CN1429835A - Preparation method of N-carboxyalkyl dipeptide type angiotensin converting enzyme inhibitor - Google Patents

Preparation method of N-carboxyalkyl dipeptide type angiotensin converting enzyme inhibitor Download PDF

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CN1429835A
CN1429835A CN 02139936 CN02139936A CN1429835A CN 1429835 A CN1429835 A CN 1429835A CN 02139936 CN02139936 CN 02139936 CN 02139936 A CN02139936 A CN 02139936A CN 1429835 A CN1429835 A CN 1429835A
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preparation
carboxylic acid
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trichloromethyl
enzyme inhibitor
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CN100387615C (en
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时惠麟
张庆文
钟静芬
单晓燕
陈国梁
周明华
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Shanghai Institute of Pharmaceutical Industry
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Abstract

A process for preparing N-carboxyalkyl dipeptide type angiotensin converting enzyme (ACE) depressant (such as enalapril maleate, ramipril, etc) includes such steps as preparing N-carboxylic acid anhydride from bis (trichloromethyl) carbonate, and coupling with relative alpha-amino acid.

Description

The preparation method of N-carboxyalkyl dipeptides type angiotensin-convertion enzyme inhibitor
Technical field
The present invention relates to the preparation method of a kind of N-carboxyalkyl dipeptides structure type angiotensin-converting enzyme (ACE) inhibitor.
Background technology
N-carboxyalkyl dipeptides structure type angiotensin-converting enzyme (ACE) inhibitor is class hypertension and a congestive heart failure medicine safely and effectively, comprise world's best-selling drugses such as enalapril maleate and lisinopril, in cardiovascular agent, occupy an important position.Its general structure is as follows:
Figure A0213993600041
Wherein: R 1=C 3H 7-; R 2=CH 3-; CF 3CONH (CH 2) 3CH 2-; NH 2(CH 2) 3CH 2-R 3=H, C 2H 5
Figure A0213993600043
Figure A0213993600051
At present existing many patent documentations have been reported the preparation method of such medicine, as: Jerry WSkiles etc. report (Organic Preparations and ProceduresInternational, 1988,20 (2): 109-115) by preparing N-carboxylic acid anhydride (N-CarboxyAnhydride earlier, NCA), prepare N-carboxyalkyl dipeptides type ACE inhibitor with corresponding a-amino acid coupling again.The advantage of this law has been to avoid the protection and the deprotection operation of the synthetic middle trouble of polypeptide, and be swift in response (can finish in 1h) reduces to the possibility of racemization minimum.Defective is to use excessive hypertoxic gas phosgene in preparation NCA process.
Report such as HeinerEckett (Angew Chem Int Ed Engl, 1987,26 (9): 894-895) adopt the substitute of two (trichloromethyl) esters of carbonic acid as phosgene.Two (trichloromethyl) esters of carbonic acid are stable crystalline solid (80 ℃ of fusing points, 206 ℃ of boiling points; Only have during boiling point and be decomposed into phosgene on a small quantity), be easy to transportation and storage, be convenient to metering.
Summary of the invention
The technical issues that need to address of the present invention are the preparation methods that disclose a kind of new N-carboxyalkyl dipeptides type angiotensin-convertion enzyme inhibitor, to overcome the above-mentioned defective that prior art exists.
Technical conceive of the present invention is such:
Use two (trichloromethyl) esters of carbonic acid to prepare NCA, as [(S)-the N-[(1-ethoxycarbonyl)-butyl)-L-L-Ala-N-carboxylic acid anhydride, (S)-N-[(1-ethoxycarbonyl)-butyl)-L-L-Ala-N-carboxylic acid anhydride and N 2-[1-(S)-ethoxycarbonyl-3-hydrocinnamyl)-N 6-trifluoroacetyl-L-Methionin-N-carboxylic acid anhydride), prepare N-carboxyalkyl dipeptides type ACE inhibitor, example hydrochloric acid quinapril, Ramipril, perindopril tert-butylamine salt, enalapril maleate and lisinopril etc. with corresponding a-amino acid coupling again.
Method of the present invention comprises the steps:
(1) two (trichloromethyl) esters of carbonic acid and compd B prepared in reaction N-carboxylic acid anhydride;
Two (trichloromethyl) esters of carbonic acid and compd B are reacted in solvent, obtain the N-carboxylic acid anhydride, temperature of reaction is-20～100 ℃, and the reaction times is 1～50 hour, and the mol ratio of two (trichloromethyl) esters of carbonic acid and compd B is 1～6: 1.Two (trichloromethyl) esters of said carbonic acid are the compound with following general structure:
Figure A0213993600061
Said compd B is the compound with following general structure:
Figure A0213993600062
R 1, R 2, R 3, R 4, R 5Same as above;
This compound can adopt commercially available prod or preparation voluntarily.
Said solvent comprises ethers, as tetrahydrofuran (THF), halogenated alkane, as methylene dichloride, aromatic hydrocarbons, as toluene and composition thereof;
(2) preparation of target product:
N-carboxylic acid anhydride that step (1) is obtained and a-amino acid or alpha-amino acid derivatives react in organic solvent, generate target product, from reaction product, collect the said N-carboxyalkyl of the present invention dipeptides type angiotensin-convertion enzyme inhibitor then, be called for short ACE;
Temperature of reaction is-20～100 ℃, and the reaction times is 1～50 hour, and the mol ratio of NCA and a-amino acid or derivatives thereof is 1: 1～3.
Said a-amino acid or alpha-amino acid derivatives comprise the ester of alpha-amino group hydrochlorate, a-amino acid, as the benzyl ester, for having the compound of following general structure:
Figure A0213993600071
R 5, R 4The same;
Said solvent comprises ethers, as tetrahydrofuran (THF), alcohols, as ethanol, ketone, as acetone, halogenated alkane, as methylene dichloride, aromatic hydrocarbons, as toluene and blend mixture thereof.Its reaction formula is:
Figure A0213993600072
Method of the present invention is particularly suitable for preparing Yipingshu, delapril, enalapril, imidapril, lisinopril, not Puli, perindopril, quinapril, Ramipril, spirapril, moexipril and Trolapril.
By above-mentioned disclosed technical scheme as seen, technology simple and effective of the present invention is fit to industrialized production.
Embodiment
Embodiment 1
(S)-preparation of N-((1-ethoxycarbonyl)-3-hydrocinnamyl)-L-L-Ala-N-carboxylic acid anhydride:
With two (trichloromethyl) ester 45g (0.15mol) of carbonic acid and (S)-N-((1-ethoxycarbonyl)-3-hydrocinnamyl)-L-L-Ala 27.9g (0.1mol) is dissolved in anhydrous tetrahydro furan 180ml, at 50 ℃ of stirring reactions to complete, pressure reducing and steaming tetrahydrofuran (THF) then.In residue, add normal hexane 90ml, stirring and crystallizing.Filter, vacuum-drying gets (S)-N-((1-ethoxycarbonyl)-3-hydrocinnamyl)-L-L-Ala-N-carboxylic acid anhydride: 68～72 ℃ of fusing points, [α] 25 D+ 11.0 ° of-+13.0 ° of (c=1, CH 3CN).
Embodiment 2
(S)-preparation of N-((1-ethoxycarbonyl)-butyl)-L-L-Ala-N-carboxylic acid anhydride:
In the 100ml reaction flask, add (S)-N-((1-ethoxycarbonyl)-butyl)-L-L-Ala 4g (18.4mmol) and methylene dichloride 20ml, add two (trichloromethyl) ester 5.5g (18.4mol) of carbonic acid and methylene dichloride 20ml solution in 20 ℃, reflux and stir 30h, be concentrated into dried.The 20ml that adds methylene chloride, reconcentration is to doing.As above operation repeats secondary again, gets oily matter, slowly solidifies, and gets (S)-N-[(1-7, the oxygen carbonyl)-butyl)-L-L-Ala-N-carboxylic acid anhydride.
The preparation of embodiment 3 enalapril maleates:
With L-proline(Pro) 17.3g (0.15mol), sodium hydroxide 6g (0.15mol) and the water-soluble 300ml of yellow soda ash 15.9g (0.15mol), add (S)-N-((1-ethoxycarbonyl)-3-hydrocinnamyl)-L-L-Ala-solution of N-carboxylic acid anhydride 30.5g (0.1mol) in tetrahydrofuran (THF) 600ml, stir 1h at 5 ℃.Transfer reaction solution pH=4.25, pressure reducing and steaming tetrahydrofuran (THF) with 6mol/L hydrochloric acid.Gained water liquid ethyl acetate extraction with concentrating under reduced pressure behind the anhydrous sodium sulfate drying, gets oily matter.
Above-mentioned oily matter is dissolved in acetonitrile 100ml at 60 ℃, adds 60 ℃ the solution of toxilic acid 11.6g (0.1mol) in acetonitrile 180ml, cooling crystallization.Filter, get enalapril maleate with the water recrystallization again, fusing point 142-143 ℃, [α] 25 D-42.6 ° of (c=1, CH 3OH).
The preparation of embodiment 4 quinapril hydrochloride:
In the 1L beaker, add (S)-1,2,3,4-tetrahydrochysene-3-isoquinoline 99.9 acid benzyl ester tosilate 64g (0.15mol), methylene dichloride 150ml and saturated sodium bicarbonate solution 500ml, stir molten entirely, the organic phase anhydrous sodium sulfate drying, standby.
Add (S)-N-((1-ethoxycarbonyl)-hydrocinnamyl)-L-L-Ala-N-carboxylic acid anhydride 45g (0.15mol) and methylene dichloride 150ml in the 1L reaction flask, room temperature adds above-mentioned reserve liquid, continues to stir 2h.Wash with sodium carbonate solution and sodium chloride solution in succession, anhydrous sodium sulfate drying is concentrated into driedly, adds ethyl acetate 250ml, adds the solution of toxilic acid 17.4g and ethyl acetate 250ml, separates out solid, maleate 77g, yield 80%, 145～146 ℃ of fusing points, [α] 25 D-11.7 ° of (c=1, CH 3OH).
Above-mentioned maleate changes into hydrochloride, gets hydrochloride 20g (31mmol), palladium 1g and dehydrated alcohol 300ml, the normal pressure catalytic hydrogenation, handle crude product, get the 11g quinapril hydrochloride with acetonitrile refining, yield 74%, [α] 25 D15.4 ° (c=2, CH 3OH).
The preparation of embodiment 5 Ramiprils:
Will (S, S, S)-2-azabicyclo [3,3,0] octane-3-carboxylic acid benzyl ester hydrochloride 17.5g (62mmol) joins ethylene dichloride 150ml, sodium hydroxide 2.7g (68mmol) and water 80ml mixed solution, handle standby dichloromethane solution.Drip (S)-N-((1-ethoxycarbonyl)-hydrocinnamyl)-L-L-Ala-N-carboxylic acid anhydride 21.7g (62mmol) and methylene dichloride 70ml solution, room temperature is stirred 5h, washes with sal enixum and sodium hydrogen carbonate solution, gets faint yellow oily thing 31g after the processing.Methyl alcohol 150ml dissolves above-mentioned oily matter, palladium carbon catalytic hydrogenation debenzylation, ether handle white solid, 23.3g, yield 90%, fusing point 107-109 ℃, [α] 25 D° 33.5 (c=1.0,0.1mol/L ethanol solution hydrochloride).
The preparation of embodiment 6 perindopril tert-butylamine salts:
In 100ml egg bottle, add (2S, 3aS, 7aS)-octahydro draws diindyl-2-benzyl carboxylate tosilate 5.8g (13mmol), saturated sodium bicarbonate solution 50ml and methylene dichloride, make (2S, 3aS, 7aS)-octahydro Indoline-2-carboxylic acid benzyl ester dichloromethane solution;
(S)-N-((1-ethoxycarbonyl)-butyl)-L-L-Ala-N-carboxylic acid anhydride 3.3g (13mmol) and methylene dichloride 50ml place the 250ml reaction flask, drip above-mentioned dichloromethane solution, reflux 4h, wash with sodium carbonate solution and sodium chloride solution in succession, anhydrous sodium sulfate drying is concentrated into oily matter.Add dehydrated alcohol 180ml and 5% palladium carbon, hydrogenation 4h concentrates, and sherwood oil is handled, and gets the 2.1g white solid, yield 42.4%, and ultimate analysis is qualified.
2.1g above-mentioned white solid (57mmol) is dissolved in ethyl acetate 300ml, slowly adds TERTIARY BUTYL AMINE 4.6g (63mmol), reflux is to dissolving, and cooling is filtered, and drying gets 2.4g training buttress Puli tert-butylamine salt, yield 95%, fusing point 154-156 ℃, [α] 25 D-64.3 ° (c=1, EtOH).
The preparation of embodiment 7 lisinoprils:
N-(N 2-(1-(S)-ethoxycarbonyl-3-hydrocinnamyl)-N 6-trifluoroacetyl-L-Methionin 43.2g (0.01mol) is dissolved in the 30ml tetrahydrofuran (THF), adds two (trichloromethyl) ester 4.5g (0.015mol) of carbonic acid and tetrahydrofuran (THF) 20ml solution, and 50 ℃ are stirred 3h, are chilled to room temperature, are evaporated to dried below 35 ℃; Add tetrahydrofuran (THF) 30ml again, be evaporated to dried below 35 ℃; Repeat aforesaid operations more once, get N 2-[1-(S)-ethoxycarbonyl-3-hydrocinnamyl)-N 6-trifluoroacetyl-L-Methionin-N-carboxylic acid anhydride.
Above-mentioned N-carboxylic acid anhydride is dissolved in tetrahydrofuran (THF) 30ml, stirs the solution that adds L-proline(Pro) 2g (15mmol) and sodium bicarbonate 1.5g (18mmol) and water 18ml down, and 25 ℃ are stirred 2.5h.40 ℃ of following pressure reducing and steaming tetrahydrofuran (THF)s add water 30ml, transfer pH4.6 with concentrated hydrochloric acid, dichloromethane extraction, anhydrous sodium sulfate drying, standby preparation lisinopril.

Claims (4)

1. the preparation method of a N-carboxyalkyl dipeptides type angiotensin-convertion enzyme inhibitor is characterized in that, comprises the steps:
(1) two (trichloromethyl) esters of carbonic acid and compd B are reacted in solvent, obtain the N-carboxylic acid anhydride, temperature of reaction is-20～100 ℃, reaction times is 1～50 hour, the mol ratio of two (trichloromethyl) esters of carbonic acid and compd B is 1～6: 1, and two (trichloromethyl) esters of said carbonic acid are the compound with following general structure: Said compd B is the compound with following general structure:
Figure A0213993600022
(2) preparation of target product:
N-carboxylic acid anhydride that step (1) is obtained and a-amino acid and derivative thereof react in organic solvent, generate target product, collect N-carboxyalkyl dipeptides type angiotensin-convertion enzyme inhibitor then from reaction product;
Temperature of reaction is-20～100 ℃, and the reaction times is 1～50 hour, and the mol ratio of N-carboxylic acid anhydride and a-amino acid and salt thereof is 1: 1～3.
Said alpha-amino acid derivatives is the compound with following general structure: Wherein: R 1=C 3H 7-; R 2=CH 3-; CF 3CONH (CH 2) 3CH 2-; NH 2(CH 2) 3CH 2-R 3=H, C 2H 5
Said solvent comprises ethers, alcohols, ketone, halogenated alkane or aromatic hydrocarbons and composition thereof.
2. method according to claim 1 is characterized in that, the solvent that step (1) adopts comprises tetrahydrofuran (THF), methylene dichloride or toluene and composition thereof.
3. method according to claim 1 is characterized in that, said solvent is tetrahydrofuran (THF), ethanol, methylene dichloride, toluene or acetone.
4. according to claim 1,2 or 3 described methods, it is characterized in that said N-carboxyalkyl dipeptides type angiotensin-convertion enzyme inhibitor comprises Yipingshu, delapril, enalapril, imidapril, lisinopril, not Puli, perindopril, quinapril, Ramipril, spirapril, moexipril and Trolapril.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101514180B (en) * 2008-02-20 2012-08-01 上海医药工业研究院 Perindopril tert-butylamine salt crystal I and method for preparing same
CN101326151B (en) * 2005-12-21 2015-01-07 塞诺菲-安万特德国有限公司 Improved method for the production of ramipril
CN108191969A (en) * 2018-01-19 2018-06-22 渤海大学 Two kinds of ace inhibitory peptides for deriving from Atlantic Ocean trout collagen
CN109021064A (en) * 2017-06-09 2018-12-18 扬子江药业集团有限公司 A kind of preparation method of enalapril maleate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9200213A (en) * 1992-09-16 1994-03-31 Krka Process for preparing alkyl-l-alanil-l-proline derivates
CN1047384C (en) * 1994-07-28 1999-12-15 北京大学 Synthetic process of Ramipril

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101326151B (en) * 2005-12-21 2015-01-07 塞诺菲-安万特德国有限公司 Improved method for the production of ramipril
CN101514180B (en) * 2008-02-20 2012-08-01 上海医药工业研究院 Perindopril tert-butylamine salt crystal I and method for preparing same
CN109021064A (en) * 2017-06-09 2018-12-18 扬子江药业集团有限公司 A kind of preparation method of enalapril maleate
CN109021064B (en) * 2017-06-09 2021-11-09 扬子江药业集团有限公司 Preparation method of enalapril maleate
CN108191969A (en) * 2018-01-19 2018-06-22 渤海大学 Two kinds of ace inhibitory peptides for deriving from Atlantic Ocean trout collagen
CN108191969B (en) * 2018-01-19 2021-01-01 渤海大学 Two ACE inhibitory peptides derived from Atlantic trout collagen

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