, the reaction solution was washed, and the organic phase was concentrated to 5L and used directly in the next reaction.

¹H NMR (400MHz, chloroform-d) 7.39(dd, J ═ 7.8,1.7Hz,2H),7.27(dd, J ═ 8.5,6.9Hz,2H),7.21-7.12(m,1H),5.87(s,1H),4.16-4.04(m,6H),3.83(s,1H),3.23(d, J ═ 12.1Hz,1H),2.99(dd, J ═ 12.7,7.0Hz,1H),2.84(s,2H),2.47-2.23(m,3H),2.06-1.62(m,12H),1.41(s,9H),1.32(t, J ═ 7.1, 6H).

The third step: preparation of compound 024

024-03(1.5Kg) was added to DCM (18.4Kg) with stirring; under the protection of nitrogen, cooling to<5 ℃; TBDMSOTf (tert-butyldimethylsilyl trifluoromethanesulfonate) (1.4Kg) was added dropwise; after the addition, heating to 10-15 ℃, and stirring for reaction for 2 hours; reaction system with H₂O, extracting until the sticky substances disappear; the aqueous phases were combined and washed with DCM until the organic phase was essentially violet-freeExternally; the aqueous phase is saturated NaHCO₃Adjusting the pH value to 8; stirring for 0.5 hour; the aqueous phase was extracted with DCM; combining the organic phases; the organic phase was washed and concentrated to give 1266g of oil. (three-step Total yield: 90%)

Compound 024:¹H NMR(400MHz,DMSO-d₆)7.40-7.24(m,4H),7.17(ddq,J＝9.2,7.3,1.2Hz,1H),4.10-3.92(m,6H),3.05(q,J＝8.3Hz,1H),2.80(dt,J＝21.9,9.5Hz,4H),2.43-2.22(m,3H),1.89(t,J＝11.3Hz,2H),1.83-1.71(m,6H),1.51(d,J＝12.4Hz,6H),1.23(td,J＝7.1,0.8Hz,6H)。

the compound of formula (2) according to the present invention is stable in the Dichloromethane (DCM) used in step (1), but the compound of formula (2) is not very stable in DMF and ethyl acetate. For example, compound 024 is stable in methylene chloride solution at 7 ℃ for at least about 13 days. However, compound 024 was slightly less stable in ethyl acetate under the same conditions.

The method for preparing the novel sulfonamide compound provided by the invention obviously reduces the production cost, shortens the production period by at least more than half, obviously improves the product yield, and is more suitable for mass production.