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CN-114380861-B - Preparation method of fosinopril sodium intermediate

CN114380861BCN 114380861 BCN114380861 BCN 114380861BCN-114380861-B

Abstract

The invention provides a method for preparing fosinopril sodium intermediate, which comprises the steps of using propionic acid-1-bromoisobutyl ester to replace propionic acid-1-chloroisobutyl ester disclosed in the prior art to react with [ hydroxy (4-phenylbutyl) phosphinyl ] benzyl acetate, wherein the method has higher non-corresponding selectivity, so that the yield of a target product left-5 is obviously improved, and the product is easier to refine.

Inventors

  • HUANG WENFENG
  • YU WENLONG
  • WANG YANAN
  • HU JIAXING

Assignees

  • 浙江华海药业股份有限公司
  • 浙江华海立诚药业有限公司

Dates

Publication Date
20260508
Application Date
20201019

Claims (15)

  1. 1. A process for preparing fosinopril sodium intermediate, left-5, said left-5 being a mixture of isomers represented by formula II-1 and formula II-2: The method comprises the following steps: a) Reacting benzyl [ hydroxy (4-phenylbutyl) phosphinyl ] acetate shown in a formula V with 1-bromoisobutyl propionate shown in a formula VIII in an organic solvent in the presence of a base, so as to obtain a reaction mixed solution containing four isomers shown in a formula III-1, a formula III-2, a formula III-3 and a formula III-4, wherein the base is selected from N-methylmorpholine, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and the organic solvent is toluene, ethyl acetate, N-hexane and dichloromethane; b) Introducing hydrogen into the reaction mixture in the presence of positive pressure and palladium-carbon, and hydrogenating the mixture of the four isomers to remove benzyl ester; c) Separating the desired isomer mixture of formula II-1 and formula II-2 from the hydrogenation reaction liquid of b).
  2. 2. The process according to claim 1, wherein in step a) the base is N-methylmorpholine.
  3. 3. The method according to claim 1, wherein the base in the step a) is N-methylmorpholine, and the feeding mass ratio of the [ hydroxy (4-phenylbutyl) phosphino ] benzyl acetate (V) to the N-methylmorpholine in the step a) is 1:0.5-1:1.
  4. 4. A process according to claim 3, wherein the base in step a) is N-methylmorpholine and the feed mass ratio of benzyl [ hydroxy (4-phenylbutyl) phosphino ] acetate (V) to N-methylmorpholine in step a) is 1:0.54.
  5. 5. The process according to claim 1, wherein the reaction solvent added in step a) is toluene.
  6. 6. The method according to claim 1, wherein the feed mass ratio of the benzyl [ hydroxy (4-phenylbutyl) phosphinyl ] acetate represented by formula V to the 1-bromoisobutyl propionate represented by formula VIII in step a) is 1:1.0 to 1:1.5.
  7. 7. The process of claim 6 wherein the feed mass ratio of benzyl [ hydroxy (4-phenylbutyl) phosphinyl ] acetate of formula V to 1-bromoisobutyl propionate of formula VIII in step a) is 1:1.05.
  8. 8. The process according to claim 1, wherein step a) is carried out at room temperature.
  9. 9. The process according to claim 1, wherein the reaction mixture is washed with dilute hydrochloric acid before the hydrogenation in step b) after the completion of the reaction in step a).
  10. 10. The process according to claim 1, wherein the hydrogenation pressure in step b) is 0.40.+ -. 0.05MPa.
  11. 11. The method according to claim 1, wherein the separation of the step c) comprises the steps of filtering the hydrogenation reaction liquid obtained in the step b), adding inorganic alkaline aqueous solution into the filtered hydrogenation reaction liquid for washing, discarding the organic layer, retaining the aqueous solution, adding hydrochloric acid into the aqueous solution for adjusting pH=1-4, adding an organic solvent for extraction, and cooling and crystallizing to obtain the required diastereoisomers shown in the formulas II-1 and II-2.
  12. 12. The process according to claim 11, wherein the inorganic base used for washing in step c) is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide.
  13. 13. The process according to claim 12, wherein the inorganic base used for washing in step c) is sodium bicarbonate.
  14. 14. The process according to claim 11, wherein the organic solvent extracted in step c) is ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, methyl tertiary butyl ether, methyl isobutyl ketone, toluene.
  15. 15. The process according to claim 14, wherein the organic solvent extracted in step c) is ethyl acetate.

Description

Preparation method of fosinopril sodium intermediate Technical Field The invention relates to a preparation method of fosinopril sodium intermediate, belonging to the field of organic chemical synthesis. Technical Field Fosinopril sodium is a potent, long-acting ACEI-like antihypertensive drug developed by the united states schdule corporation for the treatment of various types of hypertension and heart failure. Fosinopril sodium has the chemical name of 4-cyclohexyl-1- [ (2-methyl-1- (propionyloxy) propoxy) (4-phenylbutyl) phosphonoacetyl ] -L-prolin sodium, and has the structural formula shown in formula I: at present, there are a plurality of reported methods for synthesizing fosinopril sodium, and fosinopril sodium intermediate left-5 is a key intermediate for synthesizing fosinopril sodium, which is a mixture of two isomers shown in formula II-1 and formula II-2: The synthesis of the left-5 mainly comprises two steps of reaction synthesis, namely, firstly, obtaining propionic acid-1-chloroisobutyl ester shown in a formula IV from propionyl chloride shown in a formula VII and isobutyraldehyde shown in a formula VI in methylene dichloride under the catalysis of zinc chloride, and secondly, reacting the propionic acid-1-chloroisobutyl ester shown in the formula IV with a compound [ hydroxy (4-phenylbutyl) phosphinyl ] benzyl acetate shown in a formula V to obtain an intermediate shown in a formula III, wherein the intermediate shown in the formula III directly reacts under the catalysis of palladium carbon without separation to generate fosinopril sodium left-5, and the synthetic route is shown in the specification: wherein the formula III has 4 chiral isomers and is a mixture of four isomers shown in the following formula III-1, formula III-2, formula III-3 and formula III-4, Wherein the III-1/III-2 configuration is the dominant configuration, the content in the intermediate formula III is larger, the content of the III-3/III-4 configuration in the intermediate formula III is smaller, and the content ratio of (III-1/III-2) to (III-3/III-4) is called dr value. The intermediate of formula III is hydrogenated and then recrystallized to remove unwanted isomers to give fosinopril sodium left-5 as described above. Chinese patent CN1026791C discloses a method for preparing fosinopril sodium left-5, wherein propionic acid-1-chloroisobutyl ester shown in formula IV and [ hydroxy (4-phenylbutyl) phosphinyl ] benzyl acetate shown in formula V react in toluene for 18-19 hours at 95 ℃ under the condition of taking N-methylmorpholine as a base to obtain an intermediate containing a reaction solution shown in formula III, the selectivity dr is about 1.5, the reaction solution is hydrogenated after acid washing, the hydrogenation solution is extracted by sodium bicarbonate alkali-adjusting methyl isobutyl ketone, and the methyl isobutyl ketone is recrystallized for 2 times to obtain left-5, and the total yield is 44%. The process has low selectivity, can obtain the qualified left-5 only by recrystalization for 2 times, and has complex operation and low total yield. Indian patent IN754CHE2005 also reports a similar method for preparing left-5, wherein 1-chloroisobutyl propionate shown IN formula IV and benzyl [ hydroxy (4-phenylbutyl) phosphino ] acetate shown IN formula V are reacted IN toluene for 10 hours at 95-100 ℃ under the condition of using N-methylmorpholine as a base, so as to obtain an intermediate reaction solution containing formula III, the reaction solution is hydrogenated after acid washing, the hydrogenation solution is extracted by sodium bicarbonate to prepare alkali-regulated methyl tert-butyl ether, and the methyl tert-butyl ether is recrystallized for 2 times to obtain left-5, and the total yield is 45%. The process needs to be recrystallized for 2 times to obtain the qualified left-5, and is complex in operation and low in total yield. In summary, the preparation method of fosinopril sodium left-5 reported in the current patent has the defects of low reaction diastereoselectivity, complicated operation, low atom economy, low yield and the like, so that the development of the preparation method which is simple and convenient to operate, environment-friendly and safe, has high yield and can be suitable for industrialized production of fosinopril sodium left-5 is very necessary. Disclosure of Invention The invention aims to overcome the defects of the prior art and provide a method for preparing fosinopril sodium intermediate left-5, which has the advantages of high reaction diastereoselectivity, simple post-treatment, high atom economy and high yield, and is suitable for industrial production, wherein the left-5 is a mixture of isomers shown in a formula II-1 and a formula II-2: The method comprises the following steps: a) In an organic solvent and in the presence of alkali, reacting benzyl [ hydroxy (4-phenylbutyl) phosphinyl ] acetate shown in a formula V with 1-bromoisobutyl propionate shown in a