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EP1689711A1 - Procede pour produire des composes d' acide n- 1-(s)-carbalcoxy-3-phenylpropyl|-s-alanyl-2s, 3ar, 7as-octahydroindol-2-carboxylique - Google Patents

Procede pour produire des composes d' acide n- 1-(s)-carbalcoxy-3-phenylpropyl|-s-alanyl-2s, 3ar, 7as-octahydroindol-2-carboxylique

Info

Publication number
EP1689711A1
EP1689711A1 EP04797245A EP04797245A EP1689711A1 EP 1689711 A1 EP1689711 A1 EP 1689711A1 EP 04797245 A EP04797245 A EP 04797245A EP 04797245 A EP04797245 A EP 04797245A EP 1689711 A1 EP1689711 A1 EP 1689711A1
Authority
EP
European Patent Office
Prior art keywords
trandolapril
carboxylic acid
phenylpropyl
water
acetone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04797245A
Other languages
German (de)
English (en)
Inventor
Mirko Pogutter
Felix Rudolf
Hans-Ulrich Bichsel
Thomas Bader
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Azad Pharma AG
Original Assignee
Azad Pharmaceutical Ingredients AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Azad Pharmaceutical Ingredients AG filed Critical Azad Pharmaceutical Ingredients AG
Publication of EP1689711A1 publication Critical patent/EP1689711A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a process for the preparation of ⁇ N- [1- (S) -carbalkoxy-3-phenylpropyl] -S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylic acid ⁇ compounds and in particular the compound ⁇ N- [IS-carbethoxy-3-phenylpropyl] -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid ⁇ , which is also known under the name trandolapril.
  • Trandolapril is an active ingredient that, due to the inhibition of the angiotensin converting enzyme (ACE), has hypotensive properties and is used in particular for the treatment of high blood pressure and heart failure. Trandolapril corresponds to formula (I):
  • trandolapril The synthesis of trandolapril is known from EP 0 084 164 by esterifying trans-octahydroindole-2-carboxylic acid with a protective group and then with ⁇ N- [l- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine implemented in a peptide coupling. The product obtained is then chromatographically separated into the diastereomers, whereupon trandolapril is obtained by removing the protective group from the corresponding diastereomer.
  • the octahydroindole-2-carboxylic acid is in the trans configuration and is in the form of benzyl or tert.
  • peptide coupling In addition to dicyclohexylcarbodiimide or hydroxybenzotriazole, peptide coupling also uses carbonyldiimidazole. It is particularly disadvantageous that in the syntheses mentioned, the trans-octahydroindole-2-carboxylic acid has to be provided with a protective group and prior racemate separation of the racemic trans-octahydroindole-2-carboxylic acid used as coupling component is necessary.
  • EP 0 215 335 describes a process for the preparation of ⁇ N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline ⁇ by the N-carboxy anhydride of ⁇ N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ reacted with L-proline. It is found that the conversion of N-carboxyanhydrides has no general applicability for the controlled and reproducible preparation of heteropeptides and can only be used for the invention claimed in EP 0 215 335.
  • EAPPA means ⁇ N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ .
  • NCA N-carboxy anhydride
  • ECAPA-NCA means the N-carboxy anhydride from ECAPPA.
  • Racemic means “racemic”.
  • rac. trans-octahydroindole-2-carboxylic acid means a racemic mixture of tra ⁇ s-octahydroindole-2-carboxylic acid. It has now been found that it is possible to produce trandolapril by reacting rac.
  • trans-octahydroindole-2-carboxylic acid ie without a protective group
  • N-carboxyanhydride of ⁇ N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ reproducible in high yield, without troublesome side reactions, to produce and then to obtain trandolapril directly from the reaction mixture by crystallization in a very pure form. Chromatographic separation of the diastereomers is not necessary. Under rac.
  • Trans-octahydroindole-2-carboxylic acid is here to be understood specifically as a racemic mixture of (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid and (2R, 3aS, 7aR) -octahydroindole-2-carboxylic acid. The same applies in each case to the substituted compounds claimed.
  • the present invention provides a simple way to use rac as starting materials for the production of trandolapril.
  • trans-octahydroindole-2-carboxylic acid is necessary. It is surprising that trandolapril can be obtained directly from the racemate in such a pure form by crystallization.
  • the reaction according to the invention proceeds without further racemization and allows the reaction mixture to be worked up in aqueous form, i.e. of the ECAPPA-NCA reaction mixture used in the Pepid coupling, for destroying excess reagents, such as triphosgene and by-products, as further described herein.
  • the present invention also provides a process which provides a separation of the diastereomers AI and Bl (see scheme 1 below) by crystallization, so that no intermediate cleaning is required until the desired diastereomer is isolated by crystallization.
  • the diastereomers can be separated by crystallization either after salt formation (for example as hydrochloride, see further process 1) or preferably without additional conversion to a salt (see further process 2). So far, chromatographic methods which are technically difficult to use have been described for the separation of corresponding diastereomeric compounds.
  • a gentle slurry in a suitable medium such as sufficient in acetone / water or in acetone.
  • trandolapril specifically crystallizes in two different polymorphic forms and that these different forms also have different properties, such as different bioavailability, solubility and dissolution rate, which gives corresponding advantages in the production of different administration forms.
  • the compounds used according to the invention correspond to the following chemical formulas:
  • the present invention relates to a process for the preparation of optionally substituted ⁇ N- [1- (S) -carbalkoxy-3-phenylpropyl] -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid ⁇ as well as their pharmaceutically acceptable salts, which is characterized in that a racemic mixture of optionally substituted fcrans-octahydroindole-2-carboxylic acid with the N-carboxyanhydride of ⁇ N- [1- (S) -alkoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ , which is optionally substituted on the phenyl ring, is reacted in a suitable inert solvent and then the optionally substituted ⁇ N- [IS-carbalkoxy-3-phenylpropyl] -S-alanyl-2S, 3aR,
  • the compound is preferably isolated by means of crystallization.
  • the connection ⁇ N- [IS- Carbethoxy-3-phenylpropyl] -S-alanyl-2S, 3aR, 7aS-octa-hydroindole-2-carboxylic acid ⁇ (trandolapril).
  • Trandolapril-Hydroohlorid Trandolapril (Diastereomer A1) (Diastereomer A1)
  • the desired diastereomer is preferably crystallized directly from the reaction mixture, ie without prior salt formation, so that trandolapril or a derivative of this compound is obtained directly.
  • This preferred Process is referred to herein as Process 2.
  • the compound produced in this way can then be converted into a suitable salt.
  • the preparation referred to as process 2 follows scheme 1, but the compound referred to as diastereomer AI is crystallized directly without salt formation.
  • Optionally substituted trans-octahydroindole-2-carboxylic acid and its racemic mixtures are known per se.
  • the unsubstituted carboxylic acid and its racemic mixtures are preferably used.
  • the preparation of the N-carboxyanhydride of ⁇ N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ is also known.
  • salts of these optionally substituted ⁇ N- [1- (S) -carbalkoxy-3-phenylpropyl] -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid ⁇ are in particular those with hydrochloric acid, oxalic acid, tartaric acid , Methyl sulfonic acid (mesylate), benzenesulfonic acid (besylate), and the other salts described in the literature.
  • ECAPPA-NCA is produced, for example, by reacting ECAPPA with a carbonyl compound which contains suitable leaving groups, such as carbonyldiimidazole, trichloromethylchloroformate, phosgene, diphosgene or triphosgene, preferably with triphosgene.
  • suitable leaving groups such as carbonyldiimidazole, trichloromethylchloroformate, phosgene, diphosgene or triphosgene, preferably with triphosgene.
  • the process according to the invention begins with the preparation of the N-carboxyanhydride in an inert organic solvent at about 0-40 ° C. This heats ⁇ N- [l- (S) -alkoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ , which is optionally substituted on the phenyl ring, in methylene chloride or another suitable solvent, in the presence of a carbonyl compound which contains suitable leaving groups, preferably triphosgene, the NCA being formed. The solvent and the unreacted carbonyl compound are then preferably removed. The remaining product can then with rac. Octahydroindole-2-carboxylic acid to the diastereomer mixture (AI and Bl, see scheme 1) are implemented. The desired diastereomer AI, preferably trandolapril, can then be used as the salt, e.g. as hydrochloride, preferably without conversion to a salt, be crystallized from the mixture.
  • AI and Bl see scheme
  • Octahydroindole-2-carboxylic acid to the diastereomer mixture AI and Bl is preferably carried out at a temperature in the range of about -20 ° C. to room temperature, preferably in the range from about -20 ° C to 0 ° C, preferably the NCA of ⁇ N- [1- (S) -alkoxycarbonyl-3-phenylpropyl] -L-alanine ⁇ a suspension of rac.
  • trans-octahydroindole-2-carboxylic acid is added in a mixed aqueous solvent system.
  • Trans-octahydroindole-2-carboxylic acid is preferably in the range from 1: 1 to 1: 1.6, preferably about 1: 1.3.
  • the acid value (pH) is preferably kept in the basic range, preferably in the range from pH 9 to pH 10, during the reaction, which is achieved by the simultaneous addition of an inorganic or organic basic reaction compound.
  • Such inorganic or organic compounds with a basic reaction are, for example, alkali metal hydroxides, alkali metal carbonates or alkali metal bicarbonates, preferably of sodium or potassium, or secondary or tertiary amines, such as, for example, dialkylamines such as dimethylamine, diethylamine, trialkylamines such as trimethylamine, triethylamine, tripropylamine or tributylamine. Pyridine or quaternary ammonium hydroxides, for example, can also be used.
  • Mixed aqueous solvent systems are preferably mixtures of water and a water-miscible organic solvent, such as, for example, acetone, dioxane or tetrahydrofuran. Acetone is preferred.
  • the organic solvent is distilled off, giving an aqueous solution which is then obtained using an water-immiscible organic solvent, for example in an organic ester, such as, for example, methyl acetate.
  • Ethyl acetate, propyl acetate, preferably ethyl acetate is added.
  • This organic phase now contains the desired reaction product as diastereomer AI in a mixture with diastereomer B1, as shown in Scheme 1.
  • the selective crystallization of the product obtained, preferably trandolapril, from the organic phase can now be carried out.
  • the selective crystallization is preferably carried out at a temperature in the range from -5 ° C to +30 ° C.
  • the organic phase generally contains the desired reaction product as diastereomer AI in a mixture with the diastereomer B1 in a ratio of about 1: 1, it is necessary to separate the diastereomer AI from the diastereomer B1. Surprisingly, this can be done by crystallization.
  • Trandolapril both as hydrochloride (according to method 1) and as a free compound (according to method 2) the water content of the solvent plays a decisive role.
  • a water content of the organic solvent preferably in the range of 2-4% by weight, preferably 2.5-3.5% by weight and preferably approximately 3% by weight is used.
  • the desired diastereomer AI crystallizes out in high purity, while the diastereomer Bl remains largely in solution. At lower water levels, there is poor or no separation. If the water content is higher, yield losses can be expected.
  • a water content of the organic solvent preferably in the range of 0.05-4.0% by weight, preferably 1.5-3.0% by weight, is used.
  • the desired diastereomer Al crystallizes out in a surprisingly high purity, while the diastereomer B1 largely remains in solution. With higher water contents, losses in yield are to be expected, but these are not critical.
  • An organic ester such as e.g. Ethyl acetate, ethyl acetate, propyl acetate, preferably ethyl acetate.
  • the diastereomer AI is generally obtained in a purity in the range from 88.0% by weight to 98% by weight, the remaining 2-12% by weight consisting predominantly of ECAPPA and the diastereomer B1.
  • a further purification of the product obtained by crystallization can be carried out by recrystallization or preferably by sludge in an organic solvent or in a mixture of such a solvent with water.
  • Preferred solvents or solvent mixtures are: acetone / water, acetone, acetone / MTBE (methyl tert-butyl ether), ethyl acetate and ethyl acetate / - MTBE.
  • the diastereomer mixture is first converted into a suitable salt for the isolation of diastereomer AI and then subjected to the crystallization.
  • suitable salts for this purpose are, for example, the hydrochloride, sulfate, phosphate and other salts known per se.
  • the hydrochloride is preferably used.
  • the organic phase preferably ethyl acetate, now contains the desired reaction product as diastereomer AI in a mixture with diastereomer B1.
  • HCl gas is passed into the organic phase at 0-20 ° C., whereupon the hydrochloride forms.
  • trandolapril hydrochloride is crystallized from acetone / MTBE (methyl tert-butyl ether).
  • Trandolapril is preferably released from the hydrochloride in a mixture of water and a water-miscible organic solvent (for example acetone), a pH of 4.0-6.0 being set by adding a base.
  • a water-miscible organic solvent for example acetone
  • Sodium hydrogen carbonate is preferably used as the base.
  • the crystallization of the product can already begin.
  • a further purification of the end product (trandolapril) can be carried out by recrystallization or preferably by a Slurry in an organic solvent, possibly in a mixture with water.
  • the present invention also relates to two new crystalline forms of trandolapril. It has been found that two different crystalline forms, referred to herein as Form A and Form B, can be obtained in the crystallization of trandolapril.
  • the crystalline form A is characterized by the following IR and XRD data (Tables 1 and 2) and by the ORTEP representation of the corresponding crystal structure analysis ( Figure 1 and Table 3).
  • Illustration 1 Crystal structure of trandolapril (stereo ORTEP representation)
  • the stable crystalline form A can be prepared by crystallization of trandolapril from an organic solvent or a mixture of organic solvents (for example acetone / cyclohexane), the solvent should preferably have a water content of at most 0.2% by weight ( ⁇ 0.2% by weight). In this sense, the polymorphic form A can be referred to as the anhydrous form.
  • the stable polymorphic form A can be obtained from the less stable form B by slurrying in acetone.
  • the crystalline form B can be obtained in particular by crystallization of the trandolapril from water or mixed aqueous systems at 0-25 ° C.
  • the polymorphic form B can be produced in a targeted manner by crystallization of trandolapril from methanol / water or acetone / water mixtures at 0-25 ° C., the form B having a water content in the range of 4-4.4% by weight and can be called a monohydrate.
  • the two forms A and B can be used as therapeutic active substances and processed together with a suitable pharmaceutical carrier material to form a medicament.
  • This medication can be used to treat cardiovascular diseases, especially to treat high blood pressure and heart failure.
  • Suitable pharmaceutical carrier materials for the production of medicaments are known to the person skilled in the art.
  • trandolapril preparation of trandolapril and the polymorphic forms A and B of trandolapril illustrate the present invention without restricting its scope and application.
  • 61.45 g of ECAPPA are dissolved in 580 g of methylene chloride at 20-30 ° C. and a solution of 62.32 g of triphosgene in 212 g of methylene chloride is added at this internal temperature. The mixture is then heated under reflux for 14-16 hours. After conversion is complete, the mixture is concentrated in vacuo (600 to ⁇ 50 mbar) and the resulting yellow viscous oil is taken up in 126.8 g of acetone at 10-20 ° C. The solution is cooled to 0-5 ° C and added dropwise to a suspension of 33.6 g sodium hydrogen carbonate in 82 g water at 0-8 ° C. After the addition is complete, the two-phase NCA suspension is stirred at 0-5 ° C for 30-90 minutes.
  • the organic phase is separated off, dried over sodium sulfate and cooled to 0-5 ° C.
  • a total of 29.17 g of HCl gas is slowly introduced into this solution.
  • the solvent is then removed in vacuo, the resulting clear oil is taken up in 320 g of acetone and the solution is heated to 55.degree. 640 g of MTBE and then a little trandolapril hydrochloride (for inoculation) are added to the hot solution.
  • the polymorphic form B of trandolapril is, as described in Example 1, section e) and in Example 2, section e), slurried in acetone, the form B converting completely to the polymorphic form A.
  • Trandolapril is obtained in the polymorphic form B (yield: 0.93 g).
  • Example 6 (Preparation of Polymorphic Form B of Trandolapril) A solution of 1.00 g of trandolapril in 60 ml of acetone is added at 0-5 ° C. in 300 ml of water to which a little Trandolapril of Form B has been added beforehand. At this internal temperature, the solution is sation stirred (5-6 hours) and stored in the refrigerator overnight. The suspension is then filtered and the solid is dried at 40 ° C. in vacuo. Trandolapril is obtained in the polymorphic form B in a yield of 0.29 g.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne un procédé pour produire de l'{acide N-[1-(S)-carbalcoxy-3-phénylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylique} ainsi que ses sels pharmaceutiquement acceptables. Ce procédé consiste à : faire réagir dans un solvant inerte approprié un mélange racémique d'acide trans -octahydroindol-2-carboxylique éventuellement substitué avec le N-carboxyanhydride de {N-[1-(S)-alcoxycarbonyl-3-phénylpropyl]-L-alanine}, éventuellement substitué au niveau du noyau phényle; puis à isoler l'{acide N-[1-S-carbalcoxy-3-phénylpropyl]-S-alanyl-2S, 3aR, 7aS-octahydroindol-2-carboxylique} éventuellement substitué, obtenu, de préférence le trandolapril, ainsi que des formes polymorphes A et B de trandolapril.
EP04797245A 2003-11-28 2004-11-15 Procede pour produire des composes d' acide n- 1-(s)-carbalcoxy-3-phenylpropyl|-s-alanyl-2s, 3ar, 7as-octahydroindol-2-carboxylique Withdrawn EP1689711A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH20382003 2003-11-28
PCT/CH2004/000688 WO2005051909A1 (fr) 2003-11-28 2004-11-15 Procede pour produire des composes d'{acide n-[1-(s)-carbalcoxy-3-phenylpropyl]-s-alanyl-2s, 3ar, 7as-octahydroindol-2-carboxylique}

Publications (1)

Publication Number Publication Date
EP1689711A1 true EP1689711A1 (fr) 2006-08-16

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Application Number Title Priority Date Filing Date
EP04797245A Withdrawn EP1689711A1 (fr) 2003-11-28 2004-11-15 Procede pour produire des composes d' acide n- 1-(s)-carbalcoxy-3-phenylpropyl|-s-alanyl-2s, 3ar, 7as-octahydroindol-2-carboxylique

Country Status (4)

Country Link
US (1) US20070135513A1 (fr)
EP (1) EP1689711A1 (fr)
JP (1) JP2007512260A (fr)
WO (1) WO2005051909A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2614099A1 (fr) * 2005-07-05 2007-01-11 Cipla Limited Procede de synthese de l'inhibiteur de l'enzyme de conversion de l'angiotensine
US7943655B2 (en) 2006-04-05 2011-05-17 Universitat Zurich Polymorphic and pseudopolymorphic forms of trandolaprilat, pharmaceutical compositions and methods for production and use
WO2011009021A1 (fr) 2009-07-16 2011-01-20 Abbott Laboratories Procédés de synthèse d'acide (2s, 3ar, 7as)-octahydro-1h-indole carboxylique comme intermédiaire pour le trandolapril
WO2018016376A1 (fr) * 2016-07-21 2018-01-25 株式会社カネカ Procédé de fabrication de composé organique

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE55867B1 (en) * 1981-12-29 1991-02-14 Hoechst Ag New derivatives of bicyclic aminoacids,processes for their preparation,agents containing these compounds and their use,and new bicyclic aminoacids as intermediates and processes for their preparation
JPS6248696A (ja) * 1985-08-27 1987-03-03 Kanegafuchi Chem Ind Co Ltd Ｎ−〔１（ｓ）−エトキシカルボニル−３−フエニルプロピル〕−ｌ−アラニル−ｌ−プロリンの製造法
US6541635B1 (en) * 2002-03-29 2003-04-01 Everlight Usa, Inc. Method for producing angiotensin converting enzyme inhibitor

Non-Patent Citations (1)

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Title
See references of WO2005051909A1 *

Also Published As

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JP2007512260A (ja) 2007-05-17
WO2005051909A1 (fr) 2005-06-09
US20070135513A1 (en) 2007-06-14

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