WO2002006304A1

WO2002006304A1 - Process for the preparation of dipeptide derivatives

Info

Publication number: WO2002006304A1
Application number: PCT/EP2001/007067
Authority: WO
Inventors: Giovanni Camaggi; Marilena Gusmeroli; Silvia Mormile; Alexia Elmini
Original assignee: Isagro Ricerca S.R.L.
Priority date: 2000-07-13
Filing date: 2001-06-21
Publication date: 2002-01-24
Also published as: ITMI20001578A1; IT1318623B1; AU2001270584A1; ITMI20001578A0

Abstract

A process is described for the preparation of dipeptide derivatves having formula (I) characterized by reaction scheme (II).

Description

PROCESS FOR THE PREPARATION OF DIPEPTIDE DERIVATIVES

The present invention relates to a new process for the preparation of dipeptide derivatives capable of effectively controlling phytopathogens of crops of agronomic interest.

Italian patent application MI98A02583 describes dipeptide compounds having a high antifungine activity and a process for their preparation.

In particular, the above patent application describes dipeptide compounds having formula (I)

obtained according to the following reaction scheme (1!

(II) (111)

(IV) (V)

SCHEMA 1

In practice, the N-alkoxycarbonyl-L-valine (II) , obtained by the condensation of L-valine with an alkylchloroformate (III), is reacted with a second mole of an alkylchloroformate (III), to give the mixed anhydride having formula (IV). The aminoester (V) is then added to give the desired compound having formula (I) . Patent application MI98A02583 also describes that the compounds having formula (I) can be obtained according to the following alternative reaction scheme (Scheme 2) :

(VI) (V)

(VII)

SCHEMA 2

wherein the 4-isopropyl-oxazolidin-2, 5-dione (VI), obtained as described in Chemistry Letters (1973) pages 1143-1144 and Journal of American Chemical Society (1971) _93 page 2746, is reacted with the aminoester (V) in great excess or in an equimolecular quantity but in the presence of an organic or inorganic base.

The dipeptide (VII) thus obtained is reacted in dichlo- ro ethane with an alkylchloroformate (III) to give the com^¬ pounds having formula (I) .

The first reaction scheme has quite a complex synthesis method due to the operating conditions and, above all, owing to the recovery of the desired product with high yields and a good degree of purity.

A second mole of alkylchloroformate (III) is also required for activating the carboxyl group of (II) , which not only increases the cost of the raw materials, but also necessitates additional processing for removing the corresponding alcohol which is formed during the reaction.

The second reaction scheme requires, for the formation of (VII), the presence, in excess, of a base, which partly favours the opening and polymerization of the anhydride (VI), with a significant lowering of the yield to the desired product (I) .

A process has now been found, which allows the compounds having formula (I) to be obtained with overall high yields, a high chemical purity and shorter reaction times.

In particular, an object of the present invention relates to a process for the preparation of dipeptide compounds having formula (I)

Ri represents a linear or branched Cχ-Cs alkyl group;

R₂ represents a linear or branched Cι-C₈ alkyl group;

R₃ represents a group selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a eth- oxyl group, a cyano group; characterized in that an oxazolidinedione having formula (VI) is reacted with an alkylchloroformate having formula (III) to give an N-alkoxycarbonyloxazolidinedione having formula (VIII) which is subsequently reacted with an aminoester having formula (V) to give the compounds having formula (I) , according to the following reaction scheme (SCHEME 3) :

(VI) (III) (VIII)

(VIII) (V)

SCHEMA 3 The configuration of the chiral atom of the valine residue present in all the compounds having formula (I) is

S, according to the Ca n, Ingold and Prelog convention; the configuration of the chiral atom of the aromatic residue can be RS, S or R.

With respect to the process of SCHEME 1, the process of the present invention does not require the activation of the carboxyl group of compound (II) thus saving a mole of alkylchloroformate and with the absence of the corresponding al- cohol by-product.

Compared to the procedure of SCHEME 2, the process of the present invention differs in the order in which the cpm- pounds (VI) , (III) , (V) are reacted and it has the advantage of providing better yields on the whole, under simplified operating conditions during both the reaction and processing.

The process of the invention also requires the use of a single mole of base, with an additional saving and without any risk of racemization of the valine residue. This means it can also be used for the synthesis of optically active compounds at both chiral centres .

In step A, the anhydride (VI) is transformed into compound (VIII) by the addition of a suitable alkylchloroformate (III) in the presence of a tertiary organic base such as triethylamine, N-methyldioctylamine, methylpyridine, 4- (dimethylamino) pyridine, pyridine, N,N-dimethylbenzylamine,

N-methylmorpholine, N-ethylmorpholine, N-methylthiomorph- oline, N-ethylthiomorpholine, preferably N-methylmorph- oline, N-ethylmorpholine, N-methylthiomorpholine, N- ethylthiomorpholine.

The latter, in fact, have a p which is such as to allow the reaction with the alkylchloroformate of interest without causing the polymerization of (VI) .

The reaction can be carried out in an organic medium such as dichloromethane, trichloromethane, carbon tetrachlo- ride, ethyl acetate, tetrahydrofuran, dioxane, ethyl ether, toluene, N,N-dimethylformamide, dimethylsulfoxide; or it can be effected in an aqueous medium at pH 10 by means of a buffer such as, for example, potassium borate, sodium bo- rate, sodium carbonate, sodium phosphate, potassium phosphate, under stirring and at a temperature ranging from - 60°C to the boiling point of the solvent used as described in U.S. 5,028,693 and Synthetic Communication (1998) 2J3 pages 2713-2724. The preferred solvents are tetrahydrofuran, dioxane, dichloromethane and ethyl acetate at temperatures ranging from 0 to 30°C.

The preferred buffer is potassium borate.

The anhydrides (VIII) obtained when Ri has the pre- ferred meanings of iso-propyl and sec-butyl, are not known and therefore form a further object of the present invention.

In step B, the N-alkoxycarbonyloxazolidinedione having formula (VIII) is reacted with the aminoester (V) in the ab- sence or in the presence of an inorganic base such as, for example, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide.

Alternatively, a tertiary base can be used, such as, for example, triethylamine, N-methyldioctylamine, N- methylmorpholine, N-ethylmorpholine, N-methylthiomorph- oline, N-ethylthiomorpholine, pyridine, methylpyridine, 4- (dimethylamino) pyridine, N,N-dimethylbenzylamine .

The reaction is carried out in an organic solvent such as ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, dioxane, ethyl ether, toluene, xylene, chlorobenzene, N,N-dime hylfor amide, dimethyl- sulfoxide at a temperature ranging from -65°C to the boiling point of the solvent used, as described in "Houben Weyl" 15/2, page 187 onwards.

The preferred solvents are dichloromethane, ethyl acetate, tetrahydrofuran; the bases selected are potassium carbonate, N-methylmorpholine; the preferred operating temperatures range from 0 to 30°C. A further advantage of the process described herein re- lates to the possibility of effecting steps A and B of SCHEME 3 in sequence, without isolating the intermediate (VIII) , in a single organic medium such as ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, dioxane, ethyl ether, toluene, xylene, chlorobenzene, N,N-dimethylformamide, dimethylsulfoxide.

The reaction is carried out at a temperature ranging from -65°C to the boiling point of the solvent used, in the presence of a tertiary organic base such as triethylamine, N-methyldioctylamine, N-methylmorpholine, N-ethylmorpholine, N-methylthiomorpholine, N-ethylthiomorpholine, pyridine, methylpyridϊne, 4- (dimethylamino) pyridine, N,N- dimethylbenzylamine .

The preferred solvents are dichlorome hane, ethyl ace- tate, tetrahydrofuran; the bases are selected from N- methylmorpholine, N-ethylmorpholine, N-methylthiomorpholine, N-ethylthiomorpholine; the preferred operating temperatures range from 0 to 30°C

Alternatively, the reactions of steps A and B of SCHEME 3 can be carried out in sequence and without isolating the intermediate (VIII), in an aqueous medium in the presence of an inorganic base or a tertiary base, or a buffer at pH 10 and optionally in the presence of a co-solvent such as ethyl acetate, dichloromethane, trichloromethane, carbon tetra- chloride, tetrahydrofuran, dioxane, ethyl ether, toluene, xylene, chlorobenzene, N,N-dimethylformamide, dimethylsul- foxide, terbutyl ethylether, ter-amyl ethylether.

The inorganic base can be selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bi- carbonate, sodium hydroxide, potassium hydroxide; the tertiary base can be selected from N-methyImorpholine, N- ethylmorpholine, N-methylthiomorpholine, N-ethylthiomorpholine, triethylamine, or N-methyldioctylamine or, pyridine, methylpyridine, 4- (dimethylamino) pyridine, N,N- dimethyIbenzylamine.

The buffer at pH 10 can be selected from potassium borate, sodium borate, sodium phosphate, potassium phosphate.

The reaction temperature generally ranges from -65°C to the boiling point of the solvent used. The preferred co-solvents are dichloromethane, ethyl acetate, tetrahydrofuran; the bases are selected from potassium carbonate and sodium hydroxide; the preferred buffer at pH 10 is potassium borate; the preferred operating temperatures range from 0 to 30°C. If desired, it is also possible to carry out steps A and B of the process in sequence, directly in the medium in which the oxazolidinedione having formula (VI) has been prepared, without isolating it, with a consequent additional simplification of the process and cost reduction. The following examples have the sole purpose of illus- trating the present invention but do not limit its scope in any way. EXAMPLE 1

Preparation of isopropyl 4-isopropyl-2,5-dioxa-3-oxazolid- inecarboxylate

70 g (67.3 ml) of isopropylchloroformate are added to a solution of 54.5 g of 4-isopropyloxazolidine-2, 5-dione in ethyl acetate (2000 ml) . The reaction mixture is cooled to 0°C, 58 g (63 ml) of N-methylmorpholine are added dropwise and the mixture is maintained at this temperature for 1.5 h. After letting the temperature rise to room values, the reaction is left under stirring for a night. The solid present is filtered and the organic solution is evaporated at reduced pressure. The raw product thus obtained is washed with hexane to obtain, after drying in air, 84.7 g of isopropyl 4-isopropyl-2, 5-dioxa-3-oxazolidinecarboxylate. Yield 97%. The compound is characterized by the following spectroscopic data: NMR ^λE (200 MHz) in CDC1₃: 0.95 (3H, d) , 1.19 (3H, d) , 1.38 (6H, dd) , 2.53 (1H, m) , 4.58 (1H, d) , 5.1 (1H, m) . EXAMPLE 2

Preparation of sec-butyl 4-isopropyl-2, 5-dioxa-3-oxazolid- inecarboxylate .

The desired compound is obtained with a procedure and preparative scale analogous to that described in example 1, using sec-butylchloroformate. Yield 95%.

The compound is characterized by the following spectroscopic data:

NMR E (200 MHz) in CDC1₃. 0.60 (3H, t) , 0.96 (3H, d) , 1.18 (3H, d) , 1.32 (3H, d) , 1.4 (2H, m) , 2.52 (1H, m) , 4.55 (1H, d) , 4.7 (1H, ) . EXAMPLE 3

Preparation of (±) RS- [3- (N-isopropσxycarbonyl-S-valinyl) - amino]-3- (4-chlorophenyl) ethyl propanoate.

93 g of (±) RS-3-amino-3- (4-chlorophenyl) ethyl propanoate dissolved in dichloromethane (300 ml) are rapidly added dropwise to a solution of 100 g of isopropyl 4- isopropyl-2, 5-dioxa-3-oxazolidinecarboxylate in dichlo^¬ romethane (400 ml) , cooled to 0°C. After letting the tem- perature rise to room values, the reaction is left under stirring for 1 hour. The reaction mixture is concentrated to minimum volume at reduced pressure and subsequently poured into a large volume of hexane kept under vigorous stirring. The white crystal which is separated, is collected by fil- tration, is then washed with additional hexane to obtain, after drying in air, 170 g of (+) RS- [3- (N-isopropoxy- carbonyl-S-valinyl) -amino] -3- (4-chlorophenyl) -me-thyl propanoate. Yield 98%.

The compound is characterized by the following spectroscopic data: NMR ^XH (200 MHz) in CDC1₃: 0.95 (6H, m) , 1.19 (6H, ) , 2.1 (1H, ) , 2.8 (2H, t) , 3.65 (3H, d) , 4.0 (1H, m) , 4.85 (1H, m) , 5.35 (2H, m) , 7.3 (5H, m) .

[ ]_D ^25°c (c = 1, CH₂C1₂) : -12.5° GC-MS: 398 (M+) , 212, 158, 116 (100%), 72.

Claims

A process for the preparation of dipeptide compounds having formula (I) :

( i ; wherein

Ri represents a linear or branched Cx-Cs alkyl group;

R₂ represents a linear or branched Cι-C₈ alkyl group;

R₃ represents a group selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxyl group, a cyano group; characterized in that an oxazolidinedione having formula (VI) is reacted with an alkylchloroformate having formula (III) to give an N-alkoxycarbonyloxazolid- inedione having formula (VIII) which is subsequently reacted with an aminoester having formula (V) to give the compounds having formula (I) , according to the following reaction scheme (3) :

(VI) (III) (VIII)

SCHEMA 3

Intermediate compounds consisting of N-alkoxycarbonyl- oxazolidinedione having formula (VIII) wherein Ri is iso-propyl or sec-butyl.

The process according to claim 1, wherein the transformation reaction of the anhydride (VI) in compound (VIII) is effected in an organic solvent in the presence of a tertiary organic base or in an aqueous medium buffered at pH 10, at a temperature ranging from -60°C to the boiling point of the solvent used. The process according to claim 3, wherein the tertiary organic base is selected from the group consisting of N-methyImorpholine^ N-ethylmorpholine, N-methylthio- morpholine, N-ethylthiomorpholine.

5. The process according to claim 3, wherein the organic solvent is selected from tetrahydrofuran, dioxane, dichloromethane, ethyl acetate and the temperature ranges from 0 to 30°C. 6. The process according to claim 3, wherein the aqueous medium is buffered with potassium borate.

7. The process according to claim 1, wherein the N- alkoxycarbonyloxazolidinedione having formula (VIII) is reacted with the aminoester (V) in an organic solvent, optionally in the presence of an inorganic base or a tertiary base, at a temperature ranging from -65°C to the boiling point of the solvent used.

8. The process according to claim 7, wherein the solvent is selected from the group consisting of dichlo- romethane, ethyl acetate, tetrahydrofuran.

9. The process according to claim 7, wherein the base is selected from the group consisting of potassium carbonate, N-methylmorpholine.

10. The process according to claim 7, wherein the reaction temperature ranges from 0 to 30°C.

11. The process according to claim 1, wherein the reactions of steps A and B of Scheme 3 are carried out in sequence, without isolating the intermediate (VIII) , in an organic solvent, in the presence of a tertiary or- ganic base, at a temperature ranging from -65°C to the boiling point of the solvent used. 12. The process according to claim 11, wherein the solvent is selected from the group consisting of dichlo- romethane, ethyl acetate, tetrahydrofuran. 13. The process according to claim 11, wherein the organic base is selected from the group consisting of N- methylmorpholine, N-ethylmorpholine, N-methylthio- orpholine, N-ethylthiomorpholine.

14. The process according to claim 11, wherein the reaction temperature ranges from 0 to 30°C.

15. The process according to claim 11, wherein the reactions of steps A and B are carried out in an aqueous medium, in the presence of an inorganic base and optionally a co-solvent, or a buffer at pH 10 and at a temperature ranging from -65°C to the boiling point of the solvent used.

16. The process according to claim 15, wherein the co- solvent is selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran; the base is selected from the group consisting of potassium carbonate, sodium hydroxide; the buffer at pH 10 consists of potassium borate; the operating temperature ranges from 0 to 30°C.

17. The process according to claim 11, wherein the reac- tions of steps A and B are carried out directly in the medium in which the oxazolidinedione having formula (VI) was prepared, without isolating it.