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CN-121554459-B - Preparation method of zolmitriptan

CN121554459BCN 121554459 BCN121554459 BCN 121554459BCN-121554459-B

Abstract

The invention discloses a preparation method of zolmitriptan, which relates to the technical field of medicine synthesis and comprises the following steps of adding a compound 1 and a reagent 1 into a solvent 1 for a first reaction to obtain a compound 2, adding the compound 2, the reagent 2 and the reagent 3 into the solvent 2 for a second reaction to obtain a compound 3 and the like. Compared with the prior art, the invention provides a brand new synthetic route for preparing zolmitriptan, which takes L-4-bromophenylalanine as a starting material, and adopts a brand new synthetic procedure of constructing an oxazolidone structure in zolmitriptan by adopting a tertiary butanol metal salt, sodium hydride and other reagents 5, constructing an indole ring in zolmitriptan by adopting a coupling reaction and the like, thereby obviously improving the yield of the obtained target product, effectively avoiding the use of high-toxicity and high-risk reagents in the existing synthetic route, and providing a mild, high-efficiency and green synthetic route for preparing zolmitriptan.

Inventors

  • LI SHILIN
  • YANG YINGLANG
  • Shen Pi
  • WANG BO

Assignees

  • 成都天兴致远生物科技有限公司

Dates

Publication Date
20260508
Application Date
20260123

Claims (10)

  1. 1. A method for preparing zolmitriptan, comprising the steps of: adding the compound 1 and the reagent 1 into a solvent 1 to perform a first reaction to obtain a compound 2; adding the compound 2, the reagent 2 and the reagent 3 into a solvent 2 for a second reaction to obtain a compound 3; Adding the compound 3 and the reagent 4 into a solvent 3 for a third reaction to obtain a compound 4; Adding the compound 4 and the reagent 5 into a solvent 4 for a fourth reaction to obtain a compound 5; Adding the compound 5 into a solvent 5, and then adding a reagent 6, a reagent 7 and a reagent 8 for a fifth reaction to obtain a compound 6; Adding the compound 6 into a solvent 6, then adding a reagent 9 for a sixth reaction to obtain a compound 7, and then adding a reagent 10 into a reaction system for a seventh reaction to obtain the zolmitriptan; wherein, the structural formula of the compound 1 is as follows: ; the reagent 1 comprises at least one of thionyl chloride, concentrated sulfuric acid, hydrogen chloride and p-toluenesulfonic acid; the structural formula of the compound 2 is as follows: ; the reagent 2 is an amino protective agent, and the amino protective agent is di-tert-butyl dicarbonate; The reagent 3 comprises at least one of carbonate and organic base; the structural formula of the compound 3 is as follows: ; The reagent 4 comprises at least one of sodium borohydride, lithium aluminum hydride, borane dimethyl sulfide complex and borane tetrahydrofuran complex; the structural formula of the compound 4 is as follows: ; The reagent 5 comprises at least one of a tert-butanol metal salt and sodium hydride; The structural formula of the compound 5 is as follows: ; the structural formula of the reagent 6 is as follows: ; The reagent 7 comprises a copper salt; The reagent 8 comprises at least one of L-proline, 4-hydroxy-L-proline and picolinic acid; The structural formula of the compound 6 is as follows: ; the reagent 9 comprises at least one of trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid and scandium triflate; The structural formula of the compound 7 is as follows: ; The structural formula of the reagent 10 is as follows: ; The solvent 1 is methanol.
  2. 2. A process for the preparation of zolmitriptan according to claim 1 wherein the carbonate salt comprises at least one of sodium carbonate and sodium bicarbonate, the organic base comprises at least one of triethylamine and N, N-diisopropylethylamine, the t-butoxide metal salt comprises at least one of sodium t-butoxide and potassium t-butoxide, and the cuprous salt comprises cuprous iodide.
  3. 3. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the first reaction comprise that the molar ratio of the compound 1 to the reagent 1 is 1 (3-10), the temperature is 0-20 ℃ and the time is 1-10 hours; And/or the mass ratio of the compound 1 to the solvent 1 is 1 (3-20).
  4. 4. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the second reaction include that the molar ratio of the compound 2 to the reagent 2 is 1 (0.95-2.0), the molar ratio of the compound 2 to the reagent 3 is 1 (1.2-2.0), the temperature is 20-50 ℃ and the time is 1-10 hours; And/or the solvent 2 comprises at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1, 4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1 (3-10).
  5. 5. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the third reaction include that the molar ratio of the compound 3 to the reagent 4 is 1 (1.0-5.0), the temperature is 20-70 ℃ and the time is 1-10 hours; And/or the solvent 3 comprises at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1 (3-10).
  6. 6. The preparation method of zolmitriptan according to claim 1, wherein the fourth reaction condition parameters comprise that the molar ratio of the compound 4 to the reagent 5 is 1 (1.0-4.0), the temperature is 20-50 ℃ and the time is 1-10 hours; And/or the solvent 4 comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1, 4-dioxane, wherein the mass ratio of the compound 4 to the solvent 4 is 1 (3-20).
  7. 7. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the fifth reaction include that the molar ratio of the compound 5 to the reagent 6 is 1 (2.0-5.0), the molar ratio of the compound 5 to the reagent 7 is 1 (0.1-1.0), the molar ratio of the compound 5 to the reagent 8 is 1 (0.1-1.0), the temperature is 40-80 ℃ and the time is 10-20 hours; and/or the solvent 5 comprises at least one of dichloromethane, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tertiary butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1 (8-20).
  8. 8. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the sixth reaction include that the molar ratio of the compound 6 to the reagent 9 is 1 (5-20), the temperature is 20-50 ℃ and the time is 2-10 hours; And/or the solvent 6 comprises at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1 (3-15).
  9. 9. The method for preparing zolmitriptan according to claim 1, wherein the seventh reaction condition parameter comprises that the molar ratio of the compound 7 to the reagent 10 is 1 (0.9-2.0), the temperature is 65-100 ℃, and the time is 3-15 hours.
  10. 10. The preparation method of zolmitriptan according to claim 1, wherein the condition parameters of the first reaction comprise that the molar ratio of the compound 1 to the reagent 1 is 1 (4-5), the temperature is 0-20 ℃ and the time is 6-8 hours; The mass ratio of the compound 1 to the solvent 1 is 1 (5-10); The second reaction condition parameters comprise that the molar ratio of the compound 2 to the reagent 2 is 1 (1.0-1.2), the molar ratio of the compound 2 to the reagent 3 is 1 (1.2-2.0), the temperature is 20-30 ℃ and the time is 2-4 hours; The solvent 2 comprises at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1, 4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1 (5-7); the condition parameters of the third reaction comprise that the molar ratio of the compound 3 to the reagent 4 is 1 (1.0-2.0), the temperature is 45-55 ℃ and the time is 2-3 hours; The solvent 3 comprises at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1 (4-6); the fourth reaction condition parameters comprise that the molar ratio of the compound 4 to the reagent 5 is 1 (1.5-2.0), the temperature is 20-40 ℃ and the time is 2-4 hours; the solvent 4 comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1, 4-dioxane, and the mass ratio of the compound 4 to the solvent 4 is 1 (6-8); The condition parameters of the fifth reaction comprise that the molar ratio of the compound 5 to the reagent 6 is 1 (2.0-3.0), the molar ratio of the compound 5 to the reagent 7 is 1 (0.1-0.2), the molar ratio of the compound 5 to the reagent 8 is 1 (0.1-0.2), the temperature is 50-60 ℃, and the time is 10-20 hours; the solvent 5 comprises at least one of dichloromethane, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tertiary butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1 (10-12); the condition parameters of the sixth reaction comprise that the molar ratio of the compound 6 to the reagent 9 is 1 (8-10), the temperature is 20-40 ℃ and the time is 4-6 hours; The solvent 6 comprises at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1 (6-8); The seventh reaction condition parameters comprise that the molar ratio of the compound 7 to the reagent 10 is 1 (0.9-1.5), the temperature is 80-100 ℃ and the time is 6-9 hours.

Description

Preparation method of zolmitriptan Technical Field The invention relates to the technical field of medicine synthesis, in particular to a preparation method of zolmitriptan. Background Zolmitriptan, developed by the company glaucomatous Wikang, england, is a highly selective 5-HT1B/1D receptor agonist for the treatment of acute attacks of various migraine, and has the action mechanism that the 5-HT1B/1D receptor of the intracranial vascular system is directly stimulated, so that abnormal expansion of the brain and the dura mater is contracted, and the zolmitriptan can act on the nucleus caudal side of trigeminal nerve cells and synapses of trigeminal nerves to inhibit release of inflammatory neurotransmitters. Wherein, the chemical structural formula of the zolmitriptan is shown as follows: 。 At present, a plurality of patents and documents at home and abroad report on a synthesis method of zolmitriptan. The synthesis routes of the prior zolmitriptan are more, and the synthesis route adopted in the prior art 1 is shown in figure 1. However, the above-mentioned existing synthetic route of zolmitriptan has defects such as low yield and purity of the product, and involving the use of highly toxic and high-risk reagents such as highly toxic phosgene (or triphosgene) and heavy metal reagent stannous chloride, etc., and needs to be further improved. Disclosure of Invention In order to solve the problems, the invention provides a preparation method of zolmitriptan. The invention provides a preparation method of zolmitriptan, which comprises the following steps: adding the compound 1 and the reagent 1 into a solvent 1 to perform a first reaction to obtain a compound 2; adding the compound 2, the reagent 2 and the reagent 3 into a solvent 2 for a second reaction to obtain a compound 3; Adding the compound 3 and the reagent 4 into a solvent 3 for a third reaction to obtain a compound 4; Adding the compound 4 and the reagent 5 into a solvent 4 for a fourth reaction to obtain a compound 5; Adding the compound 5 into a solvent 5, and then adding a reagent 6, a reagent 7 and a reagent 8 for a fifth reaction to obtain a compound 6; Adding the compound 6 into a solvent 6, then adding a reagent 9 for a sixth reaction to obtain a compound 7, and then adding a reagent 10 into a reaction system for a seventh reaction to obtain the zolmitriptan; wherein, the structural formula of the compound 1 is as follows: ; the reagent 1 comprises at least one of thionyl chloride, concentrated sulfuric acid, hydrogen chloride and p-toluenesulfonic acid; the structural formula of the compound 2 is as follows: ; the reagent 2 is an amino protective agent; The reagent 3 comprises at least one of carbonate and organic base; the structural formula of the compound 3 is as follows: ; The reagent 4 comprises at least one of sodium borohydride, lithium aluminum hydride, borane dimethyl sulfide complex and borane tetrahydrofuran complex; the structural formula of the compound 4 is as follows: ; The reagent 5 comprises at least one of a tert-butanol metal salt and sodium hydride; The structural formula of the compound 5 is as follows: ; the structural formula of the reagent 6 is as follows: ; The reagent 7 comprises a copper salt; The reagent 8 comprises at least one of L-proline, 4-hydroxy-L-proline and picolinic acid; The structural formula of the compound 6 is as follows: ; the reagent 9 comprises at least one of trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid and scandium triflate; The structural formula of the compound 7 is as follows: ; The structural formula of the reagent 10 is as follows: 。 Further, the amino protecting agent includes di-tert-butyl dicarbonate, the carbonate includes at least one of sodium carbonate and sodium bicarbonate, the organic base includes at least one of triethylamine and N, N-diisopropylethylamine, the tert-butanol metal salt includes at least one of sodium tert-butoxide and potassium tert-butoxide, and the cuprous salt includes cuprous iodide. Further, the condition parameters of the first reaction comprise that the molar ratio of the compound 1 to the reagent 1 is 1 (3-10), the temperature is 0-20 ℃ and the time is 1-10 hours; And/or the solvent 1 comprises an alcohol solvent, wherein the alcohol solvent comprises at least one of methanol and ethanol, and the mass ratio of the compound 1 to the solvent 1 is 1 (3-20). Further, the condition parameters of the second reaction comprise that the molar ratio of the compound 2 to the reagent 2 is 1 (0.95-2.0), the molar ratio of the compound 2 to the reagent 3 is 1 (1.2-2.0), the temperature is 20-50 ℃ and the time is 1-10 hours; And/or the solvent 2 comprises at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1, 4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1 (3-10). Further, the condition parameters of the third reaction comprise that the molar ratio of the compound 3 to the reagent 4 is 1 (1.0-5.0), the temperatur