CN1106386A - Synthetic process of Ramipril - Google Patents
Synthetic process of Ramipril Download PDFInfo
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- CN1106386A CN1106386A CN 94107461 CN94107461A CN1106386A CN 1106386 A CN1106386 A CN 1106386A CN 94107461 CN94107461 CN 94107461 CN 94107461 A CN94107461 A CN 94107461A CN 1106386 A CN1106386 A CN 1106386A
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Abstract
The process for synthesizing Ramipril, a heterocyclic compound: N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl-cis, endo-2-azabicyclo 3.3.0]-octane-3S-carboxylic acid, which is a preferable medicine for curing mild or moderate and primary hypertension, renal hypertension, and moderate and malignant congestive heart failure, features rich and cheap raw materials, simple technology and equipment and easy production.
Description
The present invention relates to a kind of synthetic method of Ramipril.Described Ramipril, its chemical name is: N-(1-S-ethoxycarbonyl-3-phenyl propyl)-and the S-alanyl-suitable, interior type-2-azabicyclic [3.3.0]-octane-3-S-carboxylic acid.Belong to heterocycles.
Ramipril (Ramipril) is a kind of choice drug for the treatment of mild or moderate and essential hypertension and renal hypertension and moderate and pernicious congestive heart failure that German Hirst company (EP0079022A2) develops.The maximum characteristics of this medicine are: drug effect is fast and strong, long action time, and toxic side effect is little, and pharmaceutical dosage is little, only needs the 2.5-5 milligram every day.This medicine was put on market in Germany in 1989, now sold, used in more than 20 countries, and China does not still have sale at present.
The objective of the invention is, utilize China existing abundant, cheap raw material resources and technical equipment, design a kind of easylier, be fit to the synthetic route of general pharmaceutical factory production.Ramipril shown in formula I, is a complicated molecule that 5 chiral centres are arranged, and the configuration of these 5 asymmetric carbons in molecule is all the S type.Synthetic this molecule is selected for use the proper raw material except considering, the more important thing is that institute's final molecular configuration of synthetic need meet above-mentioned configuration requirement.For this reason, in the present invention molecule is divided into the two portions that respectively contain unsymmetrical carbon, promptly azabicyclic part and pendant moiety synthesize respectively, at last two portions are connected together, and form target molecule, the i.e. compound of formula I.
Concrete synthetic method of the present invention comprises:
1. the azabicyclic part is synthetic, comprising:
A. make cyclopentanone under catalyst action, can form in the solution of azeotropic mixture with water, reflux, divide water reaction 1-4 hour with morpholine, generate compound (1), described catalyzer can be selected tosic acid, calcium chloride or Anhydrous potassium carbonate for use, and solvent can be selected benzene,toluene,xylene, chlorobenzene or dichlorobenzene for use;
B. compound (1) in solvent dioxane, tetrahydrofuran (THF) or glycol dimethyl ether with the alpha-brominated pyruvate of equivalent, in 0-10 ℃, reacted 1-3 hour, generate compound (2);
C. compound (2) in acetate with ammonium acetate heating reflux reaction 2-4 hour, form compound (3);
D. compound (3) is dissolved in (the acid alcohol volume ratio equals 1: 40) in the acidic ethanol, under palladium/charcoal (10%) catalyst action, in 25-35 ℃, the 40-80 normal atmosphere hydrogenation 5-10 hour, gets compound (4)
E. with method in common (4) are converted into the hydrochloride (5) of its benzyl ester again, promptly suitable, interior type-2-azabicyclic [3.3.0]-octane-3-S-benzyl carboxylate hydrochloride.
2. pendant moiety is synthetic, comprising:
A. make maleic acid anhydride and benzene under the effect of aluminum trichloride (anhydrous), reflux was reacted 1-3 hour, generated compound (6);
B. (both volume ratios are that (1: 3) reflux, Fen Shui, esterification become the ethyl ester of (6), coreaction 10-15 hour in the mixed solution of ethanol and benzene, toluene or dimethylbenzene with compound (6);
C. the product among the B is dissolved in the dehydrated alcohol, makes it,, generate compound (7) in 20-30 ℃ of reaction 12-24 hour in the L-of equivalent alanine benzyl ester and triethylamine;
D. compound (7) is dissolved in the acetate, again in the mineral acid that wherein adds suitable acetate amount 1-2%, under palladium/charcoal (10%) catalyst action, in 20-45 ℃, under the 1-40 normal atmosphere hydrogenation 2-4 hour, generate compound (8), i.e. N-(1-S-ethoxycarbonyl-3-phenyl propyl)-the S-L-Ala.
3. target compound is synthetic, comprising:
A. aforesaid compound (5) and the compound (8) with equivalent is dissolved among the DMF, add 2 normal triethylamines and the normal condensing agent of 1-1.2, room temperature reaction 12-24 hour, generate compound (9), wherein available condensing agent comprises: DCC(carbonyl diimine)-HOBt(1-hydroxybenzene a pair of horses going side by side triazole), DEPBT { formula II compound }.
B. compound (9) is dissolved in the dehydrated alcohol, adds palladium/charcoal (10%) catalyzer, under the room temperature normal pressure, hydrogenolysis 0.3-0.5 hour, generate formula I compound Ramipril.Product is measured through x-ray diffraction, confirms that its 5 chiral centres are all the S configuration
The characteristics of the inventive method are: utilize domestic existing abundant, cheap raw material resources, equipment and technical qualification, design, synthesized the domestic product of selling and producing that still do not have, although when synthetic, need satisfy the configuration requirement of 5 unsymmetrical carbons in the molecule, condition is harsh, but in the present invention, satisfied above-mentioned configuration requirement, obtained highly purified qualified product with easier method.
In order to be illustrated more clearly in the present invention, enumerate following examples, but it there is not any restriction to scope of the present invention.
Embodiment
Example 1.
Synthetic compound (1)-N-1-cyclopentenyl morpholine
In 500 milliliters of round-bottomed flasks of water trap are housed, add 48 gram cyclopentanone, 104.4 gram morpholines, 10 gram tosic acid and 300 milliliters of benzene respectively, reacting by heating, branch water 4 hours.After steaming the benzene that removes in the reaction solution, 72-74 ℃/133Pa cut is collected in underpressure distillation, gets 113.1 grams (75%).
Example 2.
Synthetic compound (2)-α-cyclopentanone benzylacetone acetoacetic ester
In 250 milliliters of round-bottomed flasks, add 53.4 and digest compound (1) and 50 milliliters of glycol dimethyl ethers,, slowly drip the ethyl bromide acetone of equivalent, dripped in about 1 hour in 0-10 ℃.Continue to stir 2 hours.The hcl acidifying that adds 2N is used ether extraction to being acid.The ether extracting solution washes with water to neutrality, anhydrous sodium sulfate drying.Boil off ether, get light yellow liquid.This liquid need not purifying, can be directly used in next step reaction.
Example 3.
Synthetic compound (3)-1H, 4H, 5H, 6H-pentamethylene a pair of horses going side by side [b] pyrroles-2-carboxylic acid, ethyl ester
In 250 milliliters of round-bottomed flasks, the compound (2) that adds in the example 2 adds 80 milliliters of acetate and 55 gram ammonium acetates, reflux 4 hours again.Use ether extraction, the extracting solution anhydrous sodium sulfate drying after reaction solution is chilled to room temperature.Steam ether after product silicagel column, the methylene dichloride eluent carries out chromatographic separation, gets a yellow solid.Productive rate 50%.Get product 12 grams (24%) with the alcohol-water recrystallization.Fusing point 119.6-120.2 ℃.
IR（cm-1）3310，1670，1530，1450
H1-NMR（ppm）：1.34（t，3H），2.42（q，2H），2.62（t，2H），2.71（t，2H），4.29（q，2H），6.66（s，H），8.85（s，H）
MS（EI）：179M+
Ultimate analysis (%): calculated value C. 67.04, H. 7.26, and N. 7.82;
C10H13NO2: experimental value C. 67.03, H. 6.94, and N. 7.65.
Example 4.
Synthetic compound (5)-suitable, interior type-2-azabicyclic [3.3.0]-octane-3-carboxyl acid benzyl ester hydrochloride
Digest compound (3) with 2 and be dissolved in 30 milliliters of ethanol and the 0.8 milliliter of vitriolic solution, add 1 gram palladium/charcoal (10%) catalyzer, hydrogenation 10 hours.With the reaction solution evaporate to dryness, use the 5N hcl acidifying, to cross filtering and go out insolubles, vlil 5 hours boils off solvent, gets hydrogenation crude product 3.2 grams.Then this crude product is dissolved in 10 milliliters of benzylalcohols and the 50 milliliters of benzene, adds 2 gram tosic acid again, reflux, esterification 10 hours.Boil off benzene and add entry, use ether extraction, water is neutralized to alkalescence with 5% sodium carbonate solution.With ether extraction 3 times, merge ether extracted liquid, wash neutrality with water.Add ether solution of hydrogen chloride and get throw out, filter, drying is used the Virahol recrystallization, gets product 0.7 gram (23%).175 ℃ of fusing points.
Example 5.
Synthetic compound (6)-β-benzoyl-acrylic acid and ethyl ester (6 ') thereof
In reflux condensing tube and churned mechanically 100 milliliters of there-necked flasks are housed, add 34 gram maleic acid anhydride and 200 milliliters of benzene, add 100 gram aluminum trichloride (anhydrous)s in batches, reflux is 2 hours then.Add 200 milliliters of benzene and 50 milliliters of concentrated hydrochloric acids, stirred 1 hour.Pressure reducing and steaming benzene, extremely alkaline with yellow soda ash neutralization reaction liquid.Filter, filtrate gets solid through acidifying, filters, and drying gets thick product 50 grams (82%).Use the benzene recrystallization, get light yellow solid compound (6).Fusing point 92-4 ℃.
IR(cm-1): 3050 to 3030,3000 to 2500,1700,1665,977,730,690
Compound (6) in 500 milliliters of round-bottomed flasks of water trap are housed, are added 30.4 respectively and digests compound (6), 70 milliliters of dehydrated alcohols, 200 milliliters of benzene and 45 gram tosic acid, reflux, divided water 3-5 hour.The reaction solution ether extraction, the extracting solution anhydrous magnesium sulfate drying.Underpressure distillation, the cut of 114-116 ℃/30Pa of collection gets 28.1 gram (80%) β-Benzoylbenzene olefin(e) acid ethyl esters.
IR（cm-1）：3050，1720，1670，1630，1600
Example 6
Synthetic compound (7)-N-(1-S-ethoxycarbonyl-3-ketone group-3-phenyl propyl)-the L-alanine benzyl ester
The compound (6 ') of 28 grams (0.14mol) and the alanine benzyl ester tosilate of 49.2 grams (0.14mol) are dissolved in the dehydrated alcohol, add normal triethylamine again, stirring at room 24 hours.Reaction solution is cooled off and the adding crystal seed, freezing, separate out crystallization, to filter, filtrate is freezing again, and three times so repeatedly, be total to such an extent that product 15.8 restrains (30%), through oil mystery recrystallization, get colourless needle crystal.Fusing point 71-71.5 ℃.
[α]
20 D-15.6 ° of (C=1, CH
3OH), literature value [α]
16 D-17.9 ° of (C=1, CH
3OH)
IR（cm-1）：3330，1740-1730，1680，1600
H1-NMR（ppm）：1.23（t，3H），1.37（d，3H），2.3-2.6（s，1H），3.45（m，2H），3.66（q，1H），380（t，1H），4.17（g，2H），5.14（m，2H），7.32-7.92（m，10H）。
Example 7.
Synthetic compound (8)-N-(1-S-ethoxycarbonyl-3-phenyl propyl)-the S-L-Ala
Digest compound (7) with 8 and be dissolved in 100 milliliters of acetate, add 1.6 milliliters of vitriol oils and 1.5 gram Pd/carbon catalysts (10%) respectively, hydrogenolysis is 4 hours under 1-40 normal atmosphere, then, add 100 milliliters of chlorobenzenes, the elimination catalyzer, steam solvent, add water, use twice of ether extraction.Splash into the sodium carbonate aqueous solution to PH=6-7 in aqueous phase, have a large amount of precipitations to separate out, filter, washing, drying gets product 4.8 grams (82%).Fusing point 144-6 ℃.
[α]
20 D-26.6 ° of (C=1, CH
3OH), literature value [α]
16 D-27.6 ° of (C=1, CH
3OH)
IR（cm-1）：3280，30002500，1740，1620，1400;
MS（FAB）：280（（M+H），234（M-COOH），206（M-CO2C2H5）。
Example 8.
Synthetic compound (9)-Ramipril benzyl carboxylate
In 100 milliliters of round-bottomed flasks, add 0.5 digest compound (5) (0.002mol), the compound (8) and the solvent DMF of equivalent, add 2 normal triethylamines and 1.1 normal phosphorus reagent again, stirring at room 24 hours.Reaction solution ethyl acetate extraction three times, united extraction liquid is used dried over mgso.Boil off ethyl acetate, residue gets an oily liquids through column chromatographic isolation and purification (developping agent is ethyl acetate-sherwood oil 2: 1).
IR（cm-1）：3030，1740，1650
MS：507（M+H），433（M-CO2C2H5）
H-NMR（ppm）：7.16（m，10H），5.09-5.21（m，2H），4.15-4.21（g，2H），2.18（s，1H），1.74-2.00（m，7H），1.25-1.30（t，3H），1.21-1.23（d，3H）
Example 9.
Synthetic formula I compound-1-(N-1-S-ethoxycarbonyl-3-phenyl propyl)-and the S-alanyl-suitable, interior type-2-azabicyclic [3.3.0]-octane-3-S-carboxylic acid, i.e. Ramipril.
Digest compound (9) with 0.2 and be dissolved in 30 milliliters of dehydrated alcohols, add 0.3 gram palladium/charcoal (10%) catalyzer, room temperature normal pressure hydrogenolysis 0.5 hour.The elimination catalyzer, an oily matter, it forms crystal in ether, altogether crystalline product 120 milligrams＞0%.Fusing point 112-4 ℃.
[α]
20 D：+10.1°（C＝1，CH
3OH）
IR（cm-1）：3330，1750，1650，1200，750，700
MS（FAB）：417（M+H），371（M-COOH），343（M-CO2C2H5）
H1-NMR（ppm）：1.21-1.40（d，t，6H），1.50-2.45（m，9H），2.55-2.80（m，3H），3.18-3.22（t，1H），3.74-3.76（m，1H），4.16-4.21（g，2H），4.30-4.44（m，1H），4.60-4.70（dd，1H），4.90-5.25（s，2H），7.16-7.28（m，5H）。
The product monocrystalline is measured through x-ray diffraction, and 5 chiral carbon atoms are all identical S configuration in its space structure, requires in full accord with intrinsic configuration.
Claims (2)
1, a kind of method of synthetic formula I compound Ramipril is characterized in that, described method comprises:
1). synthesizing of azabicyclic part, comprising:
A. make cyclopentanone under catalyst action, can form in the solution of azeotropic mixture with water, reflux, divide water reaction 1-4 hour with morpholine, generate compound (1), described catalyzer can be selected tosic acid, calcium chloride for use, anhydrous or salt of wormwood.
Solvent can be selected benzene,toluene,xylene, chlorobenzene or dichlorobenzene for use;
B. compound (1) in solvent dioxane, tetrahydrofuran (THF) or glycol dimethyl ether with the alpha-brominated pyruvate of equivalent, in 0-10 ℃, reacted 1-3 hour, generate compound (2);
C. compound (2) in ammonium acetate heating reflux reaction 2-4 hour, forms compound (3) in acetate;
D. compound (3) is dissolved in (the acid alcohol volume ratio equals 1: 40) in the acidic ethanol, in 25-35 ℃, the 40-80 normal atmosphere hydrogenation 5-10 hour, gets compound (4) under palladium/charcoal (10%) catalyst action;
E. with method in common (4) are converted into the hydrochloride (5) of its benzyl ester again, promptly suitable, assorted nitrogen two ring [3.3.0]-octane-3-S-benzyl carboxylate hydrochlorides of interior type-2-.
2). synthesizing of pendant moiety, comprising:
A. make maleic acid anhydride and benzene under the effect of aluminum trichloride (anhydrous), heating reflux reaction 1-3 hour, generate compound (6);
B. (both volume ratios are that (1: 3) reflux, Fen Shui, esterification become the ethyl ester of (6), coreaction 10-15 hour in the mixed solution of ethanol and benzene, toluene or dimethylbenzene with compound (6);
C. the product among the B is dissolved in the dehydrated alcohol, makes it,, generate compound (7) in 20-30 ℃ of reaction 12-24 hour in the L-of equivalent alanine benzyl ester and triethylamine;
D. compound (7) is dissolved in the acetate, again in the mineral acid that wherein adds suitable acetate amount 1-2%, under palladium/charcoal (10%) catalyst action, in 20-45 ℃, under the 1-40 normal atmosphere hydrogenation 2-4 hour, generate compound (8), i.e. N-(1-S-ethoxycarbonyl-3-phenyl propyl)-S-L-Ala.
3). synthesizing of target compound, comprising:
A. aforesaid compound (5) and the compound (8) with equivalent is dissolved among the DMF, adds 2 normal triethylamines and the normal condensing agent of 1-1.2, and room temperature reaction 12-24 hour, generate compound (9), available condensing agent comprises: DCC-HOBt, DEPBT,
B. compound (9) is dissolved in the dehydrated alcohol, adds palladium/charcoal (10%) catalyzer, under the room temperature normal pressure, hydrogenolysis 0.3-0.5 hour, generate formula I compound Ramipril.
2, in accordance with the method for claim 1, it is characterized in that, in the described method:
1) solvent described in the .A is a benzene;
Solvent described in the B is a glycol dimethyl ether;
Hydrogenation pressure described in the D is 40 normal atmosphere;
2) mixed solution described in the .B is the mixed solution of ethanol and benzene;
Hydrogenation temperature described in the D is 20-35 ℃, and pressure is the 1-20 normal atmosphere;
3) condensing agent described in the .A is DEPBT.
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| CN94107461A CN1047384C (en) | 1994-07-28 | 1994-07-28 | Synthetic process of Ramipril |
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| CN94107461A CN1047384C (en) | 1994-07-28 | 1994-07-28 | Synthetic process of Ramipril |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6407262B1 (en) | 2001-11-21 | 2002-06-18 | Brantford Chemicals Inc. | Process for the preparation of Ramipril |
| CN100376556C (en) * | 2005-10-14 | 2008-03-26 | 浙江工业大学 | Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride |
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| US7893098B2 (en) | 2003-12-29 | 2011-02-22 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| US8053603B2 (en) | 2006-01-06 | 2011-11-08 | Sunovion Pharmaceuticals Inc. | Tetralone-based monoamine reuptake inhibitors |
| US8097760B2 (en) | 2006-03-31 | 2012-01-17 | Sunovion Pharmacuticals Inc. | Preparation of chiral amides and amines |
| US8669291B2 (en) | 2007-05-31 | 2014-03-11 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| US8877975B2 (en) | 2006-01-06 | 2014-11-04 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100387615C (en) * | 2002-12-30 | 2008-05-14 | 上海医药工业研究院 | Preparation method of N-carboxyalkyl dipeptide type angiotensin converting enzyme inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3226768A1 (en) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
| EP0331609A3 (en) * | 1988-01-27 | 1992-07-01 | Hoechst Aktiengesellschaft | Angiotensin converting enzyme inhibitors having psychotropic effects |
| CN1015520B (en) * | 1988-07-02 | 1992-02-19 | 国家机械工业委员会天津复印技术研究所 | Carbide die pressing method and dies for magnetic core of magnetic roller |
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1994
- 1994-07-28 CN CN94107461A patent/CN1047384C/en not_active Expired - Fee Related
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6407262B1 (en) | 2001-11-21 | 2002-06-18 | Brantford Chemicals Inc. | Process for the preparation of Ramipril |
| US7893098B2 (en) | 2003-12-29 | 2011-02-22 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
| CN100376556C (en) * | 2005-10-14 | 2008-03-26 | 浙江工业大学 | Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride |
| US8877975B2 (en) | 2006-01-06 | 2014-11-04 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US8053603B2 (en) | 2006-01-06 | 2011-11-08 | Sunovion Pharmaceuticals Inc. | Tetralone-based monoamine reuptake inhibitors |
| US9868718B2 (en) | 2006-01-06 | 2018-01-16 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US10562878B2 (en) | 2006-01-06 | 2020-02-18 | Sunovion Pharamceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US8097760B2 (en) | 2006-03-31 | 2012-01-17 | Sunovion Pharmacuticals Inc. | Preparation of chiral amides and amines |
| US8524950B2 (en) | 2006-03-31 | 2013-09-03 | Sunovion Pharmaceuticals Inc. | Preparation of chiral amides and amines |
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| US8669291B2 (en) | 2007-05-31 | 2014-03-11 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| US9586888B2 (en) | 2007-05-31 | 2017-03-07 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
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