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CN-121990963-A - Synthesis method of (S) - (-) -1- (4-methoxybenzene) ethylamine and intermediate compound thereof

CN121990963ACN 121990963 ACN121990963 ACN 121990963ACN-121990963-A

Abstract

The invention discloses a synthesis method of (S) - (-) -1- (4-methoxyphenyl) ethylamine and an intermediate compound thereof, belonging to the technical field of synthesis of medical intermediates. The method takes p-methoxy acetophenone as an initial raw material, chiral alcohol mixture is obtained through asymmetric reduction, then the chiral alcohol mixture is condensed with N-p-toluenesulfonyl-L-proline, an intermediate compound (R) -3A is enriched through recrystallization, and further (R) -3A is subjected to alkaline hydrolysis, azide and reduction reaction to obtain (S) - (-) -1- (4-methoxy phenyl) ethylamine. The preparation of the high optical purity (S) - (-) -1- (4-methoxyphenyl) ethylamine is realized through a chiral introduction-configuration enrichment-functional group conversion strategy, the chiral purity of the product is more than 99%, the custom high-valence catalyst is replaced by a conventional commercial reagent, and the key intermediate is recyclable, simple and convenient to operate, controllable in cost, environment-friendly and suitable for industrial mass production.

Inventors

  • ZHANG ZHONGJIAN
  • LIU XIANJUN
  • ZHOU HAIBING
  • YU FEIFEI
  • Zhou Qiansujia
  • ZHENG XINGXING

Assignees

  • 沙普利斯医药(苏州)有限公司

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. A synthesis method of a compound (R) -3A is characterized in that p-methoxyacetophenone is reduced to obtain a mixture of (R) -2A and (S) -2B, and the mixture of (R) -2A and (S) -2B is subjected to condensation reaction with a compound 1 to obtain the compound (R) -3A, wherein the synthesis route is as follows: 。
  2. 2. The method for synthesizing the compound (R) -3A according to claim 1, wherein in the step of synthesizing the mixture of (R) -2A and (S) -2B from the p-methoxyacetophenone, the reducing agent is borane dimethyl sulfide or borane tetrahydrofuran, the catalyst comprises a chiral catalyst and a cocatalyst, the chiral catalyst is R- (+) -diphenyl prolinol, the cocatalyst is trimethyl borate or triethyl borate, and the reaction solvent is one of toluene, tetrahydrofuran or dichloromethane.
  3. 3. The method for synthesizing the compound (R) -3A according to claim 2, wherein the molar ratio of the p-methoxyacetophenone to the chiral catalyst to the cocatalyst to the reducing agent is 1:0.03-0.04:0.04-0.05:0.8-0.9.
  4. 4. The method for synthesizing the compound (R) -3A according to claim 1, wherein in the step of synthesizing the compound (R) -3A from a mixture of (R) -2A and (S) -2B, the activator is one of 1-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole or N-hydroxysuccinimide, the condensing agent is N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide, and the reaction solvent is one of ethyl acetate, methylene chloride, tetrahydrofuran or toluene.
  5. 5. The method for synthesizing the compound (R) -3A according to claim 1, wherein in the step of synthesizing the compound (R) -3A from the mixture of (R) -2A and (S) -2B, the molar ratio of the mixture of (R) -2A and (S) -2B to the activator to the condensing agent is 1:1.05-1.1:0.1-0.2:1.05-1.1.
  6. 6. The method for synthesizing the compound (R) -3A according to claim 1, wherein in the step of synthesizing the compound (R) -3A from a mixture of (R) -2A and (S) -2B, the synthesis of the compound 1 comprises the steps of mixing L-proline with an inorganic base, and then carrying out a sulfonylation reaction with a p-toluenesulfonating reagent, wherein the inorganic base is one of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, the p-toluenesulfonating reagent is one of p-toluenesulfonyl chloride, p-toluenesulfonyl bromide and p-toluenesulfonyl anhydride, the reaction temperature is 70-80 ℃, and the reaction time is 2-4 h.
  7. 7. A synthetic method of (S) - (-) -1- (4-methoxybenzene) ethylamine is characterized in that p-methoxyacetophenone is reduced to obtain a mixture of (R) -2A and (S) -2B, the mixture of (R) -2A and (S) -2B is condensed with a compound 1 to obtain a compound (R) -3A, (R) -3A is hydrolyzed to obtain a compound (R) -2A, (R) -2A is hydrolyzed and azide to obtain a compound (S) -4A, and the compound (S) -5A is obtained by reduction of the compound (S) -4A), and the synthetic route is as follows: 。
  8. 8. The method for synthesizing (S) - (-) -1- (4-methoxyphenyl) ethylamine according to claim 7, wherein in the step of synthesizing the compound (R) -2A from the compound (R) -3A, the inorganic base is one of sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate, and the reaction solvent is a methanol/water mixed solvent or an ethanol/water mixed solvent.
  9. 9. The method for synthesizing (S) - (-) -1- (4-methoxybenzene) ethylamine as defined in claim 7, wherein in the step of synthesizing the compound (S) -4A from the compound (R) -2A, the azide reagent is diphenyl azide phosphate or diethyl azide phosphate, the organic base is 1, 8-diazabicyclo [5.4.0] undec-7-ene or 1, 5-diazabicyclo [4.3.0] non-5-ene, the reaction solvent is one of toluene, tetrahydrofuran, dichloromethane or acetonitrile, and the molar ratio of the compound (R) -2A to the organic base to the azide reagent is 1:1.2-1.3:1-1.3.
  10. 10. The method for synthesizing (S) - (-) -1- (4-methoxyphenyl) ethylamine according to claim 7, wherein in the step of synthesizing the compound (S) -5A from the compound (S) -4A, the reducing agent is triphenylphosphine or tributylphosphine, and the reaction solvent is one of tetrahydrofuran, ethanol or methylene chloride.

Description

Synthesis method of (S) - (-) -1- (4-methoxybenzene) ethylamine and intermediate compound thereof Technical Field The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of (S) - (-) -1- (4-methoxybenzene) ethylamine and an intermediate compound thereof. Background The chiral amine structure widely exists in natural organisms, is a core building block synthesized by chiral drugs and natural products, and is used as a key raw material of novel chiral polymers, the application requirements of the novel chiral polymers in the food, agricultural chemicals and pharmaceutical industries are continuously rising, and the requirements of the market on high selectivity and low racemization rate of the synthesis of the novel chiral polymers are increasingly stringent. The (S) - (-) -1- (4-methoxyphenyl) ethylamine is an important chiral amine intermediate, can be used as an anti-breast cancer drug precursor, has the structure of 4-methoxy benzene ring and chiral ethylamine and has the lipophilicity and chiral selectivity, and has the potential of expanding to the development of drugs in various fields such as antibiosis, antivirus and the like. The existing chiral amine synthesis method has been widely studied, but the synthesis route for (S) - (-) -1- (4-methoxyphenyl) ethylamine still has an industrial bottleneck. J. Org, chem, 2006,71,3998-4001 reports that (S) - (-) -1- (4-methoxyphenyl) ethylamine (ee value 90%) is obtained by using a chiral spiroborate catalytic system containing O 3 BN skeleton, using 4-methoxyacetophenone as a starting material, and performing three steps of oxime formation by hydroxylamine hydrochloride and potassium carbonate, etherification by sodium hydrogen and methyl iodide, and asymmetric reduction by chiral spiroborate. However, chiral spiro borate belongs to chiral customized catalysts, and the synthesis of chiral spiro borate is carried out by complicated procedures such as chiral source introduction, multi-step purification and the like, so that the preparation difficulty is high, the cost is high, and the large-scale industrial production is not facilitated. Chem, commun, 2013,49,161-163 reported a single enzyme cascade method with 3-aminocyclohexa-1, 5-diene carboxylic acid as amino donor and ω -transaminase as catalyst, the synthesis of (S) - (-) -1- (4-methoxyphenyl) ethylamine was achieved by pushing the reaction equilibrium through spontaneous tautomerism of the intermediates. Although the ee value of the product is reported to be more than 99%, the result is only realized under the condition of small test, the stability of the enzyme catalyst can be influenced during industrial scale-up, the ee value of the product is fluctuated, the single-use cost of the enzyme is high, and the recycling is difficult. In summary, the existing synthesis method of (S) - (-) -1- (4-methoxyphenyl) ethylamine generally has the problems of high catalyst cost and high recovery difficulty, and limits the industrial amplification application of the catalyst, so that development of a novel synthesis method which is controllable in cost, simple and convenient to operate, environment-friendly and suitable for large-scale production is needed. Disclosure of Invention The invention aims to provide a synthesis method of (S) - (-) -1- (4-methoxybenzene) ethylamine and an intermediate compound thereof. The synthesis route has reasonable process selection, can solve the problems of high catalyst cost and difficult separation and recovery in the prior art, and realizes the high-efficiency and low-cost large-scale preparation of target products. The invention provides a synthetic method of a compound (R) -3A, wherein the p-methoxyacetophenone is reduced to obtain a mixture of (R) -2A and (S) -2B, and the mixture of (R) -2A and (S) -2B is subjected to condensation reaction with a compound 1 to obtain the compound (R) -3A, and the synthetic route is as follows: 。 In the step of synthesizing the mixture of (R) -2A and (S) -2B from the p-methoxyacetophenone, the reducing agent is borane dimethyl sulfide or borane tetrahydrofuran, the catalyst comprises a chiral catalyst and a cocatalyst, the chiral catalyst is R- (+) -diphenyl prolyl, the cocatalyst is trimethyl borate or triethyl borate, the reaction solvent is toluene, tetrahydrofuran or dichloromethane, and the molar ratio of the p-methoxyacetophenone to the chiral catalyst to the cocatalyst to the reducing agent is 1:0.03-0.04:0.04-0.05:0.8-0.9. In the step of synthesizing the compound (R) -3A from the mixture of (R) -2A and (S) -2B, the activator is one of 1-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole or N-hydroxysuccinimide, the condensing agent is N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide, and the reaction solvent is one of ethyl acetate, dichloromethane, tetrahydrofuran or toluene. In the step of synthesizing the compound (R) -3A from the mixture of (R