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CN-114516825-B - Method for preparing (2S, 4S) -4-cyclohexyl-L-proline

CN114516825BCN 114516825 BCN114516825 BCN 114516825BCN-114516825-B

Abstract

The present invention provides a method for precipitating (2S, 4S) -4-cyclohexyl-L-proline solid by adding salting-out agent into (2S, 4S) -4-cyclohexyl-L-proline aqueous solution, thereby remarkably improving the crystallization yield of (2S, 4S) -4-cyclohexyl-L-proline.

Inventors

  • YU WENLONG
  • ZHANG XIAOGUO
  • CHEN YANG
  • HU JIAXING
  • HUANG WENFENG

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
20201120

Claims (8)

  1. 1. A method for preparing (2 s,4 s) -4-cyclohexyl-L-proline, comprising the steps of: In the first scheme, acidic aqueous solution of (2S, 4S) -4-cyclohexyl-L-proline is added with salting-out agent and sodium hydroxide is added to adjust pH value to neutral to separate out solid, or In the second scheme, salting-out agent is added into the (2S, 4S) -4-cyclohexyl-L-proline water solution with neutral pH value to separate out solid, The salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate and potassium sulfate.
  2. 2. The process as claimed in claim 1, wherein the aqueous solution of (2 s,4 s) -4-cyclohexyl-L-proline is a concentrated hydrogenated solution obtained by subjecting trans-4-phenyl-L-proline to catalytic hydrogenation reduction in an aqueous solution, followed by filtration and concentration.
  3. 3. The method according to claim 1, wherein the concentration of the aqueous solution of (2 s,4 s) -4-cyclohexyl-L-proline is in the range of 0.13 to 0.16g/L.
  4. 4. The method of claim 1, wherein the pH is neutral, i.e., aqueous solution ph=5-8.
  5. 5. The method of claim 4, wherein the pH is neutral, i.e., aqueous solution ph=6-7.
  6. 6. The method according to claim 1, wherein the salting-out agent is used in an amount of 0.10 to 0.125g/ml of the volume of the aqueous solution of (2S, 4S) -4-cyclohexyl-L-proline.
  7. 7. The method of claim 1, wherein the salting-out temperature is 30-40 ℃.
  8. 8. The method of claim 7, wherein the salting-out temperature is 35 ℃.

Description

Method for preparing (2S, 4S) -4-cyclohexyl-L-proline Technical Field The invention relates to a method for preparing (2S, 4S) -4-cyclohexyl-L-proline, belonging to the field of chemical pharmacy. Technical Field Fosinopril sodium is a representative drug of a phosphorus-containing third-generation angiotensin converting inhibitor developed by Bristol-Myers Squibb company in the United states, has the advantage of double-channel compensatory excretion of liver and kidney, is rarely accumulated in the body, and has fewer adverse reactions. Fosinopril is a prodrug that has a weak direct inhibition of ACE, but is slowly and incompletely absorbed after oral administration and rapidly converts to the more active diacid metabolite fosinopril. Fosinopril sodium has the chemical name (4S) -4-cyclohexyl-1- [ [ (R) - [ (1S) -2-methyl-1- (1-oxopropoxy) propoxy ] (4-phenylbutyl) oxyphosphinyl ] acetyl ] -L-proline sodium salt, and has the structural formula: At present, a plurality of synthesis methods of fosinopril sodium are reported, and (2S, 4S) -4-cyclohexyl-L-proline (I) is a key intermediate for synthesizing fosinopril sodium. The (2S, 4S) -4-cyclohexyl-L-proline crystal is obtained by hydrogenating the trans-4-phenyl-L-proline (I) in a hydrochloric acid aqueous solution to obtain (2S, 4S) -4-cyclohexyl-L-proline (II) hydrogenated liquid and performing alkali adjustment and crystallization treatment on the (2S, 4S) -4-cyclohexyl-L-proline hydrogenated liquid. For example, chinese patent CN101462996 reports a process for preparing (2 s,4 s) -4-cyclohexyl-L-proline (II), trans-4-phenyl-L-proline (I) is hydro-carbon using rhodium in hydrochloric acid solution, and the hydrogenation solution is neutralized with sodium hydroxide to obtain (2 s,4 s) -4-cyclohexyl-L-proline (II) in a yield of 78.6%. Disclosure of Invention The invention aims to provide a method for improving the crystallization yield of (2S, 4S) -4-cyclohexyl-L-proline, which has the advantages of simple operation and high yield and is suitable for industrial production. The invention is realized by the following technical scheme: a method for preparing (2 s,4 s) -4-cyclohexyl-L-proline, comprising the steps of: In the first scheme, salting-out agent is added into neutral pH water solution of (2S, 4S) -4-cyclohexyl-L-proline to separate out solid or In the second scheme, the acidic (2S, 4S) -4-cyclohexyl-L-proline aqueous solution is added with a salting-out agent, and sodium hydroxide is added to adjust the pH value to be neutral, so that a solid is precipitated. Referring to the specific implementation method of the invention, the aqueous solution is a concentrated hydrogenated solution obtained by catalytic hydrogenation reduction of trans-4-phenyl-L-proline in the aqueous solution, filtration and concentration. Preferably, the concentration of the (2S, 4S) -4-cyclohexyl-L-proline aqueous solution is in the range of 0.13 to 0.16g/L. The pH value is neutral, which means that the pH of the solution is=5 to 8, preferably 6 to 7. The salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, preferably sodium chloride. Preferably, the salting-out agent is used in an amount of 0.10 to 0.125g/ml by volume of the aqueous solution of (2S, 4S) -4-cyclohexyl-L-proline. The temperature of salting-out is preferably 30-40 ℃, preferably 35 ℃. Compared with the prior art, the invention has the positive technical effects that the crystallization yield of (2S, 4S) -4-cyclohexyl-L-proline (II) can be obviously improved by adding a proper amount of inorganic salt into a reaction system, the purity is not influenced, and the purity of the obtained product is not less than 99.0 percent. Detailed Description The invention is further illustrated by reference to examples. The following examples are merely illustrative of the invention and are not intended to limit the invention in any way. Reference example 1 preparation of (2S, 4S) -4-cyclohexyl-L-proline (II) hydrogenated liquid 70G of trans-4-phenyl-L-proline (I), 3g of rhodium charcoal, 700ml of water and 60ml of reagent hydrochloric acid are dissolved and then added into a hydrogenation kettle, the pressure in the kettle is controlled to be 0.8MPa, the temperature is 50 ℃ for complete hydrogenation, the (2S, 4S) -4-cyclohexyl-L-proline (II) hydrogenated liquid is obtained by filtration, the hydrogenated liquid is concentrated to 450ml for post treatment, and the concentration of the hydrogenated liquid after concentration is about 0.148g/ml. Control example: The concentrated hydrogenated liquid of referential example 1 was transferred to a 1000ml three-necked flask, and heated to 35℃and the pH of the solution was adjusted to neutrality with a 30% sodium hydroxide solution, whereby solids were precipitated during the process, and then the mixture was filtered and dried at 80℃to obtain 57.54g of (2S, 4S) -4-cyclohexyl-L-proline (II), with a yield of 79.7%