阅读说明：本技术 一种艾日布林中间体的制备方法 (Preparation method of eribulin intermediate ) 是由 徐安佗 周宁 张晓光 于 2019-08-27 设计创作，主要内容包括：本发明提供了一种艾日布林中间体的制备方法,具体涉及制备艾日布林关键中间体ERB-2,ERB和化合物P1；在制备化合物ERB-2过程中溶将化合物ERB-6中的羟基先用MMTr保护,在B片段合成过程中提前引入羟基保护基Pv,最后采用Ambelyst-15酸性离子交换树脂脱去MMTr,得到化合物ERB-2,该反应路线新颖,反应效率显著提高；在制备化合物P1过程中创造性的在反应体系中添加合适量的Mn粉,并且结合使用Cr~(3+)和配体N或M以及1,8-双二甲氨基萘,能够显著减少铬试剂的使用量,同时提高反应收率,特别适合工业化应用。(The invention provides a preparation method of eribulin intermediate, and particularly relates to preparation of eribulin key intermediate ERB-2, ERB and a compound P1; hydroxyl in a compound ERB-6 is firstly protected by MMTr in the process of preparing the compound ERB-2, a hydroxyl protecting group Pv is introduced in advance in the process of synthesizing a B fragment, and finally, the MMTr is removed by adopting amberlyst-15 acidic ion exchange resin to obtain the compound ERB-2, wherein the reaction route is novel, and the reaction efficiency is obviously improved; the proper amount of Mn powder is creatively added into the reaction system in the process of preparing the compound P1, and Cr is used in combination 3+ And a ligand N or M and 1, 8-bis-dimethylamino naphthalene, can obviously reduce the usage amount of a chromium reagent, simultaneously improve the reaction yield, and is particularly suitable for industrial application.)

1. A preparation method of a compound ERB2, which is characterized by comprising the following steps:

(1) by protecting the compound ERB-6 with a hydroxy protecting group R₁Protection, conversion to the compound ERB-5 a;

(2) selectively removing TBDPS from the compound ERB-5a and converting the TBDPS into a compound ERB-4 a;

(3) selectively removing the hydroxyl protecting group Pv from the compound ERB-4a to convert into a compound ERB-3 a;

(4) selective removal of the hydroxy-protecting group R from the compound ERB-3a₁And converted into the compound ERB-2.

2. The method of claim 1,

the reaction in the step (1) is carried out in pyridine;

taking THF as a solvent, and selectively removing TBDPS through TBA catalysis;

the reaction in the step (3) is carried out under the condition of pivaloyl chloride/DMAP;

removing a hydroxyl protecting group MMTr in the structure of the compound ERB-3a by using amberlyst-15 acidic ion exchange resin; wherein the weight ratio of amberlyst-15 acidic ion exchange resin to ERB-3a is 1: 0.8-1.2.

3. A preparation method of eribulin intermediate P1 is characterized by comprising the following steps,

(1) the preparation of ERB-2 by the process according to any one of claims 1 to 2,

(2) preparing ERB-1 by carrying out oxidation reaction on a compound ERB-2:

(3) reacting ERB-1 with ERP to obtain compound ERB:

(4) ERB was reacted with compound a via NHK to prepare compound P1:

4. the method according to claim 3, wherein the oxidizing agent used in the oxidation reaction in step (2) is Dess-Martin reagent or Swern reagent; the following ligand A or ligand B is used in the reaction process of the step (3):

preferably, the ligand A or B, cobalt phthalocyanine and Cr are added into the reaction system in the step (3)³⁺1, 8-bis-dimethylamino naphthalene, cobalt phthalocyanine, manganese powder and zirconocene dichloride, the Cr³⁺But is selected from CrCl₃Or CrBr₃Wherein the molar ratio of ERB-1 to manganese powder is 1: 0.8-1.2, the molar ratio of ERB-1 to ligand A or B is 1: 0.1-0.2, and ERB-1 and Cr are³⁺The molar ratio of (A) to (B) is 1: 0.1-0.2.

5. The method of claim 3, wherein the ERB in step (4) is converted to compound P1 by stirring with compound A in the presence of Mn powder and a chromium compound.

6. The method of claim 4, wherein the chromium reagent of step (4) is CrCl₃Or CrCl₂。

7. The method according to claim 3, wherein the molar ratio of the compound A to the chromium reagent in the step (4) is 1: 0.5-1.5, and the molar ratio of the compound A to the manganese powder is 1: 1-3.

8. The method according to claim 3, characterized in that a ligand M or N is added into the reaction system in the step (4), wherein the molar ratio of the compound A to the ligand M or N is 1: 1-5;

9. the method according to claim 3, characterized in that ligand N is added to the reaction system in the step (4), wherein the molar ratio of the compound A to the ligand N is 1: 1-2;

10. a method for preparing eribulin, comprising the step of preparing compound ERB-2 according to any one of claims 1 to 2, or preparing compound P1 according to any one of claims 3 to 4; and a step of preparing eribulin via compound ERB-2, or compound P1.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of an eribulin intermediate.

Background

Halichondrin b (halichondrin b), a polyether macrolactone compound containing only C, H, O atoms and isolated from Halichondria okadai by japanese scientists Hirata and Uemura in 1986, has a very strong in vitro anti-tumor activity. The molecular structure of halichondrin B is very complex, and contains 32 chiral centers, more than 40 hundred million isomers, and the synthesis difficulty is very large. Eribulin is a derivative of halichondrin B, is a tubulin inhibitor, and WO9965894 discloses the structure and synthesis method of eribulin for the first time. On 11/15/2010, eribulin mesylate (Halaven) injection was FDA approved for the treatment of metastatic breast cancer patients who had received at least two chemotherapy regimens.

The eribulin molecular structure contains 19 chiral centers, the synthesis is very difficult, and the compound ERB and the compound P1 are important intermediates for synthesizing eribulin.

Phillips et al disclose a preparation method of ERB, which requires a chiral ruthenium reagent and diazomethane during the reaction, and has problems of high cost and safety risk, ERB is prepared from compound 19 through five-step reaction with a total yield of only 37.6%, wherein the yield of compound 21 prepared from compound 20 is only 52% (d.r. ═ 6:1) (see angelw.chem.ind.ed., 2009,48, 2346-;

WO9317690A1 discloses a preparation method of ERB, ketone phosphate iodide and NaH are required to be used in the reaction process, the reaction is strictly carried out under anhydrous conditions, the reaction conditions are harsh, the NaH used is easy to explode, and great potential safety hazards exist during large-scale production. And CuH [ P (C) needed in the final reduction reaction process₆H₆)₃]₆Without conventional suppliers, the cost is high.

Chinese patent CN1216051C discloses splicing fragment A protected by MPM (methoxyphenylthio methyl) at the 35-position carbon with fragment B and then with fragment C.

In the above process, after the fragments A and B are spliced, a C27 diastereomer mixture is obtained in a ratio of about 3:1, and the mixture is purified by separation for a plurality of times, and the yield of the splicing reaction of the fragments A and B is only 33.6% based on the fragment B. And the fragment B is long in preparation route, the leaving MPM group is spliced with the fragment C, and the leaving MPM group needs to be converted for many times, so that the steps are complicated, and the yield is low.

Chinese patent CN104876896A discloses splicing fragment A with phenylsulfonyl-protected carbon at 35 position with fragment B and then with fragment C.

In the method, when the fragments A and B are spliced, 3.55 equivalents of chiral ligand and 3.55 equivalents of CrCl are required to be added₂The yield of the splicing reaction is 59.2% based on the fragment B, and then the fragment C is spliced, so that the total yield of the prepared eribulin is still low, a large amount of chromium reagents are required in the reaction process, the purification method is complicated, the fragment B needs multi-step reaction, the reaction route is long, the total yield is low, the selectivity of the chiral center in the reaction process is low, and the method is not suitable for industrial production.

There remains a need in the art to develop new methods to optimize the preparation of eribulin intermediates.

Disclosure of Invention

Aiming at the defects of the preparation of eribulin and intermediate ERB and P1 thereof in the prior art, the invention provides a brand-new preparation method of ERB-2 and eribulin intermediate P1.

Firstly, the invention provides a preparation method of a compound ERB2, which is characterized by comprising the following steps:

(1) by protecting the compound ERB-6 with a hydroxy protecting group R₁Protection, conversion to the compound ERB-5 a;

(2) selectively removing TBDPS from the compound ERB-5a and converting the TBDPS into a compound ERB-4 a;

(3) selectively removing the hydroxyl protecting group Pv from the compound ERB-4a to convert into a compound ERB-3 a;

(4) selective removal of the hydroxy-protecting group R from the compound ERB-3a₁To the compound ERB-2;

preferably, the step (1) reaction is carried out in pyridine;

taking THF as a solvent, and selectively removing TBDPS through TBA catalysis;

the reaction in the step (3) is carried out under the condition of pivaloyl chloride/DMAP;

removing a hydroxyl protecting group MMTr in the structure of the compound ERB-3a by using amberlyst-15 acidic ion exchange resin; wherein the weight ratio of amberlyst-15 acidic ion exchange resin to ERB-3a is 1: 0.8-1.2, and the preferable reaction solvent is MeOH, DCM, isopropanol or the mixture thereof.

Step (2) dissolving ERB-5a in a suitable solvent (preferably anhydrous tetrahydrofuran), adding tetrabutylammonium fluoride under stirring at room temperature and under a nitrogen atmosphere, and reacting. After the reaction is finished, adding l of saturated ammonium chloride aqueous solution, and extracting with methyl tert-ether; separating the organic phase to obtain ERB-4 a;

dissolving ERB-4a and DMAP in dichloromethane, cooling the reaction system to 0-5 ℃ by ice water, dropwise adding pivaloyl chloride into the system, recovering to room temperature after dropwise adding, and stirring; after the reaction is finished, dichloromethane and sodium bicarbonate aqueous solution are added, organic phase is washed by saline solution after liquid separation, and ERB-3a is obtained by column chromatography after concentration.

And (4) dissolving ERB-3a in a suitable solvent (such as THF or dichloromethane), cooling to-5 ℃, dropwise adding amberlyst-15 acidic ion exchange resin into the solution while stirring, finishing the reaction, filtering, separating to obtain ERB-2, filtering, recovering the activated ionic resin, and recycling.

On the other hand, the invention also provides a preparation method of eribulin intermediate P1, which comprises the following steps,

(1) the compound ERB-2 is prepared by the method of the invention,

(2) preparing ERB-1 by carrying out oxidation reaction on a compound ERB-2:

(3) reacting ERB-1 with ERP to obtain compound ERB:

(4) ERB was reacted with compound a via NHK to prepare compound P1:

in the above method for preparing compound P1, preferably, the oxidizing agent used in the oxidation reaction in step (2) is Dess-Martin reagent or Swern reagent; for example, ERB-2 is dissolved in dichloromethane, cooled to-5 ℃ to 5 ℃, Dess-Martin reagent is added into the dichloromethane in batches under stirring, after the reaction is finished, saturated sodium thiosulfate aqueous solution is added, an organic phase is separated, and the compound ERB-1 is obtained after purification;

further preferably, the ligand A or B, cobalt phthalocyanine and Cr are added into the reaction system in the step (3)³⁺1, 8-bis-dimethylamino naphthalene, cobalt manganese phthalocyanine powder and zirconocene dichloride, the Cr³⁺But is selected from CrCl₃Or CrBr₃Wherein the molar ratio of ERB-1 to manganese powder is 1: 0.8-1.2, the molar ratio of ERB-1 to ligand A or B is 1: 0.1-0.2, and ERB-1 and Cr are³⁺The molar ratio of (A) to (B) is 1: 0.1-0.2.

More preferably, in the above reaction, the ligand and cobalt phthalocyanine are added into a reaction bottle, 1, 8-bis-dimethylamino naphthalene and anhydrous chromium chloride) and anhydrous ethylene glycol dimethyl ether are added into the reaction bottle, the reaction mixture is stirred in a glove box and reacts at room temperature, then anhydrous lithium chloride, manganese powder and zirconocene dichloride are added, finally ERB-1 and ERP are added, the reactant is stirred in the glove box and reacts at 20-25 ℃, after the reaction is finished, diatomite is added into the reaction mixture, stirred and filtered, and the solid is washed by ethyl acetate, separated and purified to obtain ERB.

The selectivity of the above process for the new chiral center is very high, for example, up to a d.r. ═ 8:1, preferably a d.r. ═ 20: 1 and above, more preferably, 30:1 and above, and most preferably, 50:1 and above, while satisfying a significant increase in reaction yield.

Preferably, step (4) converts ERB and compound a into compound P1 by stirring in the presence of Mn powder and chromium compound; the chromium reagent is CrCl₃Or CrCl₂Preferably, the molar ratio of the compound A to the chromium reagent is 1: 0.5-1.5, the molar ratio of the compound A to the manganese powder is 1: 1-3, and preferably, a ligand M or N is required to be added into the reaction system, wherein the molar ratio of the compound A to the ligand M or N is 1: 1-5, and preferably, the molar ratio of the compound A to the ligand N is 1: 1-2;

in the method, the dosage of the chromium reagent can be obviously reduced and the reaction yield can be improved by adding the Mn powder, optimizing the charge ratio of the reaction substrate, the reaction reagent and the like. In a third aspect of the invention, there is provided a process for the preparation of eribulin, comprising the step of preparing compound ERB-2 by the aforementioned process of the invention, or preparing compound P1; and a step of preparing eribulin via compound ERB-2, or compound P1. Specific abbreviations and acronyms are used herein. The definitions of these abbreviations and abbreviations are listed below:

MMTr is p-methoxyphenyl diphenylmethyl;

pv: pivaloyl group;

TBDPS: tert-butyl diphenyl silyl;

tBu: a tertiary butyl group;

DCM: dichloromethane;

DMAP: 4-dimethylaminopyridine;

TBAF: tetrabutylammonium fluoride;

THF: tetrahydrofuran.

The invention provides a brand new method for preparing compounds ERB-2, ERB and an intermediate P1, and through a large amount of experimental research and strategic experimental design, the inventor unexpectedly discovers that hydroxyl in a compound ERB-6 is firstly protected by MMTr, then TBA is adopted to selectively remove TBDPS, and then the hydroxyl reacts with pivaloyl chloride/DMAP to obtain a compound ERB-3a with OH protected by Pv, and finally Ambelyst-15 acidic ion exchange resin is adopted to remove MMTr to obtain a compound ERB-2, the reaction route is novel, the reaction efficiency is remarkably improved, particularly, the reaction yield can be remarkably improved by removing MMTr by the Ambelyst-15 acidic ion exchange resin, the post-treatment step is simplified, and the Ambelyst-15 acidic ion exchange resin recovered by filtration after the reaction is finished can be recycled after being activated; in addition, the inventor finds that the specificity of the amberlyst-15 acidic ion exchange resin for removing a hydroxyl protecting group MMTr in the structure of the compound ERB-3a is very high, and the effect is optimal when the molar using amount ratio of the amberlyst-15 acidic ion exchange resin to the ERB-3a is 1: 0.8-1.2.

The preparation of ERB from ERB-2 of the present invention includes screening proper reaction strips with substrate, such as the reaction of ERB-1 with iodized olefine, using Mn powder as asymmetric catalyst and adding ligand A or B, cobalt phthalocyanine and Cr to the reaction system³⁺Compared with the prior art which adopts Ni/Cr-mediated asymmetric synthesis, the method has the advantages that the selectivity of the chiral center of the reaction is higher, and the reaction yield and the purity are obviously improved; the selective production of the diastereoisomerically pure chiral compound ERB is different from the prior art which generally teaches the final step of Pv protection of the side chain hydroxyl groups.

Secondly, when the compound A and the ERB are reacted to prepare the intermediate P1, the proper amount of Mn powder is creatively added into the reaction system, and Cr is used in combination³⁺And the ligand N or M and the 1, 8-bis-dimethylamino-naphthalene can obviously reduce the usage amount of the chromium reagent and improve the reaction yield, for example, the usage amount of the chromium reagent in the method can be reduced to 0.5-1.5 equivalentThe beneficial effect in industrial mass production is more obvious; in addition, the yield can be improved to the maximum extent by selecting proper Mn input amount and ligand dosage. Through a large number of experimental researches, the addition and the dosage of Mn in the reaction process have great influence on the dosage of a chromium reagent, the dosage of a ligand and the reaction effect; the use amount of Mn is too much, so that the reaction yield cannot be improved, side effects such as cost increase and the like are caused, and the use amount of Mn is too little, so that the reaction yield is low, and the utilization rate of a chromium reagent is low; and when the molar ratio of the compound A to the chromium reagent is 1: 0.5-1.5 and the molar ratio of the compound A to the manganese powder is 1: 1-3, the reaction effect is optimal.

The specific implementation mode is as follows:

the present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.

Example 1: preparation of compound ERB-5a

ERB-6(5 g, 11.4 mmol) was dissolved in 50 ml of dried pyridine, and 4-methoxytriphenylchloromethane (4.58 g, 14.8 mmol) was added with stirring. After the addition, the reaction mixture was stirred at room temperature for 17 hours. After TLC detection reaction is completed, 20 ml of ethanol is added to quench reaction, after solvent is removed by rotary evaporation, the crude product is dispersed in 40 ml of saturated sodium bicarbonate aqueous solution and 100 ml of dichloromethane, and then the crude product is subjected to standing, liquid separation, organic phase drying and concentration and column chromatography to obtain 7.62 g of product ERB-5a with the yield of 94%.

Example 2: preparation of compound ERB-4a

ERB-5a (6 g, 8.44 mmol) was dissolved in 50 ml of anhydrous tetrahydrofuran, tetrabutylammonium fluoride (1M in THF, 11 ml, 11 mmol) was added with stirring at room temperature under nitrogen atmosphere, and the reaction was continued for 16 hours. After TLC detection reaction, adding 50 ml of saturated ammonium chloride aqueous solution, and then extracting with methyl tert-ether; the organic phases were combined, dried, concentrated and purified by column chromatography to give 3.82g of ERB-4a with a yield of 96%.

Example 3: preparation of compound ERB-3a

ERB-4a (3 g, 6.35 mmol) and DMAP (44.4 mmol) were dissolved in 40 ml of dichloromethane, the reaction system was cooled to 0 to 5 ℃ with ice water, and pivaloyl chloride (4.98 g, 41.27 mmol) was added dropwise to the system. After the dropwise addition, the temperature is recovered to the room temperature, and the mixture is stirred; after completion of the TLC detection reaction, dichloromethane and an aqueous solution of sodium hydrogencarbonate were added, and the organic phase after separation was washed with brine again, concentrated and subjected to column chromatography to give 3.25 g of ERB-3a in 92% yield.

Example 3: preparation of compound ERB-2

ERB-3a (2.5 g, 4.49 mmol) was dissolved in 20 ml of dichloromethane, cooled to 0 ℃, to which was added 2.5 g amberlyst-15 acidic ion exchange resin in three portions with stirring, after the TLC detection reaction was completed, the ionic resin was filtered off and the solid was washed with methanol, the organic phase was collected, spun-dried, and column chromatography gave 1.24 g ERB-2 in 98% yield, HPLC: not less than 99 percent.

Example 4: preparation of compound ERB-1

ERB-2(0.95 g, 3.35 mmol) was dissolved in 15 ml of dichloromethane, and Dess-Martin reagent (2.84 g, 6.70 mmol) was added thereto in portions with stirring at a temperature of 0 ℃ to detect the completion of the reaction by TLC, 10 ml of saturated aqueous sodium thiosulfate solution was added, the organic phase was dried by rotary evaporation of the solvent after separation, and 0.91 g of ERB-1 was obtained by column chromatography in a yield of 96%.

Example 5: preparation of compound ERB

Ligand a (0.50 g, 0.50 mmol) and cobalt phthalocyanine (4.5 mg, 0.008 mmol) were weighed and charged into a reaction flask, which was moved into a glove box, to which 1, 8-bisdimethylaminonaphthalene (106 mg, 0.45 mmol), anhydrous chromium chloride (56 mg, 0.45 mmol) and anhydrous ethylene glycol dimethyl ether (5 ml) were added. The reaction mixture was stirred in a glove box for 1 hour, 23 ℃. Then anhydrous lithium chloride (128 mg, 3.01 mmol), manganese powder (165 mg, 3.01 mmol) and zirconocene dichloride (0.88g, 3.01 mmol) were added. Finally, a solution of ERB-1(0.85 g, 3.01 mmol) and ERP (1.45 g, 4.52 mmol) in 5 ml of anhydrous ethylene glycol dimethyl ether was added. The reactants were stirred in a glove box for 30 hours at 20-25 ℃. TLC showed the end of the reaction, to which was added 1 g of celite, stirred, filtered, and the solid was washed with ethyl acetate. The collected organic solution was concentrated and subjected to column chromatography to give 1.28 g of ERB in 95% yield, HPLC: more than or equal to 98 percent.

Wherein, the ligand A has the following structure:

example 6: preparation of compound ERB

Ligand B (0.22 g, 0.42 mmol) and cobalt phthalocyanine (3.8 mg, 0.007 mmol) were weighed and loaded into a reaction flask, which was moved into a glove box, to which was added 1, 8-bisdimethylaminonaphthalene (89 mg, 0.42 mmol), anhydrous chromium chloride (47 mg, 0.38 mmol) and anhydrous ethylene glycol dimethyl ether (5 ml). The reaction mixture was stirred in a glove box for 1 hour, 23 ℃. Then anhydrous lithium chloride (107 mg, 2.53 mmol), manganese powder (139 mg, 2.53 mmol) and zirconocene dichloride (0.74g, 2.53 mmol) were added. Finally, a solution of ERB-1(0.71 g, 2.53 mmol) and ERP (1.22 g, 3.80 mmol) in 5 ml of anhydrous ethylene glycol dimethyl ether was added. The reactants were stirred in a glove box for 30 hours at 20-25 ℃. TLC showed the end of the reaction, to which was added 1 g of celite, stirred, filtered, and the solid was washed with ethyl acetate. The collected organic solution was concentrated and subjected to column chromatography to give 1.02 g of ERB in 93.8% yield, HPLC: more than or equal to 97 percent.

Example 7: preparation of Compound P1

Wherein, the ligand N has the structure as follows:

ligand N (0.958 g, 3.57 mmol) and 1, 8-bisdimethylamino (0.765 g, 3.57 mmol) were dissolved in 10 ml acetonitrile under nitrogen protection. Reaction vial glove box was transferred into a glove box, to which chromium trichloride (0.376 g, 2.38 mmol) was added. After the reaction mixture was stirred under nitrogen for 1 hour, lithium chloride (0.20 g, 4.76 mmol), manganese powder (0.261 g, 4.76 mmol) and zirconocene dichloride (0.696 g, 2.38 mmol) were added thereto, followed by a solution of compound a (1.43g, 2.38 mmol) and compound ERB (1.37 g, 2.86 mmol) in 5 ml acetonitrile. The reaction mixture was stirred under nitrogen for 24 hours at 20-25 ℃. TLC showed the end of the reaction, to which was added 2g of celite, stirred, filtered, and the solid was washed with ethyl acetate. The collected organic solution was concentrated and subjected to column chromatography to give 2.06 g of P1 in 95.7% yield, HPLC: not less than 96 percent and d.r. not less than 55: 1.

Examples 8 to 12: preparation method of compound P1

With reference to the preparation of example 7, the following feeds were made in the following manner, the yields and purities being as follows:

examples

Compound A

Compound ERB

Mn

CrCl3

Ligand N

Ligand M

Yield of

HPLC

8

1eq

1eq

1.5eq

1eq

1eq

91.4％

95％

9

1eq

1.1eq

1.8eq

2eq

2eq

93.1％

93％

10

1eq

1.2eq

3eq

0.5qe

3qe

93.5％

94％

11

1eq

1.5eq

1eq

1.5eq

4eq

1.1％

93％

12

1eq

1eq

3eq

1.5eq

5eq

91.3％

90％

Comparative example 1: preparation of compound ERB:

referring to the similar methods of the above examples 5 to 6, ERB is prepared by substituting the ligand A or B with the ligand C, the ligand D and the ligand E, and the experimental result shows that the compound ERB prepared by using the ligands A and B has the best effect, and the ligand C is used secondly, but the preparation method of the ligand C is complex, so that the acquisition cost is higher than that of the ligands A and B in the industrial production and application process; the yields and HPLC purities of the target products were lower than those of examples 5 and 6 using ligands D and E, where the HPLC of ERB, the target product prepared using ligands D and E, was about 80%.