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CN-118084733-B - Preparation method of key intermediate for synthesizing tubulin inhibitor

CN118084733BCN 118084733 BCN118084733 BCN 118084733BCN-118084733-B

Abstract

The invention relates to a preparation method of a key intermediate for synthesizing a tubulin inhibitor, which overcomes the defects of long steps, low yield, low ee value and the like in the prior art, and the invention can prepare a target product only through reductive amination, upper protection, resolution and freeness, thereby having high reaction yield, improved ee value and unexpected technical effects. The synthesis method provided by the invention has mild reaction conditions, and the operation method is simple and convenient, so that the method is suitable for not only small-scale preparation in a laboratory, but also industrialized mass production.

Inventors

  • GAO QIANGQIANG
  • CHEN XI
  • WANG LEI
  • GUO WEI
  • ZHOU ZHIGUO
  • CHEN YONGGANG
  • GAO QIANG
  • ZHENG BAOFU

Assignees

  • 重庆皓元生物制药有限公司

Dates

Publication Date
20260512
Application Date
20240308

Claims (20)

  1. 1. A process for the preparation of compound 5 comprising the steps of: step 1, carrying out reductive amination reaction on a compound 1 in the presence of alkali and a reducing agent to obtain a compound 2, wherein the reducing agent is 2-picoline borane; Step 2, in a solvent, carrying out amino protection reaction on the compound 2 and organic carbonate in the presence of alkali to obtain a compound 3; Step 3, in a solvent, carrying out resolution reaction on the compound 3 and NH 2 -resolution base in the following formula to obtain a compound 4; Step 4, carrying out free reaction of the compound 4 in the presence of acid to obtain a compound 5; Wherein, the R is H; the alkali in the step 1 is methylamine; The solvent in the step 2 is a combination of an organic solvent and water, wherein the organic solvent is one or more selected from tertiary butanol, tetrahydrofuran and 1, 4-dioxane; The alkali in the step 2 is selected from one of potassium carbonate, sodium bicarbonate and potassium bicarbonate; In the step 3, the solvent is petroleum ether, the NH 2 -resolution base is (S) - (-) -alpha-methylbenzylamine, and the molar ratio of the compound 3 to the NH 2 -resolution base is 1 (1-2).
  2. 2. The method of claim 1, wherein the reaction of step 1 satisfies one or more of the following conditions: (1) The molar ratio of the compound 1 to the methylamine is 1 (1-7); (2) The reaction temperature of the reductive amination reaction in the step1 is room temperature; (3) The reaction time of the reductive amination reaction in the step 1 is 40-65 h, and (4) The solvent of the reaction in the step 1 is an ether solvent, and the ether solvent is one or more selected from ethylene glycol dimethyl ether, 1, 4-dioxane and tetrahydrofuran.
  3. 3. The method according to claim 1, wherein the molar ratio of the compound 1 to methylamine is 1 (2-6).
  4. 4. The process of claim 1, wherein the molar ratio of compound 1 to methylamine is 1:6.
  5. 5. The process of claim 1, wherein the methylamine is added as a methylamine alcohol solution.
  6. 6. The method according to claim 5, wherein the methylamine alcohol solution is a methylamine methanol solution or a methylamine ethanol solution.
  7. 7. The method of claim 1, wherein the molar ratio of the compound 1 to the reducing agent is 1 (1-2).
  8. 8. The method according to claim 1, wherein the molar ratio of the compound 1 to the reducing agent is 1 (1-1.5).
  9. 9. The process according to claim 1, wherein the molar ratio of compound 1 to reducing agent is 1:1.1.
  10. 10. The process according to claim 1, wherein the reductive amination reaction of step 1 takes place for a reaction time of 60 hours.
  11. 11. The process of claim 1, wherein the solvent for the reaction of step 1 is tetrahydrofuran.
  12. 12. The method of claim 1, wherein the reaction of step 2 satisfies one or more of the following conditions: (1) The solvent is a combination of tertiary butanol and water, wherein the volume ratio of the tertiary butanol to the water is 1 (0.5-1.5); (2) The alkali is potassium carbonate; (3) The organic carbonic ester in the step 2 is di-tert-butyl dicarbonate; (4) The reaction temperature of the step 2 reaction is room temperature, and (5) Reaction of step 2 reaction the time is 24-45 h.
  13. 13. The preparation method of the water-based paint, according to claim 1, wherein the solvent is a combination of tertiary butanol and water, and the volume ratio of the tertiary butanol to the water is 1 (0.5-1.5).
  14. 14. The method of claim 1, wherein the solvent is a combination of t-butanol and water, and wherein the volume ratio of t-butanol to water is 1:1.
  15. 15. The method according to claim 1, wherein the molar ratio of the compound 2 to the base is 1 (1-5).
  16. 16. The process of claim 1, wherein the molar ratio of compound 2 to base is 1:3.
  17. 17. The process according to claim 12, wherein the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1: (1-3).
  18. 18. The process according to claim 12, wherein the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:2.
  19. 19. The method of claim 1, wherein the reaction time of the step 2 is 35 to 45 hours.
  20. 20. The process of claim 1, wherein the reaction time of step 2 is 40 hours.

Description

Preparation method of key intermediate for synthesizing tubulin inhibitor Technical Field The invention relates to a preparation method of a key intermediate for synthesizing a tubulin inhibitor, and belongs to the technical field of organic synthesis. Background Microtubules are heterodimers formed from alpha-tubulin and beta-tubulin, and are a long filamentous protein polymer. Microtubules are involved in many cellular processes critical to cell function, including trafficking of organelles and vesicles, cell migration, and mitosis, among others. Microtubule inhibitors act to disrupt microtubules, thereby inhibiting chromosome segregation during cell division. Taltobulin (CAS: 228266-40-8), which is a synthetic tripeptide cysteine analog, is an effective anti-microtubule agent (antimicrotubule) that circumvents P-glycoprotein-mediated resistance in vivo and in vitro. Inhibit the polymerization of purified tubulin, destroy microtubule tissue in cells, and induce mitotic arrest and apoptosis (apoptosis). The preparation Taltobulin also commonly used a key intermediate (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -3-methyl-3-phenylbutyric acid (CAS: 228266-38-4), and the patent WO2003082268A2 (same family CN 1633289A) discloses the synthesis method of the key intermediate as follows (11 steps in total), no specific operation is given, and vii is an optically pure product (enantiomerically pure) obtained after chiral resolution, but the ee value of the product is reduced to only 80% after the next step of methyl ester hydrolysis, the total yield is only 22%, and the product quality index obtained by the method is poor and can not meet the requirement of a drug index. Patent WO2004026814A2 (same family CN 1705639A) discloses a synthesis method of the key intermediate, which comprises 9 steps, wherein the total yield is only 14.6%, and the ee value is only 97.4%, and the method is long in step, extremely low in yield, poor in atomic economy and unfavorable for industrial scale-up. Document Molecular Diversity (2014), 18 (2), 357-373 discloses that the synthesis method of the key intermediate is as follows, the total yield of 8 steps is only 45%, the ee value is only 97.1%, the quality index is poor, in addition, naH is adopted as the reaction condition, so that the method has great potential safety hazard and is not suitable for industrial amplification. Therefore, designing and implementing a synthetic method which is suitable for industrial production, simple and safe to operate and has high yield and ee value becomes an important point for research and development of the technicians in the field. Disclosure of Invention The object of the present invention is to provide a process for the preparation of key intermediates for the synthesis of tubulin inhibitors, solving the above mentioned problems of the background art. In order to solve the above technical problems, a first aspect of the present invention provides a method for preparing a compound 5, comprising the steps of: Step1, carrying out reductive amination reaction on a compound 1 in the presence of alkali and a reducing agent to obtain a compound 2; Step 2, in a solvent, carrying out amino protection reaction on the compound 2 and organic carbonate in the presence of alkali to obtain a compound 3; Step 3, in a solvent, carrying out resolution reaction on the compound 3 and NH 2 -resolution base in the following formula to obtain a compound 4; Step 4, carrying out free reaction of the compound 4 in the presence of acid to obtain a compound 5; and R is selected from H, straight-chain alkyl with 1-4 carbon atoms and alkoxy with 1-4 carbon atoms. In a preferred embodiment, the base in step 1 is methylamine, preferably, the molar ratio of the compound 1 to methylamine is 1 (1-7), for example 1 (2-6), and further for example 1:6, and preferably, the methylamine is added in the form of a methylamine alcohol solution, and preferably, the methylamine alcohol solution may be a methylamine methanol solution or a methylamine ethanol solution. In a certain preferred embodiment, the reducing agent in step 1 is 2-picoline borane, and preferably, the molar ratio of the compound 1 to the reducing agent is 1 (1-2), for example 1 (1-1.5), and further for example 1:1.1. In a preferred embodiment, the reaction temperature of the reductive amination reaction of step 1 is room temperature. In a certain preferred scheme, the reaction time of the reductive amination reaction in the step 1 is 16-65h, preferably 40-65 h, for example 60h. In a preferred embodiment, the solvent used in the reaction in step 1 is an ether solvent, and the ether solvent may be one or more selected from ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran and methyltetrahydrofuran, for example tetrahydrofuran. In a certain preferred scheme, the preparation method of the step 1 comprises the steps of adding the compound 1 into a reaction bottle, adding an organic solvent under the protecti