CN109422702B - Lisinopril intermediate and purification method thereof - Google Patents
Lisinopril intermediate and purification method thereof Download PDFInfo
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- CN109422702B CN109422702B CN201710762721.XA CN201710762721A CN109422702B CN 109422702 B CN109422702 B CN 109422702B CN 201710762721 A CN201710762721 A CN 201710762721A CN 109422702 B CN109422702 B CN 109422702B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
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Abstract
The invention relates to lisinopril intermediate (S) -2- ((S) -2,5-dioxo-4- (4- (2,2,2-trifluoroacetylamino) butyl) oxazolidin-3-yl) -4-phenylbutyric acid ethyl ester and a purification method thereof, which comprises the following steps: adding toluene into the crude lisinopril anhydride intermediate under the protection of nitrogen, heating, stirring, dissolving, and adding C 5‑10 And (3) preserving the temperature, stirring, carrying out suction filtration and drying on the alkane solvent to obtain a product I. The purification method can effectively remove high phenylalanine impurities, reduce total impurities, improve the quality of finished products, and stably obtain high-quality lisinopril by process production.
Description
Technical Field
The invention relates to lisinopril intermediate (S) -2- ((S) -2,5-dioxo-4- (4- (2,2,2-trifluoroacetylamino) butyl) oxazolidin-3-yl) -4-phenylbutyric acid ethyl ester and a purification method thereof.
Technical Field
Lisinopril is the second generation angiotensin converting enzyme inhibitor developed by Merck, usa, and was first marketed in the united states in 1987. The product is an angiotensin converting enzyme inhibitor which acts through a renin-angiotensin-aldosterone system, is suitable for the treatment of hypertension, has good positive effect on congestive heart failure and myocardial infarction, and keeps stable blood flow even improves blood flow after long-term administration. In addition, the product has long half-life period, only needs to be taken once every day, and has large annual demand all over the world. A green and environment-friendly raw material medicine preparation process with low cost and high quality is urgently needed.
At present, many patent documents report methods for preparing lisinopril.
The reported route of patent CN 1053437 is as follows:
the chiral selectivity of reductive amination in the route is too low, resulting in low overall yield and higher cost.
The patent CN 1159286 reports the following route:
the route provides a preparation method of the 1-alkoxycarbonyl-3-phenylpropyl derivative, the addition chiral selectivity is high, and the yield is greatly improved.
The reported route of patent EP 1513868 is as follows:
the first step of the substitution reaction in the route has poor chiral selectivity, and the total yield is low.
The patent CN 1539826 reports the following route:
the route provides a new synthesis intermediate and a new synthesis process of the lisinopril compound, but the total yield of the prepared lisinopril finished product is very low, and high phenylalanine impurities derived from saponification of high phenylalanine ethyl ester are very difficult to remove, so that a qualified finished product is difficult to obtain.
In summary, the advantages of each route are integrated to obtain a low-cost route:
wherein, the condensing agent DCC and N-hydroxysuccinimide adopted in the condensation step are relatively expensive, and the cost and the specific gravity are relatively high. And the DCC by-product generates a large amount of solid waste and is not environment-friendly.
Further, the condensing agent may be replaced with inexpensive phosgene or diphosphine or triphosgene.
In the process of researching and developing the anhydride preparation technology, an anhydride intermediate is unstable and is easy to degrade to generate high phenylalanine ethyl ester impurities (0.1-1.0%) and some unknown impurities (0.1-1.0%). After detailed parameter screening, the impurities of the high phenylalanine ethyl ester can be stabilized at 0.1-0.2%. Then, the high phenylalanine is derived through saponification, and 0.1 to 0.2 percent of the high phenylalanine remains in the saponification solution. In the post-treatment process and the purification process of the lisinopril crude product, high phenylalanine is difficult to purify and remove, about 0.1 percent of high phenylalanine remains in the lisinopril finished product, the qualified product and the unqualified product are different, and the product quality is difficult to ensure.
The invention provides a purification method of a lisinopril anhydride intermediate, which can purify and remove high phenylalanine ethyl ester impurities and has purification effect on other impurities, wherein the purification yield is higher than 95%, and the purification method is very efficient. The purified anhydride is condensed, saponified and refined to obtain the lisinopril finished product, the impurities of high phenylalanine content are controlled, and the total impurities are reduced. In a word, after the purification operation of the anhydride intermediate is added, the quality of the finished product is improved, and the lisinopril with high quality can be stably obtained by the process production.
Disclosure of Invention
The invention provides a purification method of a lisinopril anhydride intermediate, which comprises the following steps: after the raw material of the lisinopril anhydride intermediate is obtained by reaction, toluene and C are used 5-10 Recrystallizing the mixed solvent of the alkane solvent to obtain a pure product;
furthermore, the lisinopril anhydride intermediate is prepared by reacting lisinopril hydride with triphosgene or diphosphosgene or phosgene;
further, the recrystallization purification method is characterized in that the alkane solvent is selected from n-heptane, n-hexane, cyclohexane, petroleum ether;
further, the recrystallization purification method is characterized in that the ratio of toluene to the alkane solvent is selected from the group consisting of 10 to 1, 100, preferably 4:1 to 1; furthermore, the recrystallization purification method is characterized in that the recrystallization dissolution temperature is selected from 0-110 ℃, preferably 20-70 ℃;
furthermore, the recrystallization purification method is characterized in that the recrystallization temperature is selected from 0 ℃ to 70 ℃, preferably 20 ℃ to 50 ℃;
furthermore, the recrystallization purification method is characterized in that the recrystallization filtration temperature is selected from 0 ℃ to 70 ℃, preferably 0 ℃ to 50 ℃.
The invention provides a lisinopril anhydride intermediate with the following structure (formula I):
the specific implementation example is as follows:
for a further understanding of the invention, reference will now be made in detail to the following examples. It should be understood that the examples and their description are only intended to illustrate the invention, and not to limit the invention.
Lisinopril intermediate (S) -2- ((S) -2,5-dioxo-4- (4- (2,2,2-trifluoroacetylamino) butyl) oxazolidin-3-yl) -4-phenylbutyric acid ethyl ester and purification method thereof:
example 1
Preparation of crude lisinopril anhydride intermediate:
adding 100g of lisinopril hydride (formula II), 600mL of dichloromethane and 58g of triphosgene into a reaction vessel under the protection of nitrogen, and heating to 40 +/-2 ℃ for refluxing for 20 +/-4 hours; after the reaction is finished, the reaction liquid is decompressed and concentrated at the temperature of less than or equal to 45 ℃ to obtain crude lisinopril anhydride intermediate 115g] + 。
Purification of lisinopril anhydride intermediate:
adding 400mL of toluene into the crude lisinopril anhydride intermediate under the protection of nitrogen, adjusting the temperature to 35-40 ℃, stirring for dissolving, adding 200mL of n-hexane, adjusting the temperature to 35-45 ℃, keeping the temperature and stirring for 2 hours, performing suction filtration at 35-45 ℃, washing a solid wet product with 100mL of n-hexane, and performing vacuum drying at 45 ℃ or below for 1 hour to obtain 101g of white solid, wherein the yield is 95.2%, the purity of the derivative HPLC is 98.1%, and the LC-MS is 459M +1] + 。
Example 2.
125g of the crude product of the intermediate of lisinopril acid anhydride obtained by the method for preparing the crude product of the intermediate of lisinopril acid anhydride in example 1 is added with 200mL of toluene under the protection of nitrogen, the temperature is adjusted to 20-30 ℃, the mixture is stirred and dissolved, 800mL of n-hexane is added, the temperature is adjusted to 30-40 ℃, the mixture is kept and stirred for 2 hours, then is filtered at 30-40 ℃, 100mL of n-hexane of the wet solid is washed, and is dried in vacuum for 1 hour at the temperature of less than or equal to 45 ℃ to obtain 103g of white solid, the yield is 97.2%, the purity of the derivative HPLC is 97.5%, and LC-MS (liquid chromatography-mass spectrometry) is 459[ m ], [ M ], [ 1 ] of] + 。
Example 3.
Example 1 preparation of crude lisinopril anhydride intermediate 108g, adding 250mL of toluene under the protection of nitrogen, adjusting the temperature to 60-65 ℃, stirring to dissolve, adding 250mL of n-heptane, adjusting the temperature to 25-35 ℃, keeping the temperature and stirring for 2 hours, cooling to 10-20 ℃, performing suction filtration, washing 100mL of solid wet product with n-heptane, performing vacuum drying at the temperature of less than or equal to 45 ℃ for 1 hour to obtain 102g of white solid, wherein the yield is 96.2%, the purity of the derivative HPLC is 98.3%, and the LC-MS is 459M +1] + 。
Example 4.
117g of crude lisinopril anhydride intermediate prepared by the method of example 1 is prepared by adding 150mL of toluene under nitrogen protection, adjusting the temperature to 40-50 ℃, stirring to dissolve, adding 850mL of n-heptane, adjusting the temperature to 20-25 ℃, keeping the temperature and stirring for 2 hours, cooling to 20-25 ℃, filtering, washing 100mL of solid wet product with n-heptane, drying in vacuum at 45 ℃ or below for 1 hour to obtain 104g of white solid with yield of 98.1%, purity of derivative HPLC 97.8%, LC-MS: 459M +1] + 。
Example 5.
110g of the crude product of the intermediate of lisinopril acid anhydride obtained by the method for preparing the crude product of the intermediate of lisinopril acid anhydride in example 1 is added with 250mL of toluene under the protection of nitrogen, the temperature is adjusted to 30-40 ℃, the mixture is stirred and dissolved, 300mL of n-heptane is added, the temperature is adjusted to 30-40 ℃, the mixture is stirred for 2 hours under heat preservation, then is filtered and filtered at 30-40 ℃, 100mL of solid wet product of n-heptane is washed, and is dried for 1 hour under vacuum at the temperature of less than or equal to 45 ℃ to obtain 101g of white solid, the yield is 95.3%, the derivative HPLC purity is 98.0%, and LC-MS, 459, M +1] + 。
Claims (1)
1. A process for purifying a compound of formula i: after reaction to give the compound of formula I, toluene is reacted with C 5-10 Recrystallizing the mixed solvent of the alkane solvent to obtain a pure product;
wherein said toluene is present with said C 5-10 The volume ratio of the alkane solvent is 4:1 to 40; said C is 5-10 The alkane solvent is selected from n-heptane or n-hexane(ii) a The recrystallization dissolution temperature is 20-70 ℃; the recrystallization crystallization temperature is 20-50 ℃; the recrystallization filtering temperature is 0-50 ℃.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4716235A (en) * | 1985-08-27 | 1987-12-29 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for preparing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline |
| EP0336368A2 (en) * | 1988-04-04 | 1989-10-11 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | N2-(1-carboxy-3-phenylpropyl)-L-lysine derivative and process of producing lysinopril using the compound |
| ES2018906A6 (en) * | 1989-07-24 | 1991-05-16 | Marga Investigacion | Procedure for the preparation of new polyazabicyclo- carbonyl chloride complexes, and application thereof for the preparation of peptides via NCA. |
| JPH08253497A (en) * | 1995-03-14 | 1996-10-01 | Richter Gedeon V G Rt | Peptide-type compound |
| US5616727A (en) * | 1993-09-17 | 1997-04-01 | Degussa Aktiengesellschaft | Process for purifying 1-[N2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N6 -trifluoroacetyl]-l-lysyl-l-proline (lisinopril (TFA) ethyl ester |
| CN101985462A (en) * | 2010-10-29 | 2011-03-16 | 浙江工业大学 | Method for separating lisinopril ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0900712A2 (en) * | 2009-11-13 | 2011-10-28 | Tamas Ueberhardt | New methods and intermediers for the synthesis of ace-inhibitor |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4716235A (en) * | 1985-08-27 | 1987-12-29 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for preparing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline |
| EP0336368A2 (en) * | 1988-04-04 | 1989-10-11 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | N2-(1-carboxy-3-phenylpropyl)-L-lysine derivative and process of producing lysinopril using the compound |
| ES2018906A6 (en) * | 1989-07-24 | 1991-05-16 | Marga Investigacion | Procedure for the preparation of new polyazabicyclo- carbonyl chloride complexes, and application thereof for the preparation of peptides via NCA. |
| US5616727A (en) * | 1993-09-17 | 1997-04-01 | Degussa Aktiengesellschaft | Process for purifying 1-[N2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N6 -trifluoroacetyl]-l-lysyl-l-proline (lisinopril (TFA) ethyl ester |
| JPH08253497A (en) * | 1995-03-14 | 1996-10-01 | Richter Gedeon V G Rt | Peptide-type compound |
| CN101985462A (en) * | 2010-10-29 | 2011-03-16 | 浙江工业大学 | Method for separating lisinopril ester |
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