WO2009098251A1 - Nouveaux dérivés de cycloalcanonealanine β-substituée - Google Patents

Nouveaux dérivés de cycloalcanonealanine β-substituée Download PDF

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Publication number
WO2009098251A1
WO2009098251A1 PCT/EP2009/051312 EP2009051312W WO2009098251A1 WO 2009098251 A1 WO2009098251 A1 WO 2009098251A1 EP 2009051312 W EP2009051312 W EP 2009051312W WO 2009098251 A1 WO2009098251 A1 WO 2009098251A1
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Prior art keywords
compound
general formula
cycloalkanone
preparation
alanine derivatives
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PCT/EP2009/051312
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English (en)
Inventor
Georgios Sarakinos
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DSM IP Assets BV
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DSM IP Assets BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered

Definitions

  • the present invention relates to cycloalkanone ⁇ -substituted alanine derivatives, a process for the preparation of cycloalkanone ⁇ -substituted alanine derivatives and the use of cycloalkanone ⁇ -substituted alanine derivatives in the preparation of enantiomerically enriched ⁇ -amino acids.
  • Cycloalkanone ⁇ -substituted alanine derivatives of the general formula [1] are versatile building blocks in many synthetic approaches towards a wide variety of medicines.
  • a particularly attractive application of cycloalkanone ⁇ -substituted alanine derivatives is the use in enzyme mediated synthesis of enantiomerically pure ⁇ -amino acids.
  • R 1 is alkyl or hydrogen
  • R 2 is acyl
  • R 3 is alkyl or hydrogen
  • n is 1 , 2, 3, 4, 5 or 6 or salts thereof.
  • R 1 and R 3 preferably are, independently, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, benzyl or sec-butyl, R 2 is acetyl, phenylacetyl, carbobenzyloxy, formyl, propionyl or butyryl and n is 3 or 4.
  • the compound of the present invention is further converted into the ACE inhibitors perindopril or ramipril.
  • the second aspect of the invention a method for the preparation of the compounds of the first aspect is provided. It has been found that the cycloalkanone ⁇ -substituted alanine derivatives of the present invention can be successfully prepared starting from easily accessible compounds such as amino acids.
  • R 1 is alkyl
  • R 2 is acyl and X is halogen
  • an amine or other base such as sodium or potassium methoxide, sodium or potassium ethoxide, etc, optionally followed by removal of amine salt followed by treatment with an ester of cycloalkanone- 2-carboxylic acid in the presence of a catalytic amount of base to give the compound of general formula [1].
  • R 1 is methyl
  • R 2 is acetyl
  • X is chlorine.
  • the method as described in the first embodiment is further expanded by conversion of said compound of general formula [1] to give a compound of general formula [3]
  • n is 1 , 2, 3, 4, 5 or 6 and which has the S-configuration at the nitrogen-substituted carbon atom, preferably with an ee-value >95%, more preferably >98%, most preferably >99.5%.
  • Said conversion is carried out by hydrolysis of compound [1] followed by addition of cyanate.
  • hydrolysis is carried out under acidic conditions, for instance using hydrochloric acid under reflux.
  • Addition of cyanate is preferably carried out at neutral pH (i.e. 5.5 to 8.5, preferably 6 to 8, more preferably 6.7 to 7.5) using well-known cyanate sources of which KOCN and NaOCN are well-working examples.
  • the resulting 3-(2-oxocycloalkyl)-2-ureidopropanoic acid is then converted into the compound of formula [3] in a bioconversion using a biocatalyst.
  • said bioconversion is carried out by the action of the enzyme carbamoylase.
  • This enzyme may be used in vitro or in vivo.
  • the carbamoylase is part of a system of more enzymes, for instance a hydantoinase, a carbamoylase and hydantoin racemase.
  • 3-(2-oxocycloalkyl)-2-ureidopropanoic acid can be converted to the corresponding hydantoin at low pH and elevated temperatures prior to the bioconversion as also hydantoins are good substrates for the enzyme system mentioned above.
  • the method as described in the second embodiment is further expanded by subjecting said compound of formula [3] to hydrogenation to give a compound of general formula [4]
  • n is 1 , 2, 3, 4, 5 or 6 and which predominantly has the S,S,S-configuration, preferably >85%, more preferably >90%, most preferably >95%.
  • hydrogenation is carried out in the presence of a suitable metal-based heterogeneous catalyst or homogeneous catalyst.
  • Metal-based heterogeneous catalysts can be, for instance, Pd on carbon or Pt on carbon.
  • Metal-based homogeneous catalysts can be based on, for instance, Ru, Rh, Ir, and the like, with or without ligand.
  • Hydrogenation can be carried out in a polar solvent such as water, methanol, ethanol, acetic acid or mixtures thereof, under a pressure of hydrogen gas between 1 and 15 bar, preferably 8 to 12 bar, at a temperature between 0 and 8O 0 C, preferably between 30 and 6O 0 C.
  • a polar solvent such as water, methanol, ethanol, acetic acid or mixtures thereof
  • the method as described in the third embodiment is further expanded by reacting said compound of general formula [4] with a carboxylic acid or with an activated carboxylic acid, preferably with an "activated" form of a compound of general formula [5] or with a compound of general formula [6]
  • R 4 is alkyl or aryl, preferably -CH 3 or phenyl, to give a compound of formula [7].
  • the carboxylic acid group of compound [4] is protected prior to reaction with compound [5] or its activated form or [6] with the objective to circumvent unwanted side-reactions.
  • the person skilled in the art is aware of the various protecting groups suitable for this purpose. Particularly suitable is protection of compound [4] as a benzyl ester or as a substituted benzyl ester.
  • the resulting carboxylic acid protected derivative of compound [7] can be deprotected to furnish compound [7] using standard techniques.
  • the protecting group is a benzyl ester or as a substituted benzyl ester, deprotection can for instance be carried out using hydrogenation.
  • the compounds of the first aspect of the invention are used in the preparation of a medicament, preferably in the preparation of ramipril. Said uses can be accomplished through the method and intermediate products of the second aspect of the invention.
  • the solution obtained in the previous step was cooled to 10 0 C and by slow addition of NaOH pellets (23.3 g, 0.582 mol), the pH was brought to 7.3. Then, potassium cyanate (14.9 g, 96%, 176 mmol) was added and the mixture was heated to 60°C. After 5.5 h, the solution was cooled to 6°C in an ice-bath and acidified with 5 N aq. HCI (38 ml.) to pH 3.6 and was seeded with 20 mg product. The pH was further lowered to 1.7 with 5 N aq. HCI (19 ml.) and the green-grey slurry was stirred for 15 min and then the product was collected on a filter under suction.
  • the cultures were again incubated for 24-28 h under conditions previously mentioned and subsequently harvested by centrifugation (20 min, 5000 rpm, 4 0 C).
  • the cell pellet was resuspended in 5 ml.
  • Tris-HCI 100 mM, pH 7
  • centrifuged again (20 min, 5000 rpm, 4 0 C) and the cells were frozen at -2O 0 C.
  • 3-(2-oxocyclopentyl)-2-ureidopropanoic acid (13.5 g, 0.063 mol) was suspended in water (40 ml.) and the pH was adjusted to 7.3 with 10.8 N aq. NaOH (6.3 ml_). Then, MnCI 2 solution (3.75 ml_, 100 mmol/L) was added and the solution was flushed with N 2 for 15 min. Then 60 g of wet cell slurry obtained according to 'Expression of Hyu genes in Escherichia coli RV308' (see above) was added. The reaction was stirred at 24°C for 22 h, after which time TLC indicated complete conversion to product.
  • Example 3 To the aqueous solution obtained in Example 3 containing (S)-2-amino-3-(2- oxocyclopentyl)propanoic acid was added 5% Pt/C (3.0 g, 42% water-content) and the hydrogenation was performed under 10 bar of hydrogen gas pressure for 16 h at 70 0 C. At the end of the reaction, the catalyst was separated on filter paper under suction and the product (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid residing in solution was analyzed by HPLC. The diastereomeric ratio is 95:5.
  • the product was purified from salts and other impurities on an ion-exchange column (Amberlyst 15, 80 mL/144 meq.). Elution was initially done with water to neutral pH to remove impurities. Then, the amino acid was eluted with 2N aq. NH 3 aq. and water to neutral pH. These aqueous fractions were combined and concentrated to give the product as an off-white solid.
  • N-[(S)-1 -(ethoxycarbonyl)-3-phenyl-propyl]-L-alanylchloride HCI was synthesized from N-[(S)-1 -(ethoxycarbonyl)-3-phenyl-propyl]-L-alanine and PCI 5 in CH 2 CI 2 at 0 ⁇ 3°C and precipitated by slow addition of cyclohexane as outlined in US 2006/0079698. Filitration was carried out under an atmosphere of nitrogen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur des dérivés de cycloalcanonealanine β-substituée, sur un procédé de préparation de dérivés de cycloalcanonealanine β-substituée et sur l'utilisation de dérivés de cycloalcanonealanine β-substituée dans la préparation d'α-aminoacides énantiomériquement enrichis. De plus, la présente invention porte sur la préparation de produits pharmaceutiquement actifs tels que le périndopril et le ramipril utilisant les nouveaux dérivés de cycloalcanonealanine β-substituée.
PCT/EP2009/051312 2008-02-07 2009-02-05 Nouveaux dérivés de cycloalcanonealanine β-substituée Ceased WO2009098251A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08101354 2008-02-07
EP08101354.2 2008-02-07

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WO2009098251A1 true WO2009098251A1 (fr) 2009-08-13

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8558023B2 (en) 2010-04-20 2013-10-15 Chiral Quest, Inc. Enantioselective process for cycloalkenyl β-substituted alanines
CN103435534A (zh) * 2013-09-09 2013-12-11 嘉兴学院 具有环丙烷结构s-脯氨酸的制备方法
CN104817471A (zh) * 2015-03-12 2015-08-05 浙江昌明药业有限公司 一种环烷酮取代的丙氨酸衍生物的制备方法
WO2015189108A1 (fr) 2014-06-11 2015-12-17 Sanofi-Aventis Deutschland Gmbh Procédé pour la préparation de ramipril

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0625571A2 (fr) * 1993-05-19 1994-11-23 Degussa Aktiengesellschaft Microorganismes, leurs utilisation et méthode de production d'acides amines L-alpha
US20060149082A1 (en) * 2003-02-28 2006-07-06 Thierry Dubuffet Novel method for synthesising derivatives of (2s,3as,7as)-1-[(s)-alanyl]-octahydro,-1h-indole-2-carboxylic acid and the use thereof for perindopril synthesis
WO2007079871A1 (fr) * 2005-12-21 2007-07-19 Sanofi-Aventis Deutschland Gmbh Procede ameliore de production de ramipril

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0625571A2 (fr) * 1993-05-19 1994-11-23 Degussa Aktiengesellschaft Microorganismes, leurs utilisation et méthode de production d'acides amines L-alpha
US20060149082A1 (en) * 2003-02-28 2006-07-06 Thierry Dubuffet Novel method for synthesising derivatives of (2s,3as,7as)-1-[(s)-alanyl]-octahydro,-1h-indole-2-carboxylic acid and the use thereof for perindopril synthesis
WO2007079871A1 (fr) * 2005-12-21 2007-07-19 Sanofi-Aventis Deutschland Gmbh Procede ameliore de production de ramipril

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAGIWARA H ET AL: "Domino Michael-O-alkylation reaction: one-pot synthesis of 2,4-diacylhydrofuran derivatives and its application to antitumor naphthofuran synthesis", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, vol. 22, 1 January 2001 (2001-01-01), pages 2946 - 2957, XP003016073, ISSN: 0300-922X *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8558023B2 (en) 2010-04-20 2013-10-15 Chiral Quest, Inc. Enantioselective process for cycloalkenyl β-substituted alanines
EP2560493A4 (fr) * 2010-04-20 2015-01-21 Chiral Quest Inc Procédé énantiosélectif de production de cycloalcénylalanines bêta-substituées
CN103435534A (zh) * 2013-09-09 2013-12-11 嘉兴学院 具有环丙烷结构s-脯氨酸的制备方法
WO2015189108A1 (fr) 2014-06-11 2015-12-17 Sanofi-Aventis Deutschland Gmbh Procédé pour la préparation de ramipril
CN106536541A (zh) * 2014-06-11 2017-03-22 赛诺菲-安万特德国有限公司 制备雷米普利的方法
US10112973B2 (en) 2014-06-11 2018-10-30 Sanofi-Aventis Deutschland Gmbh Process for the preparation of ramipril
TWI675023B (zh) * 2014-06-11 2019-10-21 德商賽諾菲阿凡提斯德意志有限公司 製備雷米普利（ｒａｍｉｐｒｉｌ）之方法
CN106536541B (zh) * 2014-06-11 2021-01-08 赛诺菲-安万特德国有限公司 制备雷米普利的方法
CN104817471A (zh) * 2015-03-12 2015-08-05 浙江昌明药业有限公司 一种环烷酮取代的丙氨酸衍生物的制备方法

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