WO2004087661A1

WO2004087661A1 - Process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle

Info

Publication number: WO2004087661A1
Application number: PCT/EP2004/003614
Authority: WO
Inventors: Roland Callens; Marc Larcheveque; Cyrille Pousset; Angella Marinetti
Original assignee: Solvay (Société Anonyme)
Priority date: 2003-04-04
Filing date: 2004-04-02
Publication date: 2004-10-14
Also published as: FR2853316A1

Abstract

Process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle, said heterocycle being substituted with at least one side chain comprising a functional group of carboxyl type, such as a carboxyl group, an ester group or an amide group, which process comprises at least one step in which a prochiral unsaturated amino acid derivative of formula (I) is subjected to hydrogenation in the presence of an enantiopure hydrogenation catalyst.

Description

Process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle

The present invention relates to a process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle.

Some amino acids comprising at least one nitrogenous heterocycle and their derivatives are useful in the context of the production of peptides which can be used as medicinal products. Examples of such unnatural amino acids comprise at least one nitrogenous heterocycle.

US Patent 3,891,616 describes some biologically active peptides containing 2-pyrrolidineacetic acid. The -Boc derivative of this acid is prepared by treatment of natural L-proline with diazomethane. This known process requires the use of an enantiopure natural amino acid as starting product. The latter is subjected to conversions with a very dangerous reagent under conditions which may involve a risk of racemization.

The invention is aimed at remedying these problems.

The invention subsequently relates to a process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle, said heterocycle being substituted with at least one side chain comprising a functional group of carboxyl type, such as a carboxyl group, an ester group or an amide group, which process comprises at least one step in which a prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle, said heterocycle being substituted with at least one side chain comprising a functional group of carboxyl type, is subjected to hydrogenation in the presence of an enantiopure hydrogenation catalyst.

The process according to the invention makes it possible to produce amino acid derivatives with a virtually quantitative chemical yield for the enantioselective step, attaining high enantiomeric excesses, i.e. generally of at least 90%, and more often at least 95%, and which can reach 97% or more. The process according to the invention does not depend on the availability of suitable enantiopure natural amino acids.

The term "enantiopure compound" is intended to denote a chiral compound consisting essentially of an enantiomer. The enantiomeric excess (ee) is defined as: ee(%) = 100(xι-x₂)/(xι+X2) with xι>x₂; xi and x₂ represent the content in the mixture of enantiomer 1 or ,2 respectively. In the process according to the invention, an enantiopure hydrogenation catalyst, the enantiomeric excess of which is greater than or equal to 99%, is generally used. An enantiopure hydrogenation catalyst, the enantiomeric excess of which is greater than or equal to 99.5%, is preferred. Particularly preferably, an enantiopure hydrogenation catalyst, the enantiomeric excess of which is greater than or equal to 99.9%, is used.

In the process according to the invention, the hydrogenation catalyst is often a chiral complex of a metal of group 7, 8, 9 or 10 of the periodic table of elements (IU AC). A metal of the second or third period of groups 8, 9 or 10 is preferred. In this case, the metal is particularly preferably chosen from ruthenium, iridium and rhodium.

In the process according to the invention, the hydrogenation catalyst often contains an enantiopure chiral diphosphine. Such chiral diphosphines are commercially available or can be prepared using processs described in the state of the art. Diphosphines exhibiting C2 symmetry and those exhibiting axial chirality, such as biphenyl and binaphthyl derivatives, are preferred. Particular examples of the ligands are given in scheme 1 below. Preferred examples of the enantiopure diphosphines are chosen from di-t-bu-MeO-BIPHEP, Me-DuPHOS, Et-Ferrotane and Tol-BINAP.

A catalytic system comprising these preferred diphosphines and one of the preferred metals is more particularly preferred.

Scheme 1

(S.-BINAP (S)-TolBINAP

(S)-MeO-BIPHEP (R,R)-Me-DuPHOS Et-FerroTANE

Ir-PHOX The hydrogenation pressure is generally at least 2 bar. The pressure is more often at least 2.5 bar. The pressure is preferably at least 3 bar. The hydrogenation pressure is generally at most 100 bar. The pressure is more often at most 50 bar. The pressure is preferably at most 20 bar. The hydrogenation temperature is generally at least -20°C. The temperature is more often at least 0°C. The temperature is preferably at least -10°C. The hydrogenation temperature is generally at most 200°C. The temperature is more often at most 100°C. The temperature is preferably at most 50°C.

The hydrogenation is often carried out in a medium containing an oxygenated solvent. Preferred examples are chosen from ethers and alcohols. Methanol, ethanol and tetrahydrofuran are more particularly preferred.

In the process according to the invention, the amount of catalyst used is generally at least 0.01% by weight relative to the total weight of prochiral unsaturated amino acid derivative used. This amount is often at least 0.1% by weight. It is preferably at least 0.5% by weight. In the process according to the invention, the amount of catalyst used is generally at most 5% by weight relative to the total weight of prochiral unsaturated amino acid derivative used. This amount is often at most 2% by weight. It is preferably at most 1.5% by weight.

In the process according to the invention, the prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle often corresponds to formula (I)

In this formula, m is 0, 1, 2 or 3, preferably 1 or 2. In this formula, Z denotes H or an amino group-protecting group. By way of nonlimiting examples of amino function-protecting groups which may be represented by Z, mention may in particular be made of substituted or unsubstituted groups of acyl type, such as the formyl, acetyl, trifluoroacetyl or benzoyl group, substituted or unsubstituted groups of aralkyloxycarbonyl type, such as the benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2-(p-biphenylyl)isopropyloxy- carbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group, substituted or unsubstituted groups of alkyloxycarbonyl type, such as the tert-butyloxycarbonyl, tert-amyloxycarbonyl, diisopropylmethyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, 2-methylsulphonylethyloxycarbonyl or 2,2,2-trichloro- ethyloxycarbonyl group, groups of cycloalkyloxycarbonyl type, such as the cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl group, and groups containing a hetero atom, such as the benzenesulphonyl, p oluenesulphonyl (tosyl), mesitylenesulphonyl, methoxytrimethylphenylsulphonyl or o-nitrophenylsulphenyl group.

Among these groups Z, those comprising a carbonyl or sulphonyl group are preferred. It has been found that the presence of the carbonyl group within the substituent Z makes it possible to achieve particularly good enantioselectivities. The acyl, aralkyloxycarbonyl and alkyloxycarbonyl groups are more particularly preferred. In formula (I), Y denotes in particular a substituent which confers on the carbon of the carbonyl group the degree of oxidation+m. Y can be chosen from OH, OR, NH₂, NHR, NR₂ and SR, in which R denotes a substituent other than hydrogen. The compound containing Y is the -chosen from carboxylic acids, esters, amides and thioesters. It is preferably chosen from amides and esters.

In formula (I), the double bond of the group —COY is an exocyclic double bond formed with any one of the carbon atoms of the heterocycle.

The configuration of the double bond with respect to the group -COY and with respect to the nitrogen is preferably "E". In a particularly preferred aspect of the process according to the invention, the prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle corresponds to formula (II)

in which Z, Y and m are as defined above for formula (I), and m is 0, 1 or 2. In the process according to the invention, in the prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle, the heterocycle may comprise, in addition to the nitrogen, one or more other hetero atoms chosen, for example, from oxygen and sulphur.

The prochiral unsaturated amino acid derivatives comprising at least one nitrogenous heterocycle used in the process according to the invention can be obtained in an appropriate manner starting with carbonyl precursors by virtue of known carbonyl olefination reactions such as the (thio)-Wittig reaction or Peterson olefmation.

The example below is intended to illustrate the invention without, however, limiting it. Examples

A. Synthesis of l-methoxycarbonyIpiperidine-2-thione

2.3 g of piperidine-2-thione (20 mmol, 1 equiv.) and 100 ml of anhydrous THF were introduced into a 250 ml three-necked flask equipped with a stirring rod and a dropping funnel and placed under argon. The solution was cooled to -78°C. 14 ml of 1.6M butyllithi m in hexane (22 mmol, 1.1 equiv.) were added dropwise. The solution was then stirred for one hour at -78°C. After the addition of 1.16 ml of methyl chloroformate (25 mmol, 1.3 equiv.), the mixture was stirred for 30 minutes at -78°C and then reheated to ambient temperature. After 3 hours at ambient temperature, water was added. The aqueous phase was extracted with ether. The organic phases were pooled and dried over MgS0₄ and the residue obtained was chromatographed on a silica column with a 4/1 cyclohexane/ethyl acetate mixture as eluent. 2.6 g of a yellow oil corresponding to the expected product were isolated (yield = 75%).

¹³C _ MR: δ (CDC1₃) 206,5 (s, C=S), 1_.55,9 (s, C=O), 54,4 (s, OCH₃), 48,6 (s, CH₂N), 43,9 (s, CH₂C=S), 21,6 (s, CH₂CH₂1S , 20,1 (s, CH₂CH₂C=S).

^ NMR: δ (CDC1₃) 3,86 (s, 3H, OCH₃), 3,70 (t, ³J_H-H=6 Hz, 2H, CH₂CHJSD, 2,94 (t, ³J_H-_H=6,5. Hz, 2H,

1,75 (quint, ³J_H-_H=6,5 Hz, ³J_H-H= 5,5 Hz, 2H; CH₂CH^CH₂C=S).

LR.: (pure) 1762

1244 (vC=S). B. Synthesis of (-EVl-methoxycarbonyl-l-carbethosymethylenepiperidine

1

3.46 g ofN-methoxycarbonylpiperidine-2-thione 1 (20 mmol, 1 equiv.), 10.44 g of phosphorus ylide (30 mmol, 1.5 equiv.) and 150 ml of toluene were introduced into a 250 ml round-bottomed flask equipped with a refrigerant and an argon inlet. The mixture was refluxed. After stirring for 24 h, a further 7 g of phosphorus ylide (20 mmol, 1 equiv.) were added and the stirring at reflux was continued for 24 h. After evaporation of the solvent, the product was purified by chromatography on a silica column with an 85/15 cyclohexane/ethyl acetate mixture as eluent. 2.7 g of a white solid corresponding to the expected product were isolated (yield = 60%).

M.p. = 126°C. ¹³C MMK: δ (CDC1₃) 167,3 (s, COOEt), 155,3 (s, NCOOMe), 154,9 (s, NC=CH), 111,8 (s, NC=CH), 59,9 (s, OCH₂CH₃), 53,2 (s, OCH₃), 46,6 (s, CH₂N), 27,3 (s, CH₂C=CH), 24,2 (s, CH2CH2N), 23,2 (s, CH₂CH₂C=CH), 14,4 (s, OCH₂CH₃).

1H WMR: δ (CDCI3) 5,92 (t, ⁴J_H-_H=1.0 HZ, IH, NC=CH), 4,14 (q, ³J_H-_H=7,2 HZ, 2H, OCϊ^CH₃), 3,73 (s, 3H, OMe), 3,64 (t, HZ, 2H, CU₂C=CH), 1,71 (m, 4H, CHz

CH₃). Mass spectrometry:

M/Z: (ICP/NH₃) 228 ((M+H)⁺), 245 ((M+NH₄)").

LR.: (KBr) 1727 (vCO_ester), 1703 (vCOcarbamate), 1624 (vC=C).

Elemental analysis: '

Calculated: C 58.14%; H 7.54%; N 6.16% Measured: C 57.99%; H 7.74%; N 6.07%.

C: Synthesis of (2i?)-l-methoxycarbonyl-2-carbethoxymethyIpiperidine

3.3 mg of [(R,R)- ?-DuPHOS (COD) Rh OTfJ (0.01 mmol: 1 equiv.) and 1 ml of ethanol were introduced into a test tube placed under an argon atmosphere. The solution was stirred and then 227 mg of (£)-β-enaminoester 2 (100 eqiv.) and 1 ml of ethanol were added. The tube was then placed in an autoclave under hydrogen at a temperature of 25°C and a pressure of 3 bar. At the end of the reaction, the solution was evaporated and then filtered on a silica column (ether eluent) so as to provide the expected product.

[αg = +13,7 (c = 1,5 CH₂C1₂). ¹³C NMR: δ (CDC1₃) 171,4 (s, COOEt), 156,0 (s, NCOOMe), 60,6 (s, OCH2CH₃), 52,6 (s, OCH3), 48,1 (s, NCH), 39,5 (s, CH₂N), 35,3 (s, CH₂COOEt), 28,3 (s, CH₂CHCH₂COOEt), 25,3 (s, CH₂CH₂N), 18,8 (s, CH₂CH₂CH), 14,2 (s, OCH₂CH₃).

1H NMR: δ (CDC1₃) 4,72 (s large, IH, NCH), 4,09 (q, ³J_H-_H=7,2 Hz, 2H, OCTbOfe), 4,07 (large, IH, IH de CH₂N), 3,66 (s, 3H, OCH,), 2,83 (t, ³J_H-H=11,5 Hz, IH, IH de CH₂N), 2,81 (dd, J_H-_H=14,3 HZ, ³J_H-_H=7,4 HZ, IH, IH de CH∑COOEt), 2,51 (dd, ²J_H-H=14,3 Hz, ³J_H- _H=8 Hz, IH, IH de CHzCOOEt), 1,67-1,38 (3m, 6H,

1,23 (t, ³J_H-

Mass spectrometry: M7Z: (ICP NH₃) 230 ((M+H)⁺), 247 ((M+NH4)⁺).

The enantiomeric excess was measured by gas chromatography injection (Chirasil-DEX CB column) and was 95.5% Flow rate: helium 1 ml/min T (oven): 150°C. tr = 10.5 min for R); 11.3 min for (S).

LR-: (pure) 1735 (vCO_est_er), 1701 (vCOamide). Elemental analysis: Calculated: C 57.62%; H 8.35%; N 6.11% Measured: C 57.48%; H 8.53%; N 6.02%. D. Synthesis of ( -homopipecolic acid 5

70 mg of β-homopipecolic ester 3 (0.3 mmol, 1 equiv.), 93 mg of potassium hydroxide (1.65 mmol, 5.5 equiv.), 2 ml of ethanol and 0.5 ml of water were introduced into a 5 ml round-bottomed flask. The mixture was stirred for 48 h. After the addition of 2 ml of wate'r and extraction with ether, the aqueous phase was acidified with a 2N hydrochloric acid solution. The aqueous phase was extracted with ether. The organic phases were pooled, dried over sodium sulphate, filtered and evaporated. 45 mg of the product 4 were isolated. This was dissolved in 2 ml of a solution of hydrobromic acid in acetic acid (33%), and the mixture was stirred for 48 h. After evaporation, the residue was chromatographed onDowex ELjCl resin with a 5% aqueous ammoma solution as eluent. After lyophilization, 30 mg of a white powder corresponding to the β-homopipecolic acid in free form were obtained (overall yield: 70%).

[α]*° = -26 (c = 0.6; H₂0). Lift.¹ [α]*° = +33.5 (c = 0.6; H₂O) for the (S) compound. ¹³C J MR: δ (D₂0) 177,7 (s, COOH), 54,6 (s, NHCH), 44,6 (s, CH₂NH), 40,0 (s, CH₂COOH), 28,16 (s, CH₂CH₂CH), 21,9 (s, CH₂CH₂CH), 21,5 (s, CH₂CH₂NH).

^MR: δ (D₂O) 3,28 (m, 2H, CHbNH), 2,89 (td, ³I_H-H=12,7 Hz, ³I_H-_H=12,6 Hz, IH, NHCH), 2,37 (d, ³IH-H=6,7 HZ, 2H, CaCOQH), 1,76 (m, 3H, 2H de CH₂CaCH et IH de CaCHz H), 1,41 (m, 3H, 2H de ClfcCHzCH et IH de CTbCHaNH).

Mass spectrometry: M7Z: (ICP/NH3) 144 ((M+H)⁺).

Claims

C L AI M S

1 - Process for the enantioselective production of an amino acid derivative comprising at least one nitrogenous heterocycle, said heterocycle being substituted with at least one side chain comprising a functional group of carboxyl type, such as a carboxyl group, an ester group or an amide group, which process comprises at least one step in which a prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle, said heterocycle being substituted with at least one side chain comprising a functional group of carboxyl type, is subjected to hydrogenation in the presence of an enantiopure hydrogenation catalyst.

2 - Process according to Claim 1, in which the hydrogenation catalyst is a chiral complex of a metal of group 7, 8, 9 or 10 of the periodic table of elements.

3 - Process according to Claim 2, in which the metal is chosen from ruthenium, iridium and rhodium.

4 - Process according to any one of Claims 1 to 3, in which the hydrogenation catalyst contains an enantiopure chiral diphosphine.

5 - Process according to Claim 4, in which the diphosphine is chosen from di-t-bu-MeO-BIPHEP, Me-DuPHOS, Et-Ferrotane and Tol-BTNAP.

6 - Process according to any one of Claims 1 to 5, in which the hydrogenation is carried out at a pressure of 2 to 50 bar.

7 - Process according to any one of Claims 1 to 6, in which the hydrogenation is carried out at a temperature of -20 to 200°C.

8 - Process according to any one of Claims 1 to 7, in which the prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle corresponds to formula (I)

in which m is 0, 1, 2 or 3;

Z denotes H or an amino group-protecting group;

Y denotes a substituent which confers on the carbon of the carbonyl group the degree of oxidation+πi;

and the double bond of the group =-COY is an exocyclic double bond formed with any one of the carbon atoms of the heterocycle.

9 - Process according to Claim 8, in which the prochiral unsaturated amino acid derivative comprising at least one nitrogenous heterocycle corresponds to formula (II)

in which m is 0, 1 or 2;

Z denotes H or an amino group-protecting group;

Y denotes a substituent which confers on the carbon of the carbonyl group the degree of oxidation+HI.

10 - Process according to Claim 8 or 9, in which the configuration of the double bond with respect to the group -COY and with respect to the nitrogen is

"E" and the group Z is a nitrogen-protecting group containing a carbonyl group.