CN1047384C - Synthetic process of Ramipril - Google Patents
Synthetic process of Ramipril Download PDFInfo
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- CN1047384C CN1047384C CN94107461A CN94107461A CN1047384C CN 1047384 C CN1047384 C CN 1047384C CN 94107461 A CN94107461 A CN 94107461A CN 94107461 A CN94107461 A CN 94107461A CN 1047384 C CN1047384 C CN 1047384C
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Abstract
The present invention relates to a method for synthesizing Ramipril. The Ramipril has a chemical name of N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl-cis, endo-2-azabicyclo [3.3.0]-octane-3S-carboxylic acid, and belongs to the class of heterocyclic compounds. The compound is preferred medicine for treating mild or moderate or primary hypertension, renal hypertension and moderate or malignant congestive heart failure. The method of the present invention is a method suitable for the production in China by combining the domestic existing abundant cheap raw material resources, technology and equipment. The present invention has easy requirements for both technology and equipment, and has the advantages of convenient production and low cost.
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)-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 (EP 0079022A2) 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. makes cyclopentanone under catalyst action, at the solution that can form azeotropic mixture with water
In, reflux, divide water reaction 1-4 hour with morpholine, generate compound (1), described
Catalyzer can select tosic acid, calcium chloride or Anhydrous potassium carbonate for use, solvent can
Select 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, generated
Compound (2); C. compound (2) in acetate with ammonium acetate heating reflux reaction 2-4 hour, formationization
Compound (3); D. compound (3) is dissolved in (the acid alcohol volume ratio equals 1: 40) in the acidic ethanol, heavy
Measure under the 10% Pd/carbon catalyst effect, in 25-35 ℃, 40-80 normal atmosphere, hydrogen
Change 5-10 hour, compound (4) E. is converted into the hydrochloride (5) of its benzyl ester with method in common with (4) again, promptly suitable, in
Type-2-azabicyclic [3.3.0]-octane-3-S-benzyl carboxylate hydrochloride.
2. pendant moiety is synthetic, comprising: A. makes maleic acid anhydride and benzene under the effect of aluminum trichloride (anhydrous), and reflux is anti-
Answered 1-3 hour, and generated compound (6); B. with compound (6) in the mixed solution of ethanol and benzene, toluene or dimethylbenzene (both
Volume ratio is the ethyl ester of (1: 3) reflux, Fen Shui, esterification one-tenth (6), coreaction
10-15 hour; C. the product among the B is dissolved in the dehydrated alcohol, makes it L-L-Ala benzyl with equivalent
Ester and triethylamine in 20-30 ℃ of reaction 12-24 hour, generate compound (7); D. compound (7) is dissolved in the acetate, again in wherein adding suitable acetate volume 1-
2% mineral acid, under weight 10% Pd/carbon catalyst effect, in 20-45 ℃,
Under the 1-40 normal atmosphere hydrogenation 2-4 hour, generate compound (8), i.e. N-(1-S-second
Oxygen carbonyl-3-phenyl propyl)-the S-L-Ala.
3. target compound is synthetic, comprising: A. is dissolved in the aforesaid compound (5) and the compound (8) of equivalent among the DMF, adds 2 and works as
The triethylamine and the normal condensing agent of 1-1.2 of amount room temperature reaction 12-24 hour, are given birth to
Become 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 weight 10% Pd/carbon catalyst,
Under the room temperature normal pressure, hydrogenolysis 0.3-0.5 hour, generate formula I compound thunder rice
Puli.Product is measured through x-ray diffraction, confirms that its 5 chiral centres are all the S structure
Type meets intrinsic structural requirement.
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, N.7.82;
C10H13NO2: experimental value C.67.03, H.6.94, 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 10% Pd/carbon catalyst 25-35 ℃ of 1 gram weight, 40 normal atmosphere hydrogenations 10 hours.With the reaction solution evaporate to dryness, use the 5N hcl acidifying, remove by filter 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 with water to neutrality.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)-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]
D 20-15.6 ° of (C=1, CH
3OH). literature value [α]
D 16-17.9 ° 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)-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 weight, 10% Pd/carbon catalyst 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]
D 20+ 26.6 ° of (C=1, CH
3OH); Literature value [α]
D 16+ 27.6 (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 and digest the compound (8) and the solvent DMF of compound (5) (O.002mol), equivalent, add 2 normal triethylamines and 1.1 normal DEPBT 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)-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 weight, 10% Pd/carbon catalyst, 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]
D 20:+10.1°(C=1,CH
3OH)
IR(cm
-1):3330,1750,1650,1200,750,700
MS(FAB):417(M+H),371(M-COOHO,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. the method for a synthetic formula I compound Ramipril,
It is characterized in that described method comprises:
1). synthesizing of azabicyclic part, comprising:
A. make cyclopentanone under the effect of catalyzer, form in the solvent of azeotrope, reflux, divide water reaction 1-4 hour with morpholine in energy and water, the compound shown in the generation following formula,
Described catalyzer is selected from tosic acid, Calcium Chloride Powder Anhydrous or salt of wormwood; Solvent is selected from benzene,toluene,xylene, chlorobenzene or dichlorobenzene,
B. with the compound that generates among the above-mentioned A in solvent dioxane, tetrahydrofuran (THF) or glycol dimethyl ether with the alpha-brominated pyruvate of equivalent, at 0-10 ℃, reacted 1-3 hour, generate the compound shown in the following formula,
C. with the compound that generates among the above B in acetate, with ammonium acetate reflux, reaction 2-4 hour, form the compound shown in the following formula,
D. the compound that generates among the above-mentioned C is dissolved in acid, pure volume ratio and equals in 1: 40 acidic ethanol, under the palladium/charcoal effect of catalyst weight 10%, in 25-35 ℃, the 40-80 normal atmosphere, hydrogenation 5-10 hour, the compound shown in the following formula,
E. again with method in common, the compound that obtains among the above-mentioned D is converted into the hydrochloride of the benzyl ester shown in the following formula,
2). synthesizing of pendant moiety, comprising:
A ' makes maleic acid anhydride and benzene under the effect of aluminum trichloride (anhydrous), and reflux, reaction 1-3 hour generate the compound shown in the following formula,
In ethanol and benzene, toluene or dimethylbenzene, both volume ratios are that reflux in 1: 3 the mixed solution, Fen Shui, esterification become its ethyl ester, coreaction 10-15 hour to B ' with the compound that generates among the above A ';
C ' is dissolved in the product that generates among the above B ' in the dehydrated alcohol, makes it L-alanine benzyl ester and triethylamine with equivalent, in 20-30 ℃, react 12-24 hour, and the compound shown in the generation following formula,
D ' is dissolved in the compound that generates among the above C ' in the acetate, again in the mineral acid that wherein adds acetate volume 1-2%, and under the Pd/carbon catalyst effect of weight 10%, in room temperature, under the normal pressure, hydrogenation 2-4 hour, generate the compound shown in the following formula,
3). synthesizing of target compound, comprising:
A " compound that generates among the compound that generates among the aforementioned E with equivalent and the above-mentioned D ' 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 the compound shown in the following formula; condensing agent is selected from: DCC, HOBt or DEPBT
The compound that generates among the B " with above A " is dissolved in the dehydrated alcohol, adds the Pd/carbon catalyst of weight 10%, in room temperature, under the normal pressure, hydrogenolysis 0.3-0.5 hour, generates the formula I compound.
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,
3) .A " described in condensing agent be DEPBT.
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Cited By (1)
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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 |
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US6407262B1 (en) | 2001-11-21 | 2002-06-18 | Brantford Chemicals Inc. | Process for the preparation of Ramipril |
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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 |
ES2566479T3 (en) | 2006-01-06 | 2016-04-13 | Sunovion Pharmaceuticals Inc. | Monoamine reabsorption inhibitors based on tetralone |
AU2007205114B2 (en) | 2006-01-06 | 2012-11-08 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
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EP0079022A2 (en) * | 1981-11-05 | 1983-05-18 | Hoechst Aktiengesellschaft | Derivatives of cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylic acid, process for their preparation, medicines containing them and their use |
CN1038096A (en) * | 1988-01-27 | 1989-12-20 | 赫彻斯特股份公司 | Application with the compound of treatment psychosis effect, the reagent that contains this compounds and treatment thereof and prevention central nervous system disorder |
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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EP0079022A2 (en) * | 1981-11-05 | 1983-05-18 | Hoechst Aktiengesellschaft | Derivatives of cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylic acid, process for their preparation, medicines containing them and their use |
CN1038096A (en) * | 1988-01-27 | 1989-12-20 | 赫彻斯特股份公司 | Application with the compound of treatment psychosis effect, the reagent that contains this compounds and treatment thereof and prevention central nervous system disorder |
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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 |
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