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CN-122010959-A - Novel synthesis method of treasipril

CN122010959ACN 122010959 ACN122010959 ACN 122010959ACN-122010959-A

Abstract

The invention discloses a novel synthesis method of treasipril. The invention specifically discloses a preparation method of trehalfline, which comprises the following steps of carrying out substitution reaction on a compound 4 and a compound 5 in a solvent in the presence of alkali and a phase transfer catalyst to obtain the trehalfline. The synthesis method has the advantages of few steps, high total yield, simple operation, mild reaction conditions, low-cost and easily-obtained raw materials, no noble metal catalyst and suitability for large-scale production.

Inventors

  • ZHANG WANBIN
  • ZHANG LU
  • ZHANG YUXIN
  • TIAN PINGPING
  • FU YUJIA
  • YU WEI
  • GAO FENG
  • WU LIANG
  • LIAO KUI
  • LI JING
  • Sajid Ur Lehman Brothers
  • CAO JIAOJIAO
  • JIANG XIMING

Assignees

  • 上海上药第一生化药业有限公司
  • 上海交通大学

Dates

Publication Date
20260512
Application Date
20260113

Claims (10)

  1. 1. A process for the preparation of trehalfline comprising the steps of: in a solvent, in the presence of alkali and a phase transfer catalyst, carrying out substitution reaction on the compound 4 and the compound 5 to obtain the trazoxili; 。
  2. 2. the method of claim 1, wherein one or more of any of the following conditions are satisfied: (1) In the substitution reaction, the solvent is an amide solvent, preferably N, N-dimethylformamide or N, N-dimethylacetamide, such as N, N-dimethylformamide; (2) In the substitution reaction, the base is an alkali metal carbonate, preferably potassium carbonate or cesium carbonate, such as cesium carbonate; (3) In the substitution reaction, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphonium salt phase transfer agent, wherein the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide, more preferably tetra-n-butyl ammonium iodide, tetra-n-butyl ammonium bromide or tetra-n-butyl ammonium chloride, such as tetra-n-butyl ammonium bromide, and the quaternary phosphonium salt phase transfer catalyst is preferably triphenylphosphine halide or tetraphenylphosphine halide, such as triphenylphosphine methyl phosphine bromide or tetraphenylphosphine bromide; (4) In the substitution reaction, the molar volume ratio of the compound 4 to the solvent is 0.1-1 mol/L, preferably 0.2-0.6 mol/L, for example 0.4 mol/L; (5) In the substitution reaction, the molar ratio of the base to the compound 4 is (1-2): 1, preferably (1.2-1.8): 1, for example, 1.5:1; (6) In the substitution reaction, the molar ratio of the phase transfer catalyst to the compound 4 is (0.02-0.3): 1, preferably (0.05-0.15): 1, for example 0.1:1; (7) The temperature of the substitution reaction is 80-120 ℃, preferably 90-110 ℃, for example 100 ℃; (8) The substitution reaction time is 12-48 h, preferably 18-30 h, for example 24-h; (9) The substitution reaction further comprises the following post-treatment steps of cooling to room temperature, adding water and ethyl acetate, stirring and separating liquid, extracting the water phase with ethyl acetate, combining the organic layers, washing with water and saturated sodium chloride in sequence, and removing the solvent by rotation to obtain a crude product, and preferably comprises the steps of pulping the crude product with ethyl acetate, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain the trarasilli.
  3. 3. The preparation method according to claim 1, wherein the preparation method of trehaleli further comprises the steps of: ; In a solvent, in the presence of an oxidant, carrying out an oxidation reaction on the compound 3 to obtain a compound 4; preferably, the preparation method meets one or more of any of the following conditions: (1) In the substitution reaction, the molar volume ratio of the compound 3 to the solvent is 0.1-1 mol/L, preferably 0.2-0.6 mol/L, for example 0.4 mol/L; (2) In the substitution reaction, the molar ratio of the base to the compound 3 is (1-2): 1, preferably (1.2-1.8): 1, for example, 1.5:1; (3) In the substitution reaction, the molar ratio of the phase transfer catalyst to the compound 3 is (0.02-0.3): 1, preferably (0.05-0.15): 1, for example, 0.1:1.
  4. 4. A method of preparation according to claim 3, wherein one or more of any of the following conditions are met: (1) In the oxidation reaction, the solvent is a mixed solvent of nitrile solvent and water, wherein the nitrile solvent is preferably acetonitrile, preferably the solvent is an equal volume mixed solvent of nitrile solvent and water, preferably an equal volume mixed solvent of acetonitrile and water; (2) In the oxidation reaction, the oxidant is potassium hydrogen persulfate double salt; (3) In the oxidation reaction, the molar volume ratio of the compound 3 to the solvent is 0.05-0.5 mol/L, preferably 0.1-0.3 mol/L, for example 0.17 mol/L; (4) In the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8) 1, preferably (4-6) 1, for example 5:1; (5) The temperature of the oxidation reaction is 20-30 ℃; (6) The oxidation reaction is carried out for a period of time ranging from 2 to 12 h, more preferably from 4 to 6 h, for example 5 h; (7) The oxidation reaction also comprises the following post-treatment steps of removing most acetonitrile, extracting a water phase by using ethyl acetate, combining organic layers, washing the organic layers by using water and saturated sodium chloride in sequence, and removing a solvent by means of rotation to obtain a crude product.
  5. 5. The preparation method according to claim 3, wherein the preparation method of trehaleli further comprises the steps of: , Wherein X is halogen; In a solvent, in the presence of a base, the compound 1 and the compound 2a undergo a substituted aminolysis reaction to obtain a compound 3.
  6. 6. The method of claim 5, wherein one or more of any of the following conditions are satisfied: (1) In the compound 2a, X is Cl or Br; (2) In the substituted aminolysis reaction, the solvent is a polar aprotic solvent, preferably an amide solvent or a sulfone solvent, more preferably N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane, such as N, N-dimethylformamide; (3) In the substituted aminolysis reaction, the alkali is alkali metal carbonate or alkali metal alkoxide, preferably potassium carbonate, cesium carbonate, sodium tert-amyl alcohol or potassium tert-amyl alcohol; (4) In the substituted aminolysis reaction, the molar volume ratio of the compound 2a to the solvent is 0.2-3 mol/L, preferably 0.5-1.5 mol/L, for example 1 mol/L; (5) In the substituted aminolysis reaction, the molar ratio of the compound 2a to the compound 1 is (0.9-1.5): 1, preferably (1-1.2): 1, for example 1:1; (6) In the substituted aminolysis reaction, the molar ratio of the base to the compound 1 is (1-5): 1, preferably (2-4): 1, for example 3:1; (7) The temperature of the substituted aminolysis reaction is 80-120 o C, preferably 90-110 o C, for example 100 o C; (8) The time of the substituted aminolysis reaction is 5-20 h, preferably 8-12 h, for example 10 h; (9) The substituted aminolysis reaction also comprises the following post-treatment steps of cooling to room temperature, adding saturated ammonium chloride to quench the reaction, extracting the reaction product by using ethyl acetate, merging organic phases, and then spin-removing the solvent to obtain a crude product, and preferably, pulping the crude product by using methyl tertiary butyl ether, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain the compound 3.
  7. 7. The preparation method of claim 5, wherein the preparation method of trehaleli further comprises the steps of: in a solvent, carrying out halogenation reaction on a compound 2 in the presence of a halogenating reagent to obtain a compound 2a, wherein the compound 2 is 1-aminomethyl-1-cyclohexylol hydrochloride; Preferably, the preparation method meets one or two of the following arbitrary conditions: (1) In the substituted aminolysis reaction, the molar volume ratio of the compound 2 to the solvent is 0.2-3 mol/L, preferably 0.5-1.5 mol/L, for example 1 mol/L; (2) In the substituted aminolysis reaction, the molar ratio of the compound 2 to the compound 1 is (0.9-1.5): 1, preferably (1-1.2): 1, for example, 1:1.
  8. 8. The method of claim 7, wherein one or more of any of the following conditions are satisfied: (1) In the halogenation reaction, the solvent is a polar aprotic solvent, preferably an amide solvent or a sulfone solvent, more preferably N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or sulfolane, for example, N-dimethylformamide; (2) In the halogenation reaction, the halogenating reagent is thionyl chloride or phosphorus tribromide; (3) In the halogenation reaction, the halogenation reagent is added dropwise; (4) In the halogenation reaction, the molar volume ratio of the compound 2 to the solvent is 0.2 to 3 mol/L, preferably 0.5 to 1.5 mol/L, for example 1 mol/L; (5) In the halogenation reaction, the molar ratio of the halogenating agent to the compound 2 is (1-2): 1, preferably (1.2-1.8): 1, for example 1.5:1; (6) The halogenation reaction is carried out at a temperature of 40-80 o C, preferably 50-70 o C, for example 60 o C; (7) The halogenation reaction is carried out for a period of time of from 1 to 8h, preferably from 2 to 6h, for example 4 h.
  9. 9. A process for the preparation of compound 3 comprising the steps of: , Wherein X is halogen; In a solvent, in the presence of a base, the compound 1 and the compound 2a undergo a substituted aminolysis reaction to obtain a compound 3.
  10. 10. The preparation method according to claim 9, wherein the preparation method of the compound 3 further comprises the steps of: in a solvent, carrying out halogenation reaction on a compound 2 in the presence of a halogenating reagent to obtain a compound 2a, wherein the compound 2 is 1-aminomethyl-1-cyclohexylol hydrochloride; Preferably, the reaction conditions of the substituted aminolysis reaction are as described in claim 6 or 7; More preferably, the halogenation reaction is carried out under the reaction conditions as defined in claim 8.

Description

Novel synthesis method of treasipril Technical Field The invention belongs to the technical field of organic compounds, and relates to a novel preparation method of trehalboscalid. Background Troraxili (Trilacilib) is the first innovative drug developed by G1 Therapeutics, inc. to be administered prior to chemotherapy worldwide and possess full-line myeloprotection. On month 02 and 12 of 2021, approval by the FDA of the U.S. food and drug administration was obtained and sold by G1 Therapeutics Inc under the trade name Cosela. And 2022, 07 and 12 days, is approved by NMPA of China national drug administration, sold by Jiangsu Miao medicine Co., ltd, and has the trade name Kesaila. The trehalicillin has wide application prospect, so that a simple and efficient route is very necessary to develop. The synthesis of the trazoyside related by the application is simple and efficient and has important value. The literature reports that the synthetic route of the trehaline mainly comprises the following steps of taking N- [1- (aminomethyl) cyclohexyl ] carbamic acid benzyl ester as a raw material, obtaining an intermediate N- [ (1-aminocyclohexyl) methyl ] carbamic acid tert-butyl ester through Boc protection and debenzylation, obtaining a key mother nucleus through nucleophilic substitution, coupling, cyclization, hydrolysis, oxidation and other reactions with 5-bromo-2, 4-dichloropyrimidine, and then carrying out Buchwald-Hartwig coupling with 5- (4-methylpiperazine-1-yl) pyridine-2-amine to obtain the trehaline. This route does not give the yield of each step, the starting materials are very few commercially available, expensive and the synthesis process is reported very little. Method di-primordial research patent WO2018005865A1 subsequently reports that the primordial research reports in patent WO2018005865A1 that 4-chloro-2- (methylthio) pyrimidine-5-ethyl formate is taken as a raw material, and is subjected to substitution reaction with 1, 4-diazaspiro [5.5] undecane-3-one to obtain an intermediate 2- (methylthio) -4- (3-oxo-1, 4-diazaspiro [5.5] undecane-1-yl) pyrimidine-5-ethyl formate, and then the preparation method comprises the steps of amino protection, cyclization, sulfonation, reduction, boc removal, oxidation and coupling to obtain the trexili, wherein the yield is 16.8%. However, the starting material 1, 4-diazaspiro [5.5] undec-3-one is expensive and requires two additional steps to make (yield 35%). Method III-patent CN 114014863A preparation method of trehaline disclosed in patent CN114014863 is characterized in that 2- (methylthio) -7H-pyrrolo [2, 3-d ] pyrimidine-6-methyl formate is used as a raw material to obtain trehaline through substitution, hydrolysis, condensation and coupling reaction, and the total yield of the route is 61.4%. The synthetic route is shorter, the reaction conditions of each step are mild, column chromatography purification is not needed, and meanwhile, the method has good yield and purity, but the synthetic method of the key intermediate is not provided, and the raw materials are not sold in the market. Method four-patent CN113788837A the route reported in method four is the method with the shortest step in the current synthesis of the troraxili, 2- (methylthio) -7H-pyrrole [2, 3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol are taken as raw materials, the condensation reaction is carried out to obtain an amide product, then the product is subjected to intramolecular cyclization to obtain a key mother nucleus, and finally the mother nucleus and 1-methyl-4- (6-aminopyridine-3-yl) piperazine are subjected to substitution reaction to obtain Trilaciclib, wherein the total yield is up to 65%. But the sources of raw materials are rare, the raw materials are very expensive, the reaction conditions are harsh, and the method is not suitable for industrial production. Method five-patent CN 117903147A recently, the patent reports a method for preparing the treprostinil by using 5-bromo-2, 4-dichloropyrimidine as a starting material, wherein treprostinil mother nucleus can be obtained through substitution, cyclization, esterification, reductive aminolysis and other reactions, and finally the treprostinil mother nucleus is subjected to coupling reaction with 1-methyl-4- (6-aminopyridin-3-yl) piperazine to obtain the treprostinil with the total yield of 15%. The reaction yield is not high, so that the production cost is high. Disclosure of Invention The invention aims to overcome the defects that the initial raw materials in the prior art are expensive and difficult to obtain, the noble metal palladium catalyst is used, the reaction conditions are harsh, the steps are more, the total yield is not high, and the method is not suitable for industrial production, and provides a novel synthesis method of the troracili. The invention provides a preparation method of treasipril, which comprises the following steps: in a solvent, in the presence of alkali and a phase tran