CN101985462A - Method for separating lisinopril ester - Google Patents
Method for separating lisinopril ester Download PDFInfo
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- CN101985462A CN101985462A CN 201010525012 CN201010525012A CN101985462A CN 101985462 A CN101985462 A CN 101985462A CN 201010525012 CN201010525012 CN 201010525012 CN 201010525012 A CN201010525012 A CN 201010525012A CN 101985462 A CN101985462 A CN 101985462A
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Abstract
The invention discloses a method for separating lisinopril ester. The method comprises the following steps of: performing annular gap type centrifugal extraction on lisinopril ester-containing material liquid by using a two to eight-stage serial countercurrent centrifugal extraction system consisting of annular gap types centrifugal extractors and by taking an organic solvent as an extracting agent; and concentrating the obtained extract phase and recovering the organic solvent to obtain the lisinopril ester. Compared with the conventional production process, the method has the advantages of a small amount of solvent, stable quality, high extraction rate, short period, low three-waste energy consumption (waste water, waste gas and industrial residues), safe and reliable production, and high implementation value and social economic benefit.
Description
(1) technical field
The present invention relates to the method for a kind of process intensification extractive technique separate drug or intermediate, relate to a kind of separation method of lisinopril ester more specifically.
(2) background technology
Lisinopril (Lisinopril) was by Merck company (Merck) exploitation, in listing in 1987.Lisinopril is the lysine derivative of enalaprilat, be the long-acting angiotensin-convertion enzyme inhibitor class of third generation medicine, the structure that can treat hypertension and other cardiovascular and cerebrovascular diseases is the lysine derivative of the active metabolite Enalaprilate of enalapril, its wetting ability is bigger than other ACE inhibitor, have long-acting antihypertensive function, tolerance is good.
Lisinopril ester (I)
Lisinopril key intermediate lisinopril ester (I) contains two peptide bonds, a carboxyl, a carboxylate group; Because there have carboxyl, this material to have to be certain water-soluble; Because the carboxylate group is arranged, this material dissolves in non-polar organic solvent.The still formula extraction and separation method that conventional industries production is used because the lisinopril carboxylate is water-soluble bigger, causes extraction time many, and efficient is low, and complicated operation extracts the energy consumption height.Therefore, be badly in need of to seek a kind of easy and extraction and separation method efficiently.
The extraction separation process of lisinopril ester (I) is mainly separated two parts:
1) by the intermediate acid anhydrides NCLY (II) in the lisinopril building-up process and L-proline(Pro) (III) through the alkaline condition reaction, again hydrolysis and hydrolyzed solution contain a large amount of lisinopril esters (I), need extraction separation target product I.
2) process of the synthetic lisinopril (IV) of lisinopril ester (I) hydrolysis, because hydrolysis is incomplete, reaction solution separates in the purification IV process, need reclaim not (I) of complete hydrolysis, carries out follow-up separation and Extraction process again and obtains bulk drug lisinopril (IV).
Annular space formula Centrifugical extraction technology is a kind of liquid-liquid technique efficiently.It is compared with tower abstraction technique with traditional still formula abstraction technique, and the difference on the principle of work is that the former is the phase-splitting that realizes the two-phase mixed solution in centrifuge field, and then the both realizes phase-splitting in gravity field.With respect to the gravity extraction, annular space formula Centrifugical extraction technology has many remarkable advantages: 1) phase-splitting performance is good, and processing power is big; 2) two-phase logistics amount retained is little, and duration of contact is short; 3) mass-transfer efficiency height; 4) facility compact, used space is few; 5) can significantly reduce labor intensity and improve work situation etc.
This project intends adopting annular space formula Centrifugical extraction technology, unhydrolysed lisinopril ester in the building-up process of efficient extraction lisinopril ester and the hydrolyzed solution, solve problems such as solvent load is big, energy consumption is high, three wastes generation is big, extraction yield is low, realize the efficient extraction of lisinopril ester, meet the green chemical industry development trend.
(3) summary of the invention
The technical problem to be solved in the present invention provides that a kind of technology is reasonable, production safety is reliable, technology is simple, extraction efficiency is high, solvent load is few, the extraction and separation method of three wastes less energy consumption, operate continuously and the lisinopril ester being convenient to implement.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
The separation method of the lisinopril ester shown in a kind of formula (I), described method is a raw material with the feed liquid that contains the lisinopril ester, it is one of following that the described feed liquid that contains the lisinopril ester comes from: (a) in synthetic lisinopril process, react through alkaline condition by the L-proline(Pro) shown in the intermediate acid anhydrides NCLY shown in the formula (II) and the formula (III), again hydrolysis and must the hydrolyzed solution that contains the lisinopril ester; (b) in the lisinopril process shown in the lisinopril ester hydrolysis synthesis type (IV), reaction solution separates the feed liquid that contains the lisinopril ester that reclaims the not complete hydrolysis that obtains when purifying; Described method is: the feed liquid that will contain the lisinopril ester, with the organic solvent is extraction agent, utilizes annulus type centrifugal extractor to form 2～8 grades counter flow in series Centrifugical extraction system, carries out annular space formula Centrifugical extraction, the extraction phase of gained reclaims organic solvent through concentrating, and obtains the lisinopril ester.
The mass content of lisinopril ester is generally 2～30% in the described feed liquid that contains the lisinopril ester, and available liquid chromatography detects and obtains.
Organic solvent of the present invention is the halogenated alkane of the mixture of following one or more arbitrary proportions: C1～C5, the fatty ester of C2～C8, the alkane of C4～C10, the naphthenic hydrocarbon of C4～C10, pimelinketone, isopropylcarbinol, toluene, dimethylbenzene or sherwood oil, preferred organic solvent is the mixture of following one or more arbitrary proportions: methylene dichloride, trichloromethane, methyl acetate, ethyl acetate, methyl propionate, ethyl propionate, pimelinketone, isopropylcarbinol, toluene, dimethylbenzene, hexanaphthene or sherwood oil, most preferably organic solvent is an ethyl acetate, hexanaphthene, methylene dichloride, toluene or trichloromethane.
Extraction of the present invention is carried out under 10～50 ℃ of temperature, preferably carries out under 20～40 ℃ of temperature.
The volumetric flow rate of extraction agent of the present invention is 0.2～3.0: 1.0 with the ratio of the volumetric flow rate of the feed liquid that contains the lisinopril ester, is preferably 0.2～1.0: 1.0.
Extraction series connection progression of the present invention is 2～8 grades, is preferably 3～6 grades.Described extraction can repeat 1～6 time, promptly with single or multiple crosscurrent extraction devices, repeatedly back and forth extracts with extraction agent.The rotating speed of described annulus type centrifugal extractor is 1500～5000 rev/mins.
More specifically, preferred described method is carried out according to following steps: the feed liquid that will contain the lisinopril ester, with the organic solvent is extraction agent, utilize annulus type centrifugal extractor to form 2～8 grades counter flow in series Centrifugical extraction system, under 10～50 ℃ of temperature, carry out annular space formula Centrifugical extraction, the volumetric flow rate of described extraction agent is 0.2～3.0: 1.0 with the ratio of the volumetric flow rate of the feed liquid that contains the lisinopril ester, the rotating speed of described annulus type centrifugal extractor is 1500～5000 rev/mins, the extraction phase of gained reclaims organic solvent through concentrating, and obtains the lisinopril ester; Described organic solvent is: ethyl acetate, hexanaphthene, methylene dichloride, toluene or trichloromethane.
The present invention compared with prior art, its beneficial effect is embodied in:
The present invention adopts annular space formula Centrifugical extraction to separate the lisinopril ester, realize the high efficiency separation or the recovery of lisinopril ester, compare with existing manufacturing technique, solvent load is few, steady quality, extraction yield height, cycle is short, three wastes less energy consumption, production safety is reliable, has bigger implementary value and economic results in society.
(4) description of drawings
Fig. 1 annular space formula Centrifugical extraction tandem adverse current synoptic diagram
(5) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
The feed liquid of using in the embodiment of the invention that contains the lisinopril ester comes from Zhejiang Province Changming Pharmaceutical Co., Ltd in producing preparation lisinopril process, react through alkaline condition by intermediate acid anhydrides NCLY and L-proline(Pro), again hydrolysis and the hydrolyzed solution that contains the lisinopril ester.
Embodiment 1
The feed liquid that will contain lisinopril ester (15%, mass content, liquid chromatographic detection) is an extraction agent with the ethyl acetate, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 3000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.5/1.0, the overall flow rate of extraction agent and feed liquid are 40mL/min, extraction progression 5 (5 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 91.0%, and lisinopril purity is 95.2% (liquid chromatographic detection).
Embodiment 2
The feed liquid that will contain lisinopril ester (15%, mass content) is an extraction agent with the hexanaphthene, and service temperature is 40 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=1.0/1.0, the overall flow rate of extraction agent and feed liquid are 40mL/min, extraction progression 3 (3 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 93.3%, and lisinopril purity is 94.3%.
Embodiment 3
The feed liquid that will contain lisinopril ester (15%, mass content) is an extraction agent with the hexanaphthene, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=2.0/1.0, the overall flow rate of extraction agent and feed liquid are 40mL/min, extraction progression 2 (2 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 89.6%, and lisinopril purity is 93.9%.
Embodiment 4
The feed liquid that will contain lisinopril ester (30%, mass content) is an extraction agent with the hexanaphthene, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=3.0/1.0, the overall flow rate of extraction agent and feed liquid are 70mL/min, extraction progression 6 (6 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 96.5%, and lisinopril purity is 90.6%.
Embodiment 5
The feed liquid that will contain lisinopril ester (10%, mass content) is an extraction agent with the hexanaphthene, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 1500 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.2/1.0, the overall flow rate of extraction agent and feed liquid are 50mL/min, extraction progression 6 (6 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 86.1%, and lisinopril purity is 95.8% (liquid chromatographic detection).
Embodiment 6
The feed liquid that will contain lisinopril ester (30%, mass content) is an extraction agent with the ethyl acetate, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.2/1.0, the overall flow rate of extraction agent and feed liquid are 70mL/min, extraction progression 8 (8 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 93.2%, and lisinopril purity is 96.2%.
Embodiment 7
The feed liquid that will contain lisinopril ester (2%, mass content) is an extraction agent with the methylene dichloride, and service temperature is 25 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.3/1.0, the overall flow rate of extraction agent and feed liquid are 50mL/min, extraction progression 5 (5 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 86.8%, and lisinopril purity is 93.3%.
Embodiment 8
The feed liquid that will contain lisinopril ester (2%, mass content) is an extraction agent with toluene, and service temperature is 10 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.3/1.0, the overall flow rate of extraction agent and feed liquid are 50mL/min, extraction progression 6 (6 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 92.9%, and lisinopril purity is 93.8%.
Embodiment 9
The feed liquid that will contain lisinopril ester (2%, mass content) is an extraction agent with the chloroform, and service temperature is 50 ℃, and extraction equipment is the D20 centrifugal extractor, and rotating speed is 5000 rev/mins, and operations flows is than the volumetric flow rate V of extraction agent
1The volumetric flow rate V of/feed liquid
2=0.3/1.0, the overall flow rate of extraction agent and feed liquid are 50mL/min, extraction progression 6 (6 D20 centrifugal extractor series connection), carry out Centrifugical extraction, extraction phase reclaims organic solvent through concentrating, and obtains the lisinopril ester, extraction yield is 94.8%, and lisinopril purity is 96.5%.
Claims (8)
1. the separation method of the lisinopril ester shown in the formula (I), described method is a raw material with the feed liquid that contains the lisinopril ester, it is one of following that the described feed liquid that contains the lisinopril ester comes from: (a) in synthetic lisinopril process, react through alkaline condition by the L-proline(Pro) shown in the intermediate acid anhydrides NCLY shown in the formula (II) and the formula (III), again hydrolysis and must the hydrolyzed solution that contains the lisinopril ester; (b) in the lisinopril process shown in the lisinopril ester hydrolysis synthesis type (IV), reaction solution separates the feed liquid that contains the lisinopril ester that reclaims the not complete hydrolysis that obtains when purifying; It is characterized in that described method is: the feed liquid that will contain the lisinopril ester, with the organic solvent is extraction agent, utilize annulus type centrifugal extractor to form 2～8 grades counter flow in series Centrifugical extraction system, carry out annular space formula Centrifugical extraction, the extraction phase of gained reclaims organic solvent through concentrating, and obtains the lisinopril ester;
2. the method for claim 1 is characterized in that described organic solvent is the halogenated alkane of the mixture of following one or more arbitrary proportions: C1～C5, the fatty ester of C2～C8, the alkane of C4～C10, naphthenic hydrocarbon, pimelinketone, isopropylcarbinol, toluene, dimethylbenzene or the sherwood oil of C4～C10.
3. the method for claim 1 is characterized in that described organic solvent is the mixture of following one or more arbitrary proportions: methylene dichloride, trichloromethane, methyl acetate, ethyl acetate, methyl propionate, ethyl propionate, pimelinketone, isopropylcarbinol, toluene, dimethylbenzene, hexanaphthene or sherwood oil.
4. the method for claim 1 is characterized in that described annular space formula Centrifugical extraction can repeat 1～6 time.
5. the method for claim 1 is characterized in that described extraction carries out under 10～50 ℃ of temperature.
6. the method for claim 1, the volumetric flow rate that it is characterized in that described extraction agent is 0.2～3.0: 1.0 with the ratio of the volumetric flow rate of the feed liquid that contains the lisinopril ester.
7. the method for claim 1, the rotating speed that it is characterized in that described annulus type centrifugal extractor is 1500～5000 rev/mins.
8. the method for claim 1, it is characterized in that described method carries out according to following steps: the feed liquid that will contain the lisinopril ester, with the organic solvent is extraction agent, utilize annulus type centrifugal extractor to form 2～8 grades counter flow in series Centrifugical extraction system, under 10～50 ℃ of temperature, carry out annular space formula Centrifugical extraction, the volumetric flow rate of described extraction agent is 0.2～3.0: 1.0 with the ratio of the volumetric flow rate of the feed liquid that contains the lisinopril ester, the rotating speed of described annulus type centrifugal extractor is 1500～5000 rev/mins, the extraction phase of gained reclaims organic solvent through concentrating, and obtains the lisinopril ester; Described organic solvent is: ethyl acetate, hexanaphthene, methylene dichloride, toluene or trichloromethane.
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| CN 201010525012 CN101985462A (en) | 2010-10-29 | 2010-10-29 | Method for separating lisinopril ester |
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| CN 201010525012 CN101985462A (en) | 2010-10-29 | 2010-10-29 | Method for separating lisinopril ester |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045687A (en) * | 2014-05-21 | 2014-09-17 | 丽珠医药集团股份有限公司 | Purification method of lisinopril |
| CN109422702A (en) * | 2017-08-30 | 2019-03-05 | 上海科胜药物研发有限公司 | Lisinopril intermediate and its purification process |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US6455705B1 (en) * | 1997-07-30 | 2002-09-24 | Degussa Aktiengesellschaft | 1-[N2-((S)-ethoxycarbonyl)-3-phenylproply)-N6-trifluoroacetyl]-L-ysyl-L-proline (lisinopril (TFA) ethyl ester, LPE) |
-
2010
- 2010-10-29 CN CN 201010525012 patent/CN101985462A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US6455705B1 (en) * | 1997-07-30 | 2002-09-24 | Degussa Aktiengesellschaft | 1-[N2-((S)-ethoxycarbonyl)-3-phenylproply)-N6-trifluoroacetyl]-L-ysyl-L-proline (lisinopril (TFA) ethyl ester, LPE) |
Non-Patent Citations (1)
| Title |
|---|
| 《核科学与工程》 19830930 周嘉贞等 微型环隙式离心萃取器的性能和应用 245-250 1-8 第3卷, 第3期 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045687A (en) * | 2014-05-21 | 2014-09-17 | 丽珠医药集团股份有限公司 | Purification method of lisinopril |
| CN109422702A (en) * | 2017-08-30 | 2019-03-05 | 上海科胜药物研发有限公司 | Lisinopril intermediate and its purification process |
| CN109422702B (en) * | 2017-08-30 | 2023-04-18 | 上海科胜药物研发有限公司 | Lisinopril intermediate and purification method thereof |
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Application publication date: 20110316 |