IL120964A - PROCESS FOR THE PREPARATION OF ALKYL 4, 5-DIHYDRO -gamma, 5-DIOXO-2-ARYL -4- OXAZOLEBUTANOATES AND THEIR USE AS PRECURSORS FOR delta-AMINOLEVULINIC ACID HYDROCHLORIDE (ALA) PRODUCTION - Google Patents

Abstract

A process for the preparation of alkyl 4, 5 -dihydro-g, 5-dioxo-2- aryl- 4-oxazolebutanoates of the formula wherein Ar is an aromatic radical and R is alkyl radical, which process is characterized in that a tertiary amine or a mixture of such amines is added to a mixture of 2-aryl-5-oxazolone of the formula 209 ו' בניסן התשס" ד - March 28, 2004 and an alkyl succinyl chloride of the formula in the presence of a pyridine derivative as a catalyst and optionally in the presence of an inert solvent.

Description

120964/3 Nsitt ittin una ow»*w o*t»NUNW.i Nfcj N-4-bw-2-wpwvt-5,y -mwr- 5,4 bpbN ¾> iii ii Process for the preparation of alky] 4,5-dihydro-y,5-dioxo-2-aryl-4-oxazoIebutanoates and their use as precursors for δ-aminolevulinic acid hydrochloride (ALA) production Finetech Ltd. »"½ p©_»i> The Inventors: 1. Arie L. GUTMAN ΐαουη Ν .1 2. Genady NISNEVICH \>:ηυ·} η» .2 3. Eleonora SHKOLNIK 4. Igor ZALTZMAN 5. Boris TISHIN wo u .5 6. Maxim SOTRIHIN Vnnvm?on?p» .6 C.110943 The present invention relates to a novel process for the preparation of oxazolone derivatives. More particularly the invention relates to a novel process for the preparation of alkyl 4,5-dihydro-Y,5-dioxo-2-aryl- 4-oxazolebutanoates derivatives, which can be used for conversion into the pharmaceutically, important δ- Aminolevulinic acid hydrochloride (ALA).

BACKGROUND OF THE INVENTION Oxazolebutanoates derivatives are well-known compounds useful as starting materials for the manufacture of medicines and pesticides. A scheme for obtaining such compounds can be found in the following references: ■ 1. Hearn, W. R., Widfeuer, M. R, Analytical Biochemistry, v. 2, 140 (1961); 2. Zavjalov, S. I., Aronova, N. I., Machova, N. N., Volkenshtein, J. B., IZV.

AKAD. NAUK SSSR, SER. KHIM. 1973, 657, and compounds were suggested using - Aronova, N. I., Machova, N. N., Zavjalov, S. I., IZV.

AKAD. NAUK SSSR, SER. KHIM. 1972, 401; 3. Malik Z, Kostenich, G., Roitman, B., Ehrenberg, B., Orenstein, A., Jornal of Photochemistry and Phobiology, 28, 1995, 213; Peng, Q., Moan, J., Iani, V., Nesland, J. M., SPIE, Vol. 2625, 51, 1989.

[IV] m Scheme 1 usable as an intermediate for the biosynthesis of porphirines, and as such of increasing imporance in the treatment of skin cancer in combination with a suitable light Source3 It is known that oxazolone of formula [IV] can be obtained by reacting Hyppuric acid [VI] with Methyl Chloro Succinate [VII] in the, presence of picolines, as shown below: was added to the mixture of compound [VIII] and [VII] in ie so called "reversed charging order".

[VIII] [VII] [IX] Scheme 3 According to the E.P. patent application No. 344,963, it was suggested to use aliphatic tertiary amines, instead of picolines. According to this reference, the "straight charging order" is used, in which chloroanhydride [II] was added to a mixture of the compound [VIII] and a tertiary aliphatic amine. However, the aliphatic tertiary amine used in this process are aken in a very large excess over the stochiometrically quantity required, a fact which imposes great difficalry in its recovery and product isolation.

After intensive investigations, in order to overcome the above mentioned disadvantages, it was found according to the present invention, that the "reversed charging order" will result in the desired C-alkylation product [III] by using a catalytic amount of pyridine derivatives. This unexpected result was investigated with different types of tertiary amines and it was concluded that not only aliphatic but other types of tertiary amines may be used in producing of compound [III].

Another unexpected result of the present invention was the high yield of the compound [III] in the reaction of Scheme 4 in the presence of up to 3 moles of tertiary amines to 1 mole of compound [I].

BRIEF DESCRIPTION OF THE INVENTION The invention relates to a process for the preparation of alkyl 4,5-dihydro-Y,5-dioxo»2-afyl 4-oxazolebutanoates, having the general formula [ΪΪΙ] by reacting *» compound of the general formula [Ϊ] with a compound of the general formula [II] in the presence of a tertiary amine and a pyridine derivative as catalysts (Cat) as shown below: wherein Ar, represents an aromatic hydrocarbon residue and R represents an alkyl residue.

Scheme 4 Preferably, a catalyst such (DMAP) or 4-(4-Methylpiperidino)pyridine, may be added in which case the yield is significantly increased.

DETAILED DESCRIPTION OF THE INVENTION The process described in the present patent application is characterised by the inexpensive and readily available starting materials which are required.

The tertiary amines used in this process are: diisopropylethylamine, triethylamine, other aliphatic tertiary amines; 1-ethylpiperidine, 1-butylpyrrolidine and other heterocyclic tertiary amines; Ν,Ν,Ν',Ν'-tetramethylethylenediamine and other tertiary polyamines.

Preferably, the catalyst used for this process is selected from 4-Dimethylaminopyridine (DMAP) or 4-(4-Methylpiperidino)pyridine, its amount is preferably 1/100 to 1/10 w/w to the compound [Γ|.

The preferred solvents may be selected from a broad range, such as: ethers, halogenated and aromatic hydrocarbons, esters, lactones. Among the ethers, it should be mentioned: diethyl ether, tetrahydrofuran and dioxane. Among the halogenated and aromatic hydrocarbons the following may be mentioned: chloroform, dichloromethane, dichloroethane, benzene, toluene and xylene. Among the esters and lactones it should be mentioned: ethyl acetate, butyl acetate and γ-butyrolactone.

The process of the present invention is preferably conducted at a temperature in the range of - 20 to 20 °C.

The compound of formula [I] can be produced by a known process comprising, for example, reaction of compound [VI] with a carboxylic acid anhydride or an acyl halide such as acetyl chloride, benzoyl chloride or compound of formula [H]. Therefore, it is possible to produce the compound |1] in situ and at the same time the compound [III] by reacting the compound [VI] with compound [II]. In this case two moles of compound [II] are necessary: one used for the production of compound [I] and another mol thereof is used for the production of the compound [VI].

Conversion of compound [IV] into the pharmaceutically important δ- Aminolevulinic acid hydrochloride (ALA) or its derivatives can be achived in accordance with known processes comprising, for example, acidic hydrolysis of compond [IV] followed by isolation of ALA as its hydrochloride or another salts (Scheme 1).

The invention will be hereafter illustrated by the following Examples being understood that these are presented only for a better understanding, without implying any limitation to the invention as covered by the following Claims.

EXAMPLE 1 "REVERSED CHARGING ORDER" Process for preparation of Methyl 4,5-Dihydro-y,5-dioxo-2-phenyl-4-oxazolebutanoate [IV] according to Scheme 5: Scheme 5 The solution of 98.8 g (0.61 moles) of compound [VIII] and 5 g DMAP in 900 mL dry THF was charged under argon into the 3-L reactor equipped with mechanical stirrer, thermometer, dropping funnel with pressure equalisation arm and an ice-salt bath. The stirred mixture was cold to -3 - 8 °C and 92.4 g (0.61 moles) of chloroanhydride [VII] were added during the period of 10 min. The mixture was stirred at the same temperature for an additional 5 min. and 207 g (1.83 moles) of 1-Ethylpiperidine were added during the period of 1.5 hours. After addition was complete, the mixture was stirred at the same temperature for an additional 4 hours and left without stirring overnight at the temperature of about 0 °C. The reaction mass was poured into a 30-L plastic drum containing 7 Kg ice-water mixture (1:1) and equipped with a mechanical stirrer. An aqueous solution of hydrochloric acid 32 % (about 220 mL) was added dropwise to the stirred mixture to pH 1 - 2. The obtained mixture was stirred for an additional 10 min and the precipitate was filtered off through a microporous filter. The solid was washed on the filter with 2 L water, 2 x 150 mL MeOH, 2 x 100 mL of Ether and dried under reduced pressure to constant weight. Red crystals of the crude product [IV] were obtained with yield of 85 % (142 g). The pure product was obtained by recrystallisation from 900 mL of Chloroform to give 106.7 g (64 ) of light pink crystals.

Similar results and a similar yield of crude product was obtained in the preparation of Ethyl 4}5-Dihydro-Y,5 -dioxo- 2-phenyI -4-oxazolebutanoate [ΧΪΙΪ] in the reaction of compound [VIII] with Ethyl Chloro Succinate [XIV] Scheme 6: mm [xiv] , Scheme 6 EXAMPLES 2 TO 10 The procedures set forth in Example 1 were followed with the exceptions apparent from Table 1. The synthesis is described by the following Scheme 7: mm wm ovi Scheme ? Table 1 EXAMPLE 11 "STRAIGHT CHARGING ORDER" A solution of 98.8 g (0.61 moles) of compound [VIII] and 5 g DMAP in 900 mL dry THF was charged under argon into the 3-L reactor equipped with a mechanical stirrer, thermometer, dropping funnel with pressure equalisation arm and an ice-salt bath. The stirred mixture was cold to -3 - 8 °C and 238 g (1.84 moles) of Diisopropylethylamine were added during the period of 10 min. The mixture was stirred at the same temperature for an additional 5 min and 92.4 g (0.61 moles) of chloroanhydride [VII] was added during the period of 1.5 hours. After addition was complete, the mixture was stirred at the same temperature for additional 4 hours and left without stirring overnight at the temperature of about 0 °C. The reaction mass was poured into a 30-L plastic drum equipped with a mechanical stirrer and containing 7 Kg ice-water mixture (1:1). An aqueous solution of hydrochloric acid 32 % (about 220 mL) was added dropwise to the stirred mixture to pH 1 - 2. The obtained mixture was stirred for an additional 10 min and the precipitate was filtered off through a microporous filter. The solid was washed on the filter with 2 L water, 2 x 150 mL MeOH, 2 x 100 mL of Ether and dried under reduced pressure to constant weight. The red crystals of the crude product [IV] were obtained with yield of 59 %; (99.2 g).

EXAMPLES 12 TO 14 .

The procedures set forth in Example 11 were followed with the exceptions apparent from Table 2. The synthesis is described by the above Scheme 7.

Table 2 No [Vlli] [X] [X]/[V1H] Yield, % Yield, % mole/mole crude Γ IV] pure [TV] 12 10.8 Tnethylamine 2.0 34 13 10.0 Tnethylamine 3.0 75 45 * 14 22.0 i-Ethylpiperidine 3.0 42 20

Claims (7)

120964/3 CLAIMS:

1. A process for the preparation of alkyl 4,5-dihydro-y, 5-dioxo-2-aryl-4-oxazolebutanoates of the general formula [III]: wherein Ar is an aromatic radical and R is an alkyl radical, which process is characterized in that a tertiary amine or a mixture of such amines is added to a mixture of 2-aryl-5-oxazolone of the formula [I]: m and an alkyl succinyl chloride of the formula [IIJ: I in the presence of a pyridine derivative as a catalyst and optionally in the presence of an inert solvent. · *-j ≤» -1 1 - 120964/3

2. A process according to Claim 1 weherein said tertiary amines are selected from 1-ethylpiperidine, 1-butylpyrrolidine, diisopropylethylamine, triethylamine, Ν,Ν,Ν',Ν'-tetramethylethylenediamine; or mixture thereof.

3. A process according to Claim 1 wherein 4-dimethylaminopyridine, 4-(4-methylpiperidino)pyridine and 4-pyrrolidinopyridine or mixtures thereof are used as catalysts.

4. A process according to Claim 1 wherein the amines, or their solution in an inert solvent, are added to a stirred mixture of a compound of formula [II] and a compound of formula [III] or to their solution in an inert solvent, in the presence of a pyridine derivative as a catalyst.

5. A process according to Claim 4 wherein the inert solvent is selected from ethers, halogenated hydrocarbons, aromatic hydrocarbons, esters and lactones.

6. A process according to Claim 5 wherein said inert solvent is selected from: methylenechloride, chloroform, dichloroethane, toluene, xylenes, ethyl acetate, γ-butyrolactone, tetrahydrofuran, dioxane, diethyl ether, or mixture thereof.

7. Methyl-4,5-dihydro-y,5-dioxo-2-phenyl-4-oxazolebutanoate for use in producing δ-aminolevulinic acid (ALA) by acidic hydrolysis. For the Applicants, REINHOLD COHN AND PARTNERS By: