CN114516825A - Method for preparing (2S,4S) -4-cyclohexyl-L-proline - Google Patents
Method for preparing (2S,4S) -4-cyclohexyl-L-proline Download PDFInfo
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- CN114516825A CN114516825A CN202011308087.0A CN202011308087A CN114516825A CN 114516825 A CN114516825 A CN 114516825A CN 202011308087 A CN202011308087 A CN 202011308087A CN 114516825 A CN114516825 A CN 114516825A
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- proline
- cyclohexyl
- aqueous solution
- salting
- neutral
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 238000005185 salting out Methods 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 18
- 230000007935 neutral effect Effects 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- JHHOFXBPLJDHOR-ZJUUUORDSA-N (2s,4s)-4-phenylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-ZJUUUORDSA-N 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 235000002639 sodium chloride Nutrition 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 3
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 3
- 235000011151 potassium sulphates Nutrition 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 230000001376 precipitating effect Effects 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000000643 oven drying Methods 0.000 description 6
- 229960001880 fosinopril sodium Drugs 0.000 description 4
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 2
- -1 1-oxopropoxy Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960002490 fosinopril Drugs 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention provides a method for precipitating (2S,4S) -4-cyclohexyl-L-proline solid by adding a salting-out agent into a (2S,4S) -4-cyclohexyl-L-proline aqueous solution, so that the crystallization yield of (2S,4S) -4-cyclohexyl-L-proline is obviously improved.
Description
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 dual-channel compensatory excretion of liver and kidney, is rarely accumulated in the body, and has few adverse reactions. Fosinopril is a precursor drug, has weak direct inhibition effect on ACE, but is slowly and incompletely absorbed after being orally taken, and is rapidly converted into a diacid metabolite fosinopril with stronger activity.
Fosinopril sodium has the chemical name (4S) -4-cyclohexyl-1- [ [ (R) - [ (1S) -2-methyl-1- (1-oxopropoxy) propoxy ] (4-phenylbutyl) oxyphosphoryl ] acetyl ] -L-proline sodium salt and has the structural formula:
at present, a plurality of methods for synthesizing 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 (II) hydrogenated liquid is mainly obtained by hydrogenating trans-4-phenyl-L-proline (I) in a hydrochloric acid aqueous solution, and the (2S,4S) -4-cyclohexyl-L-proline (II) hydrogenated liquid is subjected to alkali adjustment and crystallization treatment to obtain the (2S,4S) -4-cyclohexyl-L-proline crystal, so that the overall yield is low.
For example, chinese patent CN101462996 reports a method for preparing (2S,4S) -4-cyclohexyl-L-proline (ii), trans-4-phenyl-L-proline (I) is hydrogenated in hydrochloric acid solution by using rhodium, and the hydrogenated liquid is neutralized by sodium hydroxide to obtain (2S,4S) -4-cyclohexyl-L-proline (ii) with 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 process for preparing (2S,4S) -4-cyclohexyl-L-proline comprising the steps of:
the first scheme is as follows: adding a salting-out agent into a pH neutral (2S,4S) -4-cyclohexyl-L-proline aqueous solution to precipitate a solid; or
Scheme II: adding salting-out agent into acidic (2S,4S) -4-cyclohexyl-L-proline aqueous solution, adding sodium hydroxide to adjust pH value to be neutral, and precipitating solid.
Referring to the specific implementation method of the invention, the aqueous solution is a concentrated hydrogenated liquid obtained by carrying out catalytic hydrogenation reduction on trans-4-phenyl-L-proline in the aqueous solution, filtering and concentrating.
The concentration of the (2S,4S) -4-cyclohexyl-L-proline aqueous solution is preferably 0.13-0.16 g/L.
The pH value is neutral, namely the pH value of the solution is 5-8, preferably 6-7.
The salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate and potassium sulfate, and preferably is sodium chloride.
Preferably, the dosage of the salting-out agent is 0.10-0.125 g/ml of the volume of the (2S,4S) -4-cyclohexyl-L-proline aqueous solution.
Preferably, the salting-out temperature is 30-40 ℃, and preferably 35 ℃.
Compared with the prior art, the invention has the following positive technical effects: the crystallization yield of the (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 more than or equal to 99.0 percent.
Detailed Description
The present invention will be further described with 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 carbon, 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 controlled to be 50 ℃, the hydrogenation is completed, a (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 concentrated hydrogenated liquid is about 0.148 g/ml.
Comparative example:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, heated to 35 ℃ and the pH of the solution was adjusted to neutrality with 30% sodium hydroxide solution, during which a solid precipitated, filtered and dried at 80 ℃ to obtain 57.54g of (2S,4S) -4-cyclohexyl-L-proline (II), with a yield of 79.7% and a purity of 99.0% or more.
Example 1:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and 50g of sodium chloride was added thereto and stirred until it became clear. Heating to 35 deg.C, adjusting pH of the solution to neutral with 30% sodium hydroxide solution, separating out solid in the process, filtering, and oven drying at 80 deg.C to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 66.22g, with yield of 91.7% and purity of 99.0% or more.
Example 2:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and the pH of the solution was adjusted to neutral with 30% sodium hydroxide solution. Heating to 35 deg.C, adding 50g sodium chloride, stirring, separating out solid, filtering, and oven drying at 80 deg.C to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 66.00g with yield 91.4%. The purity is more than or equal to 99.0 percent.
Example 3:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and 50g of lithium chloride was added thereto and stirred until it became clear. Heating to 35 deg.C, adjusting pH of the solution to neutral with 30% sodium hydroxide solution, separating out solid in the process, filtering, and oven drying to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 62.31g, with yield 86.3% and purity greater than or equal to 99.0%.
Example 4:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and 50g of potassium chloride was added thereto and stirred until it became clear. Heating to 35 deg.C, adjusting pH of the solution to neutral with 30% sodium hydroxide solution, separating out solid in the process, filtering, and oven drying to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 63.17g, with yield 87.5% and purity not less than 99.0%.
Example 5:
the concentrated hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and 50g of sodium sulfate was added thereto and stirred until it became clear. Heating to 35 deg.C, adjusting pH of the solution to neutral with 30% sodium hydroxide solution, separating out solid in the process, filtering, and oven drying to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 62.59g, with yield of 86.7% and purity of 99.0% or more.
Example 6:
the hydrogenated liquid of reference example 1 was transferred to a 1000ml three-necked flask, and 50g of potassium sulfate was added thereto and stirred until it was clear. Heating to 35 deg.C, adjusting pH of the solution to neutral with 30% sodium hydroxide solution, separating out solid in the process, filtering, and oven drying to obtain (2S,4S) -4-cyclohexyl-L-proline (II) 62.88g, with yield of 87.1% and purity of 99.0% or more.
Claims (9)
1. A process for the preparation of (2S,4S) -4-cyclohexyl-L-proline comprising the steps of:
the first scheme comprises the following steps: adding a salting-out agent into an acidic (2S,4S) -4-cyclohexyl-L-proline aqueous solution, adding sodium hydroxide to adjust the pH value to be neutral, and separating out a solid; or
Scheme II: adding salting-out agent into pH neutral (2S,4S) -4-cyclohexyl-L-proline water solution to precipitate solid.
2. The process according to claim 1, wherein the aqueous solution of (2S,4S) -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, and then filtering and concentrating.
3. The method according to claim 1, wherein the concentration of the (2S,4S) -4-cyclohexyl-L-proline aqueous solution is in the range of 0.13-0.16 g/L.
4. The method according to claim 1, wherein the pH value is neutral, and the pH value of the aqueous solution is 5-8.
5. The method according to claim 4, wherein the pH value is neutral, and the pH value of the aqueous solution is 6-7.
6. The method of claim 1, wherein the salting-out agent is selected from lithium chloride, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate.
7. The method according to claim 1, wherein the salting-out agent is used in an amount of 0.10 to 0.125g/ml based on the volume of the aqueous solution of (2S,4S) -4-cyclohexyl-L-proline.
8. The method according to claim 1, wherein the salting-out temperature is 30 to 40 ℃.
9. The method of claim 8, the salting out temperature is 35 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011308087.0A CN114516825A (en) | 2020-11-20 | 2020-11-20 | Method for preparing (2S,4S) -4-cyclohexyl-L-proline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011308087.0A CN114516825A (en) | 2020-11-20 | 2020-11-20 | Method for preparing (2S,4S) -4-cyclohexyl-L-proline |
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| Publication Number | Publication Date |
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| CN114516825A true CN114516825A (en) | 2022-05-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011308087.0A Pending CN114516825A (en) | 2020-11-20 | 2020-11-20 | Method for preparing (2S,4S) -4-cyclohexyl-L-proline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114516825A (en) |
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2020
- 2020-11-20 CN CN202011308087.0A patent/CN114516825A/en active Pending
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