CN109422702A - Lisinopril intermediate and its purification process - Google Patents
Lisinopril intermediate and its purification process Download PDFInfo
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- CN109422702A CN109422702A CN201710762721.XA CN201710762721A CN109422702A CN 109422702 A CN109422702 A CN 109422702A CN 201710762721 A CN201710762721 A CN 201710762721A CN 109422702 A CN109422702 A CN 109422702A
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- lisinopril
- acid anhydrides
- purification process
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- toluene
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- 238000000746 purification Methods 0.000 title claims abstract description 13
- 108010007859 Lisinopril Proteins 0.000 title abstract description 31
- 229960002394 lisinopril Drugs 0.000 title abstract description 31
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 title abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 30
- -1 lisinopril acid anhydrides Chemical class 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 14
- 239000000047 product Substances 0.000 abstract description 14
- 239000012535 impurity Substances 0.000 abstract description 8
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 7
- 238000005352 clarification Methods 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 abstract description 6
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- WFLQXECQLHZKMV-NSHDSACASA-N ethyl (2s)-2-amino-4-phenylbutanoate Chemical compound CCOC(=O)[C@@H](N)CCC1=CC=CC=C1 WFLQXECQLHZKMV-NSHDSACASA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D263/44—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to lisinopril intermediate (S) -2- ((S) -2; 5- dioxo -4- (4- (2; 2; 2- trifluoroacetamido) butyl) oxazolidine -3- base) -4-phenylbutyrate ethyl ester and its purification process; it includes the following steps: that toluene is added into lisinopril acid anhydrides crude intermediate under nitrogen protection; after heating stirring dissolved clarification, C is added5‑10Alkane solvents filter after insulated and stirred, dry, obtain product I.The purification process can remove effectively homophenylalanin impurity, and always miscellaneous also to reduce, final product quality is improved, and technique produces the lisinopril that can stably obtain high-quality.
Description
Technical field
The present invention relates to lisinopril intermediate (S) -2- ((S) -2,5- dioxo -4- (4- (2,2,2- trifluoroacetyl ammonia
Base) butyl) oxazolidine -3- base) -4-phenylbutyrate ethyl ester and its purification process.
Technical background
Lisinopril is the second generation angiotensin converting enzyme inhibitors developed by Merck company, the U.S., head in 1987
It is secondary to be listed in the U.S..This product is the angiotensin converting enzyme suppression worked by renin-angiotensin-aldosterone system
Preparation has good positivity effect, long-term administration suitable for the treatment of hypertension, and to congestive heart failure, myocardial infarction
When, make blood flow keep stablizing, or even can make moderate progress.In addition, this product long half time, only needs medication primary daily, the whole world
Annual requirement is big.Urgent need one is environmentally protective, low in cost, and can guarantee the bulk pharmaceutical chemicals preparation process of high-quality.
Currently, having there is the preparation method of many patent literature report lisinoprils.
Patent CN 1053437 reports that route is as follows:
The chiral selectivity of the route reduction amination is too low, causes total recovery low, higher cost.
Patent CN 1159286 reports that route is as follows:
This route provides a kind of preparation method of 1- alkoxycarbonyl-3-phenylpropyl derivatives, addition chiral selectivity compared with
Height, yield have greatly improved.
Patent EP 1513868 reports that route is as follows:
This route first step substitution reaction chiral selectivity is poor, causes total recovery low.
Patent CN 1539826 reports that route is as follows:
This route provides the new synthetic intermediate of lisinopril class compound and completely new synthesis technologies, but are prepared
Lisinopril finished product total recovery it is very low, and the homophenylalanin impurity that derives of homophenylalanin ethyl ester saponification is very difficult removes,
Hardly result in qualified finished product.
In conclusion collecting the advantage of each route, low-cost route is obtained:
Wherein, condensation step use condensing agent DCC, n-hydroxysuccinimide is relatively expensive, cost specific gravity compared with
Greatly.And DCC by-product generates a large amount of solid waste, not environmentally.
Further, condensing agent can be substituted with cheap phosgene or two phosgene or triphosgene.
It researches and develops in acid anhydrides preparation process, acid anhydrides intermediate is unstable, and it is miscellaneous to be easy degradation generation homophenylalanin ethyl ester
Matter (0.1%-1.0%) and some unknown impurities (0.1%-1.0%).After detailed choice of parameters, homophenylalanin second
Ester impurity can be stablized in 0.1%-0.2%.It is derived as homophenylalanin using saponification, 0.1%- is remained in saponification liquor
0.2%.In last handling process and lisinopril purifying crude process, homophenylalanin is difficult to be purified removing, in lisinopril
Remain about 0.1% in finished product, it is qualified with it is unqualified between, product quality it is difficult to ensure that.
The present invention provides the purification process of lisinopril acid anhydrides intermediate, remove homophenylalanin second in addition to that can purify
Ester impurity also has purification effect to other impurities, and purifying yield is greater than 95%, very efficiently.Acid anhydrides after purification is using contracting
It closes, be saponified and refine, obtained lisinopril finished product, not only homophenylalanin impurity is controlled, and total impurities also reduce.Always
For it, increase acid anhydrides purification of intermediate operation after, final product quality is improved, technique production can stably obtain height
The lisinopril of quality.
Summary of the invention
The present invention provides the purification process of lisinopril acid anhydrides intermediate: it is thick that reaction obtains lisinopril acid anhydrides intermediate
After product, with toluene and C5-10The mixed solvent of alkane solvents is recrystallized to give sterling；
Further, lisinopril acid anhydrides intermediate is lisinopril hydride and triphosgene or two phosgene or phosgene reaction
It is made；
Further, the recrystallization purifying method, it is characterised in that the alkane solvents-are selected from normal heptane,
N-hexane, hexamethylene, petroleum ether；
Further, the recrystallization purifying method, it is characterised in that the ratio of the toluene and alkane solvents
Selected from 10:1 to 1:100, preferably 4:1 to 1:10；Further, the recrystallization purifying method, it is characterised in that recrystallization
Solution temperature is selected from 0 DEG C~110 DEG C, preferably 20~70 DEG C；
Further, the recrystallization purifying method, it is characterised in that recrystallization crystallization temperature is selected from 0 DEG C~70 DEG C,
It is preferred that 20~50 DEG C；
Further, the recrystallization purifying method, it is characterised in that recrystallization filtration temperature is selected from 0 DEG C~70 DEG C,
It is preferred that 0~50 DEG C.
The present invention provides lisinopril acid anhydrides intermediate structure (formula I) is as follows:
Example is embodied:
For a further understanding of invention, below with reference to embodiment, the present invention will be described in detail.It is understood that real
It applies example and its explanation is used merely to explain the present invention, rather than limit the present invention.
((S) -2,5- dioxo -4- (4- (2,2,2- trifluoroacetamido) butyl) is disliked lisinopril intermediate (S) -2-
Oxazolidine -3- base) -4-phenylbutyrate ethyl ester and its purification process:
Embodiment 1
The preparation of lisinopril acid anhydrides crude intermediate:
100g lisinopril hydride (formula II) is added into reaction vessel under nitrogen protection, 600mL methylene chloride,
58g triphosgene is warming up to 40 ± 2 DEG C and flows back 20 ± 4 hours；After reaction, reaction solution is concentrated under reduced pressure in≤45 DEG C, get Lai Nuo
Puli acid anhydrides crude intermediate 115g, LC-MS:459 [M+1]+。
Lisinopril acid anhydrides purification of intermediate:
Under nitrogen protection to addition 400mL toluene in above-mentioned lisinopril acid anhydrides crude intermediate, 35- is adjusted the temperature to
200mL n-hexane is added in 40 DEG C of stirring dissolved clarifications, after adjusting the temperature to 35-45 DEG C, insulated and stirred 2 hours, filters in 35-45 DEG C,
After the washing of solid wet product 100mL n-hexane, it is dried in vacuo 1 hour in≤45 DEG C, obtains white solid 101g, yield 95.2% spreads out
Raw HPLC purity 98.1%, LC-MS:459 [M+1]+。
Embodiment 2.
Lisinopril acid anhydrides crude intermediate 125g is obtained by 1 lisinopril acid anhydrides crude intermediate preparation method of embodiment,
200mL toluene is added thereto under nitrogen protection, adjusts the temperature to 20-30 DEG C of stirring dissolved clarification, 800mL n-hexane is added, adjusts
Temperature is saved to after 30-40 DEG C, insulated and stirred 2 hours, is filtered in 30-40 DEG C, after the washing of solid wet product 100mL n-hexane, in≤
45 DEG C are dried in vacuo 1 hour, obtain white solid 103g, yield 97.2%, derivative HPLC purity 97.5%, LC-MS:459 [M+1
]+。
Embodiment 3.
Lisinopril acid anhydrides crude intermediate 108g is obtained by 1 lisinopril acid anhydrides crude intermediate preparation method of embodiment,
250mL toluene is added thereto under nitrogen protection, adjusts the temperature to 60-65 DEG C of stirring dissolved clarification, 250mL normal heptane is added, adjusts
Temperature is saved to after 25-35 DEG C, insulated and stirred 2 hours, being cooled to 10-20 DEG C of suction filtration, after solid wet product 100mL normal heptane washs,
It is dried in vacuo 1 hour in≤45 DEG C, obtains white solid 102g, yield 96.2%, derivative HPLC purity 98.3%, LC-MS:459
[M+1]+。
Embodiment 4.
Lisinopril acid anhydrides crude intermediate 117g is obtained by 1 lisinopril acid anhydrides crude intermediate preparation method of embodiment,
150mL toluene is added thereto under nitrogen protection, adjusts the temperature to 40-50 DEG C of stirring dissolved clarification, 850mL normal heptane is added, adjusts
Temperature is saved to after 20-25 DEG C, insulated and stirred 2 hours, being cooled to 20-25 DEG C of suction filtration, after solid wet product 100mL normal heptane washs,
It is dried in vacuo 1 hour in≤45 DEG C, obtains white solid 104g, yield 98.1%, derivative HPLC purity 97.8%, LC-MS:459
[M+1]+。
Embodiment 5.
Lisinopril acid anhydrides crude intermediate 110g is obtained by 1 lisinopril acid anhydrides crude intermediate preparation method of embodiment,
250mL toluene is added thereto under nitrogen protection, adjusts the temperature to 30-40 DEG C of stirring dissolved clarification, 300mL normal heptane is added, adjusts
Temperature is saved to after 30-40 DEG C, insulated and stirred 2 hours, is filtered in 30-40 DEG C, after the washing of solid wet product 100mL normal heptane, in≤
45 DEG C are dried in vacuo 1 hour, obtain white solid 101g, yield 95.3%, derivative HPLC purity 98.0%, LC-MS:459 [M+1
]+。
Claims (7)
1. the purification process of type I compound: after reaction obtains type I compound, with toluene and C5-10The mixed solvent of alkane solvents
It is recrystallized to give sterling；
。
2. type I compound as described in claim 1 is by II compound of formula and triphosgene or two phosgene or phosgene reaction system
?；
。
3. the method as described in claim 1, it is characterised in that the alkane solvents are selected from normal heptane, n-hexane, hexamethylene
Alkane, petroleum ether.
4. the method as described in claim 1, it is characterised in that the ratio of the toluene and alkane solvents is selected from 10:1 extremely
1:100, preferably 4:1 are to 1:10.
5. the method as described in claim 1, it is characterised in that recrystalizing solvent temperature is selected from 0 DEG C to 110 DEG C, and preferably 20 DEG C extremely
70℃。
6. the method as described in claim 1, it is characterised in that recrystallization crystallization temperature is selected from 0 DEG C to 70 DEG C, and preferably 20 DEG C extremely
50℃。
7. the method as described in claim 1, it is characterised in that recrystallization filtration temperature is selected from 0 DEG C to 70 DEG C, preferably 0 DEG C to 50
℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710762721.XA CN109422702B (en) | 2017-08-30 | 2017-08-30 | Lisinopril intermediate and purification method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710762721.XA CN109422702B (en) | 2017-08-30 | 2017-08-30 | Lisinopril intermediate and purification method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN109422702A true CN109422702A (en) | 2019-03-05 |
| CN109422702B CN109422702B (en) | 2023-04-18 |
Family
ID=65503942
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|---|---|---|---|
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| Country | Link |
|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113845490A (en) * | 2020-06-28 | 2021-12-28 | 浙江华海药业股份有限公司 | Preparation method of lisinopril intermediate |
Citations (7)
| 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 |
| HUP0900712A2 (en) * | 2009-11-13 | 2011-10-28 | Tamas Ueberhardt | New methods and intermediers for the synthesis of ace-inhibitor |
-
2017
- 2017-08-30 CN CN201710762721.XA patent/CN109422702B/en active Active
Patent Citations (7)
| 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 |
| HUP0900712A2 (en) * | 2009-11-13 | 2011-10-28 | Tamas Ueberhardt | New methods and intermediers for the synthesis of ace-inhibitor |
| CN101985462A (en) * | 2010-10-29 | 2011-03-16 | 浙江工业大学 | Method for separating lisinopril ester |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113845490A (en) * | 2020-06-28 | 2021-12-28 | 浙江华海药业股份有限公司 | Preparation method of lisinopril intermediate |
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|---|---|
| CN109422702B (en) | 2023-04-18 |
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