A process for the preparation of (2S,4S)-4-cyclohexyl-L-proline

Abstract

The present application provides a method for precipitating (2S, 4S)-4-cyclohexyl-L-proline solid by adding a salting agent to an aqueous solution of (2S, 4S)-4-cyclohexyl-L-proline, thereby significantly improving the crystallization yield of (2S, 4S)-4-cyclohexyl-L-proline.

Description

Technical Field

[0001] This invention relates to a method for preparing (2S,4S)-4-cyclohexyl-L-proline, belonging to the field of chemical pharmaceuticals. Technical Background

[0002] Fosinopril sodium is a representative third-generation angiotensin-converting inhibitor (ACE) containing phosphorus, developed by Bristol-Myers Squibb in the United States. It has the advantage of compensatory excretion through both the liver and kidneys, resulting in minimal accumulation in the body and fewer adverse reactions. Fosinopril is a prodrug with a weak direct inhibitory effect on ACE, but it is slowly and incompletely absorbed after oral administration and rapidly converted into the more potent diacid metabolite, fosinopril.

[0003] Fosinopril sodium has the chemical name (4S)-4-cyclohexyl-1-[[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)oxophosphoryl]acetyl]-L-proline sodium salt, and its structural formula is:

[0004]

[0005] Currently, there are many reported methods for the synthesis of fosinopril sodium, and (2S,4S)-4-cyclohexyl-L-proline (I) is a key intermediate in the synthesis of fosinopril sodium. The main process involves hydrogenating trans-4-phenyl-L-proline (I) in hydrochloric acid aqueous solution to obtain a hydrogenated solution of (2S,4S)-4-cyclohexyl-L-proline (II). The (2S,4S)-4-cyclohexyl-L-proline hydrogenated solution is then subjected to alkali adjustment and crystallization treatment to obtain (2S,4S)-4-cyclohexyl-L-proline crystals, but the overall yield is relatively low.

[0006]

[0007] For example, Chinese patent CN101462996 reports a method for preparing (2S,4S)-4-cyclohexyl-L-proline (II), in which trans-4-phenyl-L-proline (I) is hydrogenated with rhodium in hydrochloric acid solution, and the hydrogenated solution is neutralized with sodium hydroxide to obtain (2S,4S)-4-cyclohexyl-L-proline (II) with a yield of 78.6%. Summary of the Invention

[0008] The purpose of this invention is to provide a method for improving the crystallization yield of (2S,4S)-4-cyclohexyl-L-proline. This method has the advantages of simple operation and high yield, and is suitable for industrial production.

[0009] This invention is achieved through the following technical solution:

[0010] A method for preparing (2S,4S)-4-cyclohexyl-L-proline includes the following steps:

[0011] Option 1: Add a salting-out agent to a pH-neutral aqueous solution of (2S,4S)-4-cyclohexyl-L-proline to precipitate a solid; or

[0012] Option 2: Add salting-out agent to an acidic aqueous solution of (2S,4S)-4-cyclohexyl-L-proline, and add sodium hydroxide to adjust the pH to neutral, precipitating a solid.

[0013] Referring to the specific implementation method of the present invention, the aqueous solution described in the present invention is a concentrated hydrogenated liquid obtained by catalytic hydrogenation reduction of trans-4-phenyl-L-proline in an aqueous solution, followed by filtration and concentration.

[0014] The preferred concentration range of the (2S,4S)-4-cyclohexyl-L-proline aqueous solution is 0.13–0.16 g / L.

[0015] The pH value being neutral means that the solution pH is 5 to 8, preferably 6 to 7.

[0016] The salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate, with sodium chloride being preferred.

[0017] Preferably, the amount of the salting-out agent is 0.10 to 0.125 g / ml of the volume of the (2S,4S)-4-cyclohexyl-L-proline aqueous solution.

[0018] The preferred temperature for salting out is 30–40°C, with 35°C being the most preferred.

[0019] Compared with the prior art, the positive technical effects of this invention are as follows: adding an appropriate amount of inorganic salt to the reaction system can significantly improve the crystallization yield of (2S,4S)-4-cyclohexyl-L-proline (II) without affecting the purity, and the purity of the obtained products is ≥99.0%. Detailed Implementation

[0020] The present invention will be further described in conjunction with embodiments. The following embodiments are merely illustrative of the invention and are not intended to limit the invention in any way.

[0021] Reference Example 1: Preparation of (2S,4S)-4-cyclohexyl-L-proline (II) hydrogenated liquid

[0022] 70g of trans-4-phenyl-L-proline (I), 3g of rhodium carbon, 700ml of water and 60ml of reagent hydrochloric acid were dissolved and added to a hydrogenation reactor. The pressure inside the reactor was controlled at 0.8MPa and the temperature at 50℃ until hydrogenation was complete. The solution was filtered to obtain (2S,4S)-4-cyclohexyl-L-proline (II) hydrogenated solution. The hydrogenated solution was concentrated to 450ml for further processing. The concentration of the concentrated hydrogenated solution was approximately 0.148g / ml.

[0023] Example for comparison:

[0024] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask and heated to 35 °C. The pH of the solution was adjusted to neutral using 30% sodium hydroxide solution. During the process, a solid precipitated out. The solution was filtered and dried at 80 °C to obtain 57.54 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 79.7% and a purity of ≥99.0%.

[0025] Example 1:

[0026] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and 50 g of sodium chloride was added and stirred until dissolved. The solution was heated to 35 °C and the pH was adjusted to neutral with 30% sodium hydroxide solution. During the process, a solid precipitated out. The solid was filtered and dried at 80 °C to obtain 66.22 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 91.7% and a purity ≥99.0%.

[0027] Example 2:

[0028] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and the pH of the solution was adjusted to neutral with 30% sodium hydroxide solution. 50 g of sodium chloride was added and stirred while heating to 35 °C. A solid precipitated during the process; the solid was filtered and dried at 80 °C to obtain 66.00 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 91.4%. Purity ≥ 99.0%.

[0029] Example 3:

[0030] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and 50 g of lithium chloride was added and stirred until dissolved. The solution was heated to 35 °C and the pH was adjusted to neutral with 30% sodium hydroxide solution. During the process, a solid precipitated out. The solid was filtered and dried to obtain 62.31 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 86.3% and a purity of ≥99.0%.

[0031] Example 4:

[0032] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and 50 g of potassium chloride was added and stirred until dissolved. The solution was heated to 35 °C and the pH was adjusted to neutral with 30% sodium hydroxide solution. During the process, a solid precipitated out. The solid was filtered and dried to obtain 63.17 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 87.5% and a purity ≥99.0%.

[0033] Example 5:

[0034] The concentrated hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and 50 g of sodium sulfate was added and stirred until dissolved. The solution was heated to 35 °C and the pH was adjusted to neutral with 30% sodium hydroxide solution. During the process, a solid precipitated out. The solid was filtered and dried to obtain 62.59 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 86.7% and a purity of ≥99.0%.

[0035] Example 6:

[0036] The hydrogenated solution from Reference Example 1 was transferred to a 1000 ml three-necked flask, and 50 g of potassium sulfate was added and stirred until dissolved. The solution was heated to 35 °C and the pH was adjusted to neutral with 30% sodium hydroxide solution. During the process, a solid precipitated out. The solid was filtered and dried to obtain 62.88 g of (2S,4S)-4-cyclohexyl-L-proline (II), with a yield of 87.1% and a purity of ≥99.0%.

Claims

1. A method for preparing (2S,4S)-4-cyclohexyl-L-proline, comprising the following steps: Option 1: Add a salting-out agent to an acidic aqueous solution of (2S,4S)-4-cyclohexyl-L-proline, adjust the pH to neutral with sodium hydroxide, and precipitate the solid; or Option 2: Add a salting-out agent to a pH-neutral aqueous solution of (2S,4S)-4-cyclohexyl-L-proline to precipitate a solid. The salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate.

2. The method according to claim 1, wherein the (2S,4S)-4-cyclohexyl-L-proline aqueous solution is a concentrated hydrogenated liquid obtained by catalytic hydrogenation reduction of trans-4-phenyl-L-proline in aqueous solution, followed by filtration and concentration.

3. The method according to claim 1, wherein the concentration range of the (2S,4S)-4-cyclohexyl-L-proline aqueous solution is 0.13~0.16 g / L.

4. The method according to claim 1, wherein the pH value is neutral, meaning the aqueous solution has a pH of 5 to 8.

5. The method according to claim 4, wherein the pH value is neutral, meaning the aqueous solution has a pH of 6 to 7.

6. The method according to claim 1, wherein the amount of salting-out agent is 0.10~0.125 g / ml of the volume of the (2S,4S)-4-cyclohexyl-L-proline aqueous solution.

7. The method according to claim 1, wherein the salting-out temperature is 30~40℃.

8. The method according to claim 7, wherein the salting-out temperature is 35°C.

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