WO2003016264A1 - Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides - Google Patents
Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides Download PDFInfo
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- WO2003016264A1 WO2003016264A1 PCT/US2002/026142 US0226142W WO03016264A1 WO 2003016264 A1 WO2003016264 A1 WO 2003016264A1 US 0226142 W US0226142 W US 0226142W WO 03016264 A1 WO03016264 A1 WO 03016264A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
- 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
- C07C233/51—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 an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- This invention relates to processes suitable for the large-scale preparation of enantiomerically enriched N-acyl ⁇ -amino acid derivatives.
- it relates to enantioselective hydrogenation ofthe corresponding (Z)-enamide precursors.
- ⁇ -amino acids are found in many natural products, such as ⁇ -peptides (Gellman, Ace. Chem. Res., 1998, 31, 160 and references cited therein). These and other compounds derived from ⁇ -amino acid building blocks have a wide spectrum of biomedical applications and therefore ⁇ -amino acids have become important commercial targets.
- Suitable precursors are ⁇ -(acylamino)acrylate esters (i), as either (E)- or (Z)-isomers, in which the N-acyl group serves as a binding site for transition metal-based catalysts containing chiral ligands.
- i ⁇ -(acylamino)acrylate esters
- E E
- Z Z-isomers
- These substrates are easily prepared through standard protocols, most conveniently from the corresponding ⁇ -keto ester by reaction of with ammonia followed by N-acylation (Zhu, Chen and Zhang, J. Org.
- This invention is based on the discovery that the use of alcohol solvents enables the rapid and highly enantioselective catalytic hydrogenation ofthe (Z)-enamide precursors of N-acyl ⁇ -amino acid derivatives, catalysed by cationic rhodium complexes of chiral phosphine ligands.
- This simple expedient provides the basis of an industrially useful and atom-efficient process to these products.
- the present invention encompasses a novel process as depicted in Figure 2, and provides an effective means of accessing an enantiomerically enriched ⁇ -amino acid derivative of formula (1), or the opposite enantiomer thereof, from the (Z)-enamide precursor (2).
- R 1 is an optionally substituted alkyl, aryl or heteroaryl group of up to 20 C atoms
- R 2 is an alkyl group of up to 20 C atoms
- R 3 is H or an alkyl or aryl group of up to 20 C atoms.
- the process comprises asymmetric hydrogenation ofthe substrate (2) and is distinguished from the prior art by the use of an alcohol solvent or cosolvent in combination with, as catalyst, a cationic rhodium complex of a chiral phosphine ligand having the partial formula (3), wherein n is 0 to 6 and R represents at least one non-hydrogen organic group of up to 20 C atoms. Where two or more R groups are present, such R groups may be the same or different, may optionally be joined to form a ring, and may optionally obtain heteroatoms. Ligands having such structural variations will be readily identifiable by those skilled in the art.
- the (Z)-enamide precursor (2) may either be used in geometrically pure form or in admixture with (E)-enamide precursor (4).
- (4) also undergoes hydrogenation to afford (1), enriched in the same enantiomer as obtainable from (2) and usually at a rate comparable to or faster than (2).
- this can provide a highly atom-efficient route to the desired product (1).
- R 1 , R 2 and R 3 are each independently alkyl and are more preferably methyl or n-alkyl, R 2 typically being methyl or ethyl.
- the alcohol solvent or cosolvent is typically selected from the group comprising methanol, ethanol, isopropan ⁇ l and triflouroethanol.
- the moiety R 2 OH and the alcohol can be the same, so as to preclude the side reaction of ester exchange. However, this is not always necessary; for example trifluoroethanol can be an effective solvent for substrates (2) in which R 2 is methyl or ethyl.
- the chiral phosphine ligand is usually of formula (5) or (6), wherein Linker and R' are independently any non-hydrogen organic or organometallic group of up to 30 C atoms.
- the ligand is a bidentate ligand of formula (6) and n is 2; more preferably, the ligand is of formula (7), or an opposite enantiomer thereof, the optimum group R being dependent on the particular hydrogenation substrate, and readily determined by screening a series of catalysts.
- R is a non-hydrogen organic group of up to 20 C atoms and is usually is a C 1-8 linear or branched alkyl group.
- the cationic rhodium complex used as catalyst is usually of the form [Rh(6)(COD)] + BF 4 , although it will be recognised by those skilled in the art that COD (1,5-cyclooctadiene) may be replaced by an alternative diene such as NBD (2,5-norbornadiene), and that BF 4 " may be replaced by an alternative counterion such as PF 6 " .
- the term "catalyst” refers to the isolated pre-catalyst that is added to the reaction vessel for hydrogenation and which typically undergoes a change in composition in situ to generate one or more catalytically active species. Equivalent catalysis may be achieved by generation of catalytically active species from the chiral ligand (6) and an achiral rhodium-containing precursor.
- ethyl 3-acetamido-2-butanoate was obtained through the rapid and highly enantioselective asymmetric hydrogenation of (Z)-ethyl 3- acetamido-2-butenoate [(Z)-10] under carefully selected conditions (Figure 3).
- Results of comparative experiments are summarised in Table 2.
- Entry 1 Rh-MeDuPHOS catalyst and toluene solvent
- Entry 2 shows the marked effect of changing the solvent to methanol, the same reaction proceeding to completion in less than 1 minute.
- Entries 3 & 4 show incremental improvements in enantioselectivity through use of homologous catalysts containing EtDuPHOS and 'PrDuPHOS ligands. With the latter, an effective process is also achieved at a higher substrate:catalyst ratio (Entry 5).
- Entries 6-9 show further experiments with the preferred Rh-'PrDuPHOS catalyst and variation of the alcohol solvent.
- Trifluoroethanol (TFE) gives the best process in terms of both rate and enantioselectivity (Entry 8) and is also highly effective when used as a cosolvent with methanol (Entry 9).
- Entries 10-12 show highly effective enantioconvergent hydrogenation of a 1:1 mixture of (Z)-10 and (E)-10. Entry 13 is a control experiment showing rapid and highly selective asymmetric hydrogenation of pure (E)-10 in TF ⁇ .
- [( 1 PrDuPHOS)Rh(COD)]BF 4 was shown to be an effective catalyst for the asymmetric hydrogenation of (Z)-ethyl 3-acetamido-2- phenyl-2-propenoate, to produce ethyl 3-acetamido-2-phenylpropanoate in 77 percent ee (at 140 psi H 2 pressure), increasing to 89 percent ee at 30 psi H 2 .
- the process ofthe present invention provides an effective means of preparing a wide range of enantiomerically enriched N-acyl ⁇ -amino acid derivatives.
- enantiomeric enrichment ofthe product obtained by asymmetric hydrogenation is at least 70 percent ee, and is preferably at least 90 percent ee, or higher. If necessary, any shortfall in ee can subsequently be corrected by standard techniques such as selective enzyme-catalysed hydrolysis ofthe ester or amide group of the unwanted enantiomer ofthe hydrogenation product.
- the precatalyst (0.01 mmol) and the starting material (171 mg, 1.0 mmol) were weighed.
- a stirring cross was added and the liner was placed in a 50 mL autoclave.
- the autoclave was purged 4 times with 120-160 psi N 2 and 7-8 times with H 2 (same pressure).
- Methanol (3 mL; reagent grade) was added and the autoclave purged with 140 psi H 2 , at least 8 times. Vigorous stirring was started.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02757176A EP1421059A1 (en) | 2001-08-17 | 2002-08-16 | Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides |
JP2003521193A JP2005518339A (en) | 2001-08-17 | 2002-08-16 | Process for producing enantiomerically rich N-acyl-β-amino acid derivatives by enantioselective hydrogenation of the corresponding (Z) enamide |
US10/485,188 US20040186314A1 (en) | 2001-08-17 | 2002-08-16 | Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0120167A GB0120167D0 (en) | 2001-08-17 | 2001-08-17 | Asymmetric hydrogenation |
GB0120167.2 | 2001-08-17 |
Publications (1)
Publication Number | Publication Date |
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WO2003016264A1 true WO2003016264A1 (en) | 2003-02-27 |
Family
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2002/026142 WO2003016264A1 (en) | 2001-08-17 | 2002-08-16 | Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1421059A1 (en) |
JP (1) | JP2005518339A (en) |
GB (1) | GB0120167D0 (en) |
WO (1) | WO2003016264A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005011863A1 (en) * | 2003-08-05 | 2005-02-10 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A chiral ligand metalcomplex catalyst system and its preparation and applications |
WO2006100165A1 (en) * | 2005-03-23 | 2006-09-28 | Degussa Gmbh | Electron-deficient bisphospholane ligands and catalysts |
WO2011146610A2 (en) * | 2010-05-19 | 2011-11-24 | Dr. Reddy's Laboratories Ltd. | An enantioselective synthesis of chiral amines for the production of rotigotine |
US8791143B2 (en) | 2010-06-15 | 2014-07-29 | Bayer Cropscience Ag | Anthranilic diamide derivatives having cyclic side-chains |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR043515A1 (en) * | 2003-03-19 | 2005-08-03 | Merck & Co Inc | PROCEDURE TO PREPARE CHIRAL DERIVATIVES BETA AMINO ACIDS BY ASYMMETRIC HYDROGENATION |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06271520A (en) * | 1993-03-19 | 1994-09-27 | Daicel Chem Ind Ltd | Production of optically active beta-amino acids |
US5371256A (en) * | 1992-04-02 | 1994-12-06 | Ciba-Geigy Corporation | Ferrocenyl diphosphines as ligands for homogeneous catalysts |
EP1225166A1 (en) * | 2001-01-11 | 2002-07-24 | Degussa AG | Process for the preparation of enantiomer-enriched beta-amino acids |
-
2001
- 2001-08-17 GB GB0120167A patent/GB0120167D0/en not_active Ceased
-
2002
- 2002-08-16 WO PCT/US2002/026142 patent/WO2003016264A1/en not_active Application Discontinuation
- 2002-08-16 JP JP2003521193A patent/JP2005518339A/en active Pending
- 2002-08-16 EP EP02757176A patent/EP1421059A1/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5371256A (en) * | 1992-04-02 | 1994-12-06 | Ciba-Geigy Corporation | Ferrocenyl diphosphines as ligands for homogeneous catalysts |
JPH06271520A (en) * | 1993-03-19 | 1994-09-27 | Daicel Chem Ind Ltd | Production of optically active beta-amino acids |
EP1225166A1 (en) * | 2001-01-11 | 2002-07-24 | Degussa AG | Process for the preparation of enantiomer-enriched beta-amino acids |
Non-Patent Citations (2)
Title |
---|
HELLER D ET AL: "PRESSURE DEPENDENT HIGHLY ENANTIOSELECTIVE HYDROGENATION OF UNSATURATED BETA-AMINO ACID PRECURSORS", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 66, no. 20, 5 October 2001 (2001-10-05), pages 6816 - 6817, XP002198463, ISSN: 0022-3263 * |
PATENT ABSTRACTS OF JAPAN vol. 018, no. 680 (C - 1291) 21 December 1994 (1994-12-21) * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005011863A1 (en) * | 2003-08-05 | 2005-02-10 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A chiral ligand metalcomplex catalyst system and its preparation and applications |
WO2006100165A1 (en) * | 2005-03-23 | 2006-09-28 | Degussa Gmbh | Electron-deficient bisphospholane ligands and catalysts |
WO2011146610A2 (en) * | 2010-05-19 | 2011-11-24 | Dr. Reddy's Laboratories Ltd. | An enantioselective synthesis of chiral amines for the production of rotigotine |
WO2011146610A3 (en) * | 2010-05-19 | 2012-03-15 | Dr. Reddy's Laboratories Ltd. | An enantioselective synthesis of chiral amines for the production of rotigotine |
US8791143B2 (en) | 2010-06-15 | 2014-07-29 | Bayer Cropscience Ag | Anthranilic diamide derivatives having cyclic side-chains |
Also Published As
Publication number | Publication date |
---|---|
JP2005518339A (en) | 2005-06-23 |
GB0120167D0 (en) | 2001-10-10 |
EP1421059A1 (en) | 2004-05-26 |
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