阅读说明：本技术 一种格拉吉布中间体的制备方法 (Preparation method of Geragibo intermediate ) 是由 吴泽颖 向梅 张震威 丁琳琳 魏雪姣 于 2020-04-28 设计创作，主要内容包括：本发明提供一种格拉吉布中间体的制备方法,涉及有机合成技术领域,包括如下步骤：将脱氢N-甲基-4-哌啶酮与(S)-叔丁基亚磺酰胺发生脱水缩合反应,将脱水缩合反应的产物与N-对甲苯磺酰基-苯并咪唑基-2-锂发生迈克尔加成反应,再通过三乙酰氧基硼氢化钠对加成反应的产物进行还原,对得到的还原产物中加入浓盐酸进行水解,在水解产物中加入碱进行中和,得到格拉吉布中间体。本发明提供的格拉吉布中间体的合成方法,起始原料廉价易得,且各步骤均为常规反应,对设备要求不高,能够较好地降低格拉吉布中间体的生产成本。(The invention provides a preparation method of a Geragibo intermediate, which relates to the technical field of organic synthesis and comprises the following steps: dehydro-N-methyl-4-piperidone and (S) -tert-butyl sulfinamide are subjected to a dehydration condensation reaction, a product of the dehydration condensation reaction and N-p-toluenesulfonyl-benzimidazolyl-2-lithium are subjected to a Michael addition reaction, the product of the addition reaction is reduced by sodium triacetoxyborohydride, concentrated hydrochloric acid is added into the obtained reduction product for hydrolysis, and alkali is added into the hydrolysis product for neutralization, so that a Glabra intermediate is obtained. According to the synthesis method of the grangible intermediate, the starting raw materials are cheap and easy to obtain, all the steps are conventional reactions, the requirement on equipment is not high, and the production cost of the grangible intermediate can be well reduced.)

1. A preparation method of a grangibib intermediate is characterized by comprising the following steps:

s1: carrying out dehydration condensation reaction on the dehydrogenated N-methyl-4-piperidone and (S) -tert-butyl sulfinamide to obtain (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with chiral auxiliary group;

s2: carrying out Michael addition reaction on the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide and N-p-toluenesulfonyl-benzimidazolyl-2-lithium to obtain (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide;

s3: reducing the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide by sodium triacetoxyborohydride to obtain (2R,4R) -N-methyl-2- (N-p-toluenesulfonyl benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide;

s4: and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butyl sulfenamide is hydrolyzed by adding concentrated hydrochloric acid, and the hydrolysate is neutralized by adding alkali to obtain the Glabra gibb intermediate.

2. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S1 comprises:

s11: dissolving the dehydro-N-methyl-4-piperidone in a benzene solvent, adding pyridinium p-toluenesulfonate and the (S) -tert-butyl sulfinamide, and refluxing and water dividing for 15-20 h at 110-130 ℃ to obtain a dehydration condensation reaction solution;

s12: concentrating the dehydration condensation reaction solution under reduced pressure to obtain a dehydration condensation crude product;

s13: dissolving the crude dehydration condensation product by using dichloromethane, and taking a dehydration condensation organic phase;

s14: and sequentially carrying out water washing, anhydrous sodium sulfate drying and concentration on the dehydration condensation organic phase, and then recrystallizing by an ester solvent to obtain the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfenimide.

3. The process for preparing a grangibib intermediate as claimed in claim 2, wherein the molar ratio of the dehydro N-methyl-4-piperidone, the pyridinium p-toluenesulfonate and the (S) -tert-butylsulfinamide in step S11 is (25-75): 1: 50.

4. the process for preparing a grangibib intermediate as claimed in claim 1, wherein the dehydro N-methyl-4-piperidone is prepared by oxidation of N-methyl-4-piperidone.

5. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S2 comprises:

s21: dissolving the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfimide in an ether solvent, cooling to-50 to-30 ℃, adding the N-p-toluenesulfonyl-benzimidazolyl-2-lithium under the stirring condition, stirring for 15min, heating to-30 to-10 ℃, and continuing stirring for addition reaction for 15 to 20 hours to obtain an addition reaction solution;

s22: adding an ammonium chloride solution into the addition reaction liquid to quench the reaction, and separating an addition organic phase; extracting the aqueous phase by using ethyl acetate, and combining the organic phase obtained by extraction with the addition organic phase;

s23: and (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinyl imine is obtained by sequentially washing the addition organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and recrystallizing with an alcohol solvent.

6. The process for preparing a glargib intermediate according to claim 5, wherein the molar ratio of the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide to the N-p-toluenesulfonyl-benzimidazolyl-2-lithium in step S21 is 1: (0.8 to 1.2).

7. The process for preparing a grubbs intermediate according to claim 1, wherein the N-p-toluenesulfonyl-benzimidazolyl-2-lithium is prepared in situ from N- (p-toluenesulfonyl) benzimidazole and lithium diisopropylamide.

8. The process for preparing a grangibib intermediate as claimed in claim 1, wherein step S3 comprises:

s31: dissolving the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butyl sulfinimide in a halogenated hydrocarbon solvent, adding sodium triacetoxyborohydride in batches under stirring at room temperature, and stirring for 4-24 h at the temperature of 0-10 ℃ to obtain a reduction reaction solution;

s32: adding water to dilute the reduction reaction solution, and separating and reducing an original organic phase; extracting the reduction water phase by using dichloromethane, and combining the obtained organic phase with the reduction organic phase; and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide is obtained by sequentially washing the reduced organic phase with water, drying with anhydrous sodium sulfate and concentrating.

9. The process for preparing a grubbs intermediate as claimed in claim 8, wherein the molar ratio of (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide to sodium triacetoxyborohydride in step S31 is (0.8 to 1.2): 1.

10. the process for preparing a grangibib intermediate as claimed in claim 1, wherein step S4 comprises:

s41, dissolving the (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide in an ether solvent, adding concentrated hydrochloric acid, raising the reaction temperature to 30-50 ℃, and stirring for 10-14 h to obtain a hydrolysis reaction solution;

s42: cooling the hydrolysis reaction liquid in an ice bath, adding sodium hydroxide solution for neutralization, and performing suction filtration on the neutralized hydrolysis reaction liquid to obtain a solid product;

s43: washing the solid product with n-hexane and diethyl ether to obtain a crude product of the grangib intermediate;

s44: recrystallizing the crude product by using an alcohol solvent to obtain the Geragibo intermediate.

Technical Field

The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a grangible intermediate.

Background

Acute Myeloid Leukemia (AML), the most common malignant leukemia in adults, is the one of the lowest survival types of leukemia. Since many adult patients with AML are unable to undergo intensive chemotherapy due to various complications, as well as chemotherapy-related toxicities, more than half of the patients have died. Glargib (glasdegib) was found to be very effective in AML, mainly in treating newly diagnosed patients with age above 75 years, or Acute Myeloid Leukemia (AML) which cannot receive high-intensity chemotherapy due to co-morbidity. [ patent: GB 2519344(GB 2013-18461); ACS med.chem.lett.2012,3, 106-; org.Lett.2014,16,860-863 ]. The new medicine is expected to greatly improve the cure rate of AML patients, especially the AML patients of the old; therefore, the demand for grangil cloth will be more and more increased in the future, and the grangil cloth main synthetic route [ ACS med.chem.lett.2012,3,106-; org.Lett.2014,16,860-863] all require to synthesize a chiral intermediate compound (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine shown as a structural formula 1, and then condense the chiral intermediate compound with a substrate of another segment, wherein the synthetic route is shown as the following formula:

therefore, the method for preparing the intermediate of (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine, namely the glatiribbean intermediate, which has the advantages of cheap and easily obtained raw material source, economic synthetic route and simple and convenient purification steps, has very important significance.

At present, the preparation method of the intermediate of the grahamib is mainly as follows, wherein the first method uses a complex chiral intermediate shown in a structural formula M1 as a starting material, and firstly converts hydroxyl into amino through three steps of hydroxyl activation, azide substitution and reduction to obtain an intermediate shown in a structural formula M2; then protecting amino group, and hydrolyzing ester group to obtain intermediate shown in structural formula M3; the intermediate shown in the structural formula M3 is subjected to condensation reaction with o-phenylenediamine to obtain an intermediate shown in the structural formula M4, then the intermediate shown in the structural formula M5 is prepared through three steps of intramolecular ring closure, deprotection, reductive amination and the like, and finally the target compound shown in the structural formula 1, namely the Geragibb intermediate [ ACSMed. chem. Lett.2012,3, 106-plus 111 ]; specific synthetic routes are given in the following formula:

secondly, taking N- (p-toluenesulfonyl) benzimidazole as a starting material, firstly forming a lithium reagent shown as a structural formula M7 under the action of LDA, then carrying out addition reaction with an intermediate shown as a structural formula M8, then carrying out hydrolysis two-step reaction to obtain an intermediate shown as a structural formula M9, then selectively reducing double bonds of the intermediate shown as a structural formula M9 by using a reducing agent to obtain an intermediate shown as a structural formula M10, then removing a protecting group to obtain an intermediate shown as a structural formula M11, and finally adopting a very key biological enzyme catalyst ATA-36 to carry out one-step chiral amination reduction to obtain a target compound shown as a structural formula 1, namely a Glabra intermediate [ Org.Lett.2014,16,860-863 ]; specific synthetic routes are given in the following formula:

the two synthesis methods have the defects that the first synthesis method has complex initial raw materials, long synthesis steps (up to 10 steps) and low total yield, and relates to highly toxic and explosive substances such as sodium azide, sodium cyanoborohydride and the like in the middle, so that the method brings danger to the production process, is easy to pollute the environment and has no industrial value.

The second synthesis method comprises 6 steps, wherein tert-butoxy lithium hydrogen is used in selective reduction of unsaturated double bonds, the substance is easy to emulsify to form colloid in post-treatment, the amplification reaction is not friendly, the separation and purification of post-treatment products are inconvenient, a special chiral bio-enzyme catalyst is needed in the most critical reaction for chiral formation, the substance is not easy to obtain and expensive, the bio-enzyme catalytic chiral synthesis has the defect of difficult separation at the level above a pilot plant test, the amplification reaction is not easy to carry out, and the later-stage large-scale production has great challenges.

In view of this, it is an urgent need to solve the problem of establishing a preparation method of a glatirib intermediate with easily available raw materials and simple and convenient steps.

Disclosure of Invention

The technical problem solved by the invention is that the raw materials required by the existing preparation method of the grangible intermediate are complex and are not easy to obtain.

In order to solve the problems, the invention provides a preparation method of a grangibib intermediate, which comprises the following steps:

s1: carrying out dehydration condensation reaction on the dehydrogenated N-methyl-4-piperidone and (S) -tert-butyl sulfinamide to obtain (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with chiral auxiliary group;

s2: carrying out Michael addition reaction on the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide and N-p-toluenesulfonyl-benzimidazolyl-2-lithium to obtain (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide;

s3: reducing the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide by sodium triacetoxyborohydride to obtain (2R,4R) -N-methyl-2- (N-p-toluenesulfonyl benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide;

s4: and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butyl sulfenamide is hydrolyzed by adding concentrated hydrochloric acid, and the hydrolysate is neutralized by adding alkali to obtain the Glabra gibb intermediate.

For ease of description, the glatiramer intermediate is represented herein as compound 1, wherein the structural formula of the glatiramer intermediate is represented by the following formula:

in order to prepare the compound 1, the dehydro-N-methyl-4-piperidone shown as a compound 2 is used as a starting material, the dehydro-N-methyl-4-piperidone firstly undergoes a dehydration condensation reaction with (S) -tert-butyl sulfinamide, and the (S) -tert-butyl sulfinamide is used as a chiral auxiliary agent to induce and generate a chiral target product, namely, (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfinyl imine with a chiral auxiliary group shown as a compound 3.

Then, the lithium reagent shown as compound 4, N-p-toluenesulfonyl-benzimidazolyl-2-lithium, is subjected to Michael addition reaction with compound 3, and compound 4 can only attack from the back side of compound 3 due to the presence of the tert-butyl chiral auxiliary group in compound 3, so as to obtain the chiral target product shown as compound 5, namely (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide.

The resulting compound 5 was then reduced with sodium triacetoxyborohydride, again due to the presence of a chiral prosthetic group, and triacetoxyborohydride was able to attack only from the back of the tert-butyl group, thus giving (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide, shown as compound 6.

Finally, the two sulfone groups of the compound 6 are hydrolyzed and removed under the condition of concentrated hydrochloric acid, and then are neutralized by alkali to obtain (2R,4R) -2- (1-hydrogen-benzoxazolyl) -4-amino-1-methylpiperidine, namely a Glabra intermediate, which is shown in the formula in the specification, wherein the synthesis route is shown in the following formula:

according to the synthesis method of the grangible intermediate, the initial raw materials are cheap and easy to obtain, chiral sulfoxide is selected as a chiral source, a substrate is used for inducing to form a chiral center, a main product can be conveniently separated and purified, the problem of enantiomer selectivity does not exist, all steps are conventional reactions, the requirement on equipment is not high, a complex separation and purification means is not needed, the production cost of the grangible intermediate can be well reduced, and the grangible intermediate has good industrial potential and commercial value.

Optionally, step S1 includes:

s11: dissolving the dehydro-N-methyl-4-piperidone in a benzene solvent, adding pyridinium p-toluenesulfonate and the (S) -tert-butyl sulfinamide, and refluxing and water dividing for 15-20 h at 110-130 ℃ to obtain a dehydration condensation reaction solution;

s12: concentrating the dehydration condensation reaction solution under reduced pressure to obtain a dehydration condensation crude product;

s13: dissolving the crude dehydration condensation product by using dichloromethane, and taking a dehydration condensation organic phase;

s14: and sequentially carrying out water washing, anhydrous sodium sulfate drying and concentration on the dehydration condensation organic phase, and then recrystallizing by an ester solvent to obtain the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfenimide.

The names of the dehydration condensation reaction liquid, the dehydration condensation crude product, the dehydration condensation organic phase, the addition reaction liquid, and the methal organic phase in the present application are only used to distinguish the reactants, the products, and the like in the respective reaction steps, and do not limit the specific substances.

In the step S12, the benzene solvent can be recovered during the vacuum concentration of the dehydration condensation reaction solution, and the recovered solvent can be reused after being re-evaporated, so as to reduce the cost and pollution.

Optionally, the mole ratio of the dehydro-N-methyl-4-piperidone, the pyridinium p-toluenesulfonate and the (S) -tert-butylsulfinamide in the step S11 is (25-75): 1: 50; so as to obtain higher yield while the dehydration condensation reaction is smoothly carried out.

Alternatively, the dehydro-N-methyl-4-piperidone is prepared from N-methyl-4-piperidone by oxidation.

Therefore, the compound 2 can be prepared from a cheap and easily available commercial reagent N-methyl-4-piperidone (see the literature Chemical Communications (Cambridge, United Kingdom),2016,52(99), 14314-.

Optionally, step S2 includes:

s21: dissolving the (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butyl sulfimide in an ether solvent, cooling to-50 to-30 ℃, adding the N-p-toluenesulfonyl-benzimidazolyl-2-lithium under the stirring condition, stirring for 15min, heating to-30 to-10 ℃, and continuing stirring for addition reaction for 15 to 20 hours to obtain an addition reaction solution;

s22: adding an ammonium chloride solution into the addition reaction liquid to quench the reaction, and separating an addition organic phase; extracting the aqueous phase by using ethyl acetate, and combining the organic phase obtained by extraction with the addition organic phase;

s23: and (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinyl imine is obtained by sequentially washing the addition organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and recrystallizing with an alcohol solvent.

The synthesis process of the part is shown as the following formula:

alternatively, the molar ratio of (S, Z) -2-methyl-N- (1-methyl) -2, 3-dihydropyridine-4-tert-butylsulfinimide to the N-p-toluenesulfonyl-benzimidazolyl-2-lithium in step S21 is 1: (0.8 to 1.2); so as to obtain higher yield while the addition reaction is smoothly carried out.

Alternatively, the N-p-toluenesulfonyl-benzimidazolyl-2-lithium is prepared in situ from N- (p-toluenesulfonyl) benzimidazole and lithium diisopropylamide.

Optionally, step S3 includes:

s31: dissolving the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butyl sulfinimide in a halogenated hydrocarbon solvent, adding sodium triacetoxyborohydride in batches under stirring at room temperature, and stirring for 4-24 h at the temperature of 0-10 ℃ to obtain a reduction reaction solution;

s32: adding water to dilute the reduction reaction solution, and separating and reducing an original organic phase; extracting the reduction water phase by using dichloromethane, and combining the obtained organic phase with the reduction organic phase; and (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide is obtained by sequentially washing the reduced organic phase with water, drying with anhydrous sodium sulfate and concentrating.

Alternatively, the molar ratio of the (R, Z) -N-methyl-2- (N-p-toluenesulfonyl-benzimidazolyl) -piperidine-4- (S) -tert-butylsulfinimide to the sodium triacetoxyborohydride in step S31 is (0.8-1.2): 1; so as to obtain higher yield while ensuring the smooth proceeding of the reduction reaction.

Optionally, step S4 includes:

s41, dissolving the (2R,4R) -N-methyl-2- (N-p-toluenesulfonylbenzimidazolyl) -piperidine-4- (S) -tert-butylsulfinamide in an ether solvent, adding concentrated hydrochloric acid, raising the reaction temperature to 30-50 ℃, and stirring for 10-14 h to obtain a hydrolysis reaction solution;

s42: cooling the hydrolysis reaction liquid in an ice bath, adding sodium hydroxide solution for neutralization, and performing suction filtration on the neutralized hydrolysis reaction liquid to obtain a solid product;

s43: washing the solid product with n-hexane and diethyl ether to obtain a crude product of the grangib intermediate;

s44: recrystallizing the crude product by using an alcohol solvent to obtain the Geragibo intermediate.

Compared with the prior art, the preparation method of the Geragibo intermediate provided by the invention has the following advantages:

according to the synthesis method of the grangible intermediate, the initial raw materials are cheap and easy to obtain, chiral sulfoxide is selected as a chiral source, a substrate is used for inducing to form a chiral center, a main product can be conveniently separated and purified, the problem of enantiomer selectivity does not exist, all steps are conventional reactions, the requirement on equipment is not high, a complex separation and purification means is not needed, the production cost of the grangible intermediate can be well reduced, and the grangible intermediate has good industrial potential and commercial value.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, specific embodiments thereof are described in detail below.