WO1998054162A1

WO1998054162A1 - PREPARATION OF ALKYL 4,5-DIHYDRO-η,5-DIOXO-2-ARYL-4-OXAZOLEBUTANOATES

Info

Publication number: WO1998054162A1
Application number: PCT/IL1998/000251
Authority: WO
Inventors: Arie L. Gutman; Genady Nisnevich; Eleonora Shkolnik; Igor Zaltzman; Boris Pertsikov; Boris Tishin; Maxim Sotrikhin
Original assignee: Finetech Ltd.
Priority date: 1997-06-01
Filing date: 1998-05-29
Publication date: 1998-12-03
Also published as: IL120964A0; IL120964A; AU7546398A

Abstract

An industrially acceptable process is provided for the synthesis of alkyl 4,5-dihydro-η,5-dioxo-2-aryl-4-oxazolebutanoates which are important intermediates in the preparation of the pharmaceutically important δ-aminolevulinic acid hydrochloride (ALA.HCl). The process comprises the addition of amines to a mixture of 2-aryl-5-oxazolone and alkyl succinyl chloride in the presence of pyridine derivatives as a catalyst. The process provides both high selectivity and high yields.

Description

Preparation of Alkyl 4,5-Dihydro-γ,5-dioxo-2-aryl-4-oxazolebutanoates

FIELD OF THE INVENTION

The present invention provides an industrially acceptable process for the synthesis of alkyl 4,5-dihydro-γ,5-dioxo-2-aryl-4-oxazolebutanoates which are intermediates in the preparation of the pharmaceutically important δ-aminolevulinic acid hydrochloride (ALA-HCl). The process provides both high selectivity and high yields.

BACKGROUND OF THE INVENTION

Oxazolebutanoate derivatives are known compounds used as starting

1 2 5 7 materials in the preparation of medicines and pesticides. For example ' ' ^" , methyl 4,5-dihydro-γ,5-dioxo-2-phenyl-4-oxazolebutanoate of formula [ V ] can be hydrolysed by hydrochloric acid to obtain γ-aminolevulinic acid hydrochloride (ALA-HCl) of the formula [ VI ]:

Scheme 1

Compound [VI] is an useful intermediate in the biosynthesis of porphirines, and as such it plays an important role in the treatment of skin cancer, when

1 1 12 combined with a suitable light source ^" .

A traditional synthetic route 1"8 to alkyl 4,5-dihydro-γ,5-dioxo-2-aryl-4- oxazolebutanoate of formula [ I ] is the reaction of N-aroylglycine of formula [XIII] or 2-aryl-5-oxazolone [ II ] with alkyl succinyl chloride [ III ] in the presence of picolines (Scheme 2):

Scheme 2

wherein Ar is an aromatic radical; and R is an alkyl residue.

Since picolines are used in a large excess, serving also as a solvent, they have to be recovered in order to carry out the process efficiently. However, picolines have a high boiling point and are soluble in water and, therefore, the recovery thereof and the yield of the product is quite unsatisfactory. Another serious drawback of this approach is the difficulty to scale-up the reaction.

There are known some other approaches, wherein aliphatic tertiary amines are used instead of picolines ' . In these references, the "straight charging order" was used, in which alkyl succinyl chloride [ III ] was added to a mixture of the 2-aryl-5-oxazolone [ II ] and an aliphatic tertiary amine in tetrahydrofuran (THF) (Scheme 3). Low temperature reaction conditions and use of THF make this approach unacceptable for scaling-up.

Scheme 3

[ II ] [ III ] [ I ]

wherein Ar is an aromatic radical and R is an alkyl radical.

Another attempt to explore the "reversed charging order" comprises the addition of an amine to a mixture of 2-aryl-5-oxazolone [ II ] and alkyl succinyl chloride [ III ] in benzene, resulting only in the O-Acylation product of formula [X]⁸.

[ X ] wherein Ar is an aromatic radical and R is an alkyl radical.

All these methods for the preparation of compounds of formula [ I ] have serious drawbacks when manufacturing bulk material to be used as a drug. A desirable goal, met by the present invention, was to develop synthetic methods which avoid low temperature reaction environment and the use of unacceptable solvents, and which cleanly produce the desired alkyl 4,5-dihydro-γ,5-dioxo- 2-aryl-4-oxazolebutanoate, avoiding tedious and expensive purification steps.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the synthesis of alkyl 4,5-dihydro-γ,5-dioxo-2-aryl-4-oxazolebutanoate [ I ], with high C-acylation selectivity and increased yield. The process is particularly useful for preparing ethyl [ XII ] and methyl [ V ] 4,5-dihydro-γ,5-dioxo-2-phenyl-4-oxazolebutanoate which are the key intermediates in the preparation of δ-aminolevulinic acid hydrochloride (ALA-HCl) [ VI ].

Thus, the present invention relates to a process for the preparation of alkyl 4,5-dihydro-γ,5-dioxo-2-phenyl-4-oxazolebutanoates of the general formula [I]:

wherein Ar is an aromatic radical and R is an alkyl radical, which comprises the addition of an amine or a mixture of amines to a mixture of 2-aryl-5-oxazolone of the formula [ II ]:

and an alkyl succinyl chloride of the formula [ HI ]:

[ EH ]

in -the presence of a pyridine derivative as a catalyst and optionally in the presence of an inert solvent.

Other features and advantages will be apparent from the specification and claims.

DETAILED DESCRIPTION OF THE INVENTION

Preferably the amines used in the reaction of 2-aryl-5-oxazolone [ II ] with alkyl succinyl chloride [ HI ] are tertiary amines or sterically hindered secondary amines or mixture thereof. For example, said tertiary amines are: 1-ethylpiperidine, 1-butylpyrrolidine and other heterocyclic tertiary amines; diisopropylethylamine, triethylamine, other aliphatic tertiary amines; N,N,N',N'-tetramethylethylenediamine and other tertiary polyamines; or mixtures thereof. Examples of sterically hindered secondary amines are: diisopropylamine, dicyclohexylamine 2,2,6,6-tetramethylpiperidine or mixtures thereof. Preferably, the molar ratios [amine] : [ III ] vary from about 0.5 to about 4.5, and especially from about 3.0 to 4.0.

Although any pyridine derivative may be used as a catalyst, it is preferred to use 4-dimethylaminopyridine (DMAP), 4-(4-methylpiperidino)pyridine, and 4-pyrrolidino-pyridine or mixtures thereof, in amounts of 1/100 to 1/10 w/w relative to the compound [I]. Preferably, the catalyst is added after the mixing of 2-aryl-5-oxazolone [ II ] with alkyl succinyl chloride [ III ].

Although the reaction could be carried out without a solvent, it is preferable to use the following charging manner: amines, or their solution in an inert solvent, are added to a stirred mixture of 2-aryl-5-oxazolone [ II ] and alkyl succinyl chloride [ HI ] in an inert solvent in the presence of a pyridine derivative as a catalyst.

Any reaction-inert solvent may be used. The expression "reaction-inert solvent" refers to a solvent which does not react or decompose with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. In general, the solvent can comprise a single entity, or contain multiple components. Preferably the solvent is a non-protic solvent and it is especially preferred that the solvent is selected from: methylenechloride, chloroform, dichloroethane and other halogenated hydrocarbons; toluene, xylenes and other aromatic hydrocarbons; ethyl acetate and other esters; γ-butyrolactone and other lactones; tetrahydrofuran, dioxane, diethyl ether, other ethers or mixture thereof.

The process of the present invention is preferably conducted at a temperature of about - 50 °C to about 50 °C, and preferably from about -20 °C to 20 °C. 2-aryl-5-oxazolone of formula [ II ] can be produced by a known process comprising, for example, reaction of N-aroylglycine of formula [ XIII ] with a carboxylic acid anhydride or an acyl halide. Therefore, it is possible to obtain 2-aryl-5-oxazolone [ II ] in situ during the preparation of alkyl 4,5-dihydro-γ, 5-dioxo-2-aryl-4-oxazolebutanoate [ I ] by reacting N-aroylglycine [ XIII ] with alky 1 succinyl chloride [ III ] . In this case two moles of alkyl succinyl chloride [ III ] are necessary: one is used for the formation of 2-aryl-5-oxazolone [ II ] and another mole thereof is used for the preparation of the desired compound [ I ].

Conversion of compound [ I ] into the pharmaceutically important δ-aminolevulinic acid hydrochloride (ALA-HCl) can be achieved in accordance with known processes comprising, for example, hydrolysis of compound [ I ] by hydrochloric acid, followed by isolation of ALA as its hydrochloride salt

(Scheme 4).

Scheme 4

r

[ I ] [ VI ]

wherein

Ar is an aryl radical; and R is an alkyl radical.

It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following claims. EXAMPLE 1

Process for the preparation of ethyl 4,5-dihydro- γ,5-dioxo-2-phenyl-4- oxazolebutanoate [ XII ] according to Scheme 5:

Scheme 5

[ IX ] [ XI ] [ XII ]

A solution of 5,780 g (35.8 moles) of 2-phenyl-5-oxazolone [ IX ] in 52 kg methylene chloride was charged under nitrogen into a 100-L double wall reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel with a pressure equalisation arm. The stirred mixture was cooled to - 5 °C and 6,518 g

(39.6 moles) of ethyl succinyl chloride [ XI ] were added during a period of 25 min.

Then, a solution of 286.4 g of DMAP in 2 kg of methylenechloride were added dropwise. The mixture was stirred at -5° C and 12,195 g (108 moles) of

1-ethylpiperidine were added during a period of 4 hours at - 5°C to -1°C. After addition was completed, the mixture was stirred at the same temperature for an additional period of 6 hours and left without stirring overnight at the same temperature. The reaction mixture was poured into a 200-L reactor equipped with a mechanical stirrer, a thermometer, a pH meter and containing 100 L of water and

22 Kg of ice. The mixture was stirred for 10 min. and an aqueous solution of hydrochloric acid 32 % (7 L) was added dropwise to the stirred mixture to obtain pH 1 - 2. The obtained mixture was stirred for an additional period of 20 min. and the precipitate was filtered off. The solid was washed on the filter with 25 L of water and 55 L of acetone chilled to 0° C, and then was triturated with hot acetone (25 L). The residue was cooled to 5° C and filtered off, washed with chilled acetone and dried under reduced pressure to give 5,172 g (64.0 %) of yellowish crystals, purity by titration 99.9 %, m.p. 172.6 - 174.6 °C (corrected).

EXAMPLE 2

Process for the preparation of methyl 4,5-dihydro- γ,5-dioxo-2-phenyl-4- oxazolebutanoate [ V ] according to Scheme 6:

Scheme 6

A solution of 98.8 g (0.61 moles) of compound [ IX ] in 900 mL dry THF was charged under argon into a 3-L reactor equipped with a mechanical stirrer, thermometer, a dropping funnel with a pressure equalisation arm and an ice-salt bath. The stirred mixture was cooled to -8 to -3° C and 92.4 g (0.61 moles) of chloroanhydride [ VIII ] were added during a period of 10 min and thereafter 5 g DMAP were added in one portion. The mixture was stirred at the same temperature for an additional 5 minutes and 207 g (1.83 moles) of 1-ethylpiperidine were added during a period of 1.5 hours. After addition was complete, the mixture was stirred at the same temperature for an additional period of 4 hours and left without stirring overnight at a temperature of about 0 °C. The reaction mass was poured into a 30-L HDPE drum containing 7 Kg of an 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 of water, 2 x 150 mL of MeOH, 2 x 100 mL of ether and dried under reduced pressure to constant weight. Red crystals of the crude product [ V ] were obtained, with a yield of 89 % (148.7 g). The pure product was obtained after recrystallisation from 900 mL of chloroform to give 118.4 g (71.0 %) of light pink crystals.

Comparison example of "Straight Charging Order":

A solution of 98.8 g (0.61 moles) of compound [ IX ] in 900 of mL of dry THF was charged under argon into the 3-L reactor equipped with a mechanical stirrer, a thermometer, a dropping funnel with a pressure equalisation arm and an ice-salt bath. The stirred mixture was cooled to -8 to -3° C and 207.0 g (1.83 moles) of 1-ethylpiperidine were added during a period of 10 min and thereafter 5 g DMAP were added in one portion. The mixture was stirred at the same temperature for an additional period of 5 min and 92.4 g (0.61 moles) of chloroanhydride [ VIII ] were added during a period of 1.5 hours. After addition was complete, the mixture was stirred at the same temperature for an additional period of 4 hours and left without stirring overnight at a temperature of about 0 °C.

The reaction mass was poured into a 30-L HDPE drum equipped with a mechanical stirrer and containing 7 Kg of an 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 period of 10 min and the precipitate was filtered off through a microporous filter. The solid was washed on the filter with 2 L of water, 2 x 150 mL of MeOH, 2 x 100 mL of ether and dried under reduced pressure to constant weight. The red crystals of the crude product [ V ] were obtained with a yield of 59 % (99.2 g).

EXAMPLES 3 TO 7

The procedure set forth in Example 2 was followed with the exceptions apparent from Table 1. The synthesis is described by the following Scheme 7:

Scheme 7

[ IX ] [ VIII ] [ V ]

Table 1

EXAMPLES 8 TO 10

The procedure set forth in Example 2 was followed with the exceptions apparent from Table 2. The synthesis is described by the following Scheme 8. Scheme 8

1-Ethylpιpeπdιne

Catalyst [ XV ]

Table 2

References:

1. Hearn, W. R., Widfeuer, M. E., Analytical Biochemistry, v. 2, 140 (1961);

2. Gurne, D., Shemin, D., Science, v. 180, 1188 (1973); 3. Aronova N. I., Makhova N. N., Zavyalov S. I., Bull. Acad. Sci. USSR, Div. Chem. Sci. v. 19, 687 (1970);

4. Baj, S., Jarza, J., Chemica Analyticzna, v. 29, 751 (1984);

5. Aronova, N. I., Machova, N. N. Zavyalov, S. I., Bull. Acad. Sci. USSR, Div. Chem. Sci. v. 21, 349 (1972); 6. Zavyalov, S. I., Aronova, N. L, Machova, N. N., Volkenshtein, Yu. B., Bull. Acad. Sci. USSR, Div. Chem. Sci. v. 22, 632 (1973);

7. Aronova N. I., Makhova N. N., Zavyalov S. I., Volkenshtein, J. B., Kunitskaya G. M., United States Patent 3846490 (1974);

8. Zavyalov, S. I., Knyazkova N. E., Kulikova L. B., Bull. Acad. Sci. USSR, Div. Chem. Sci. v. 31, 2223 (1982);

9. South Africa Patent Application 818206 ( 1982) assigned to Imperial Chemical Industries PLC;

10. European Patent Application 344 963 (1989) assigned to Nippon Oil Co., Ltd.; 11. Malik Z, Kostenich, G., Roitman, B., Ehrenberg, B., Orenstein, A., Jornal of Photochemistry and Phobiology, B: Biology, v. 28, 213 (1995); 12. Dierickx, C. C, Anderson, R. R., International Photodynamics, v. 5, 2 (1996);

Claims

1. A process for the preparation of alkyl 4,5-dihydro-╬│,5-dioxo-2- phenyl-4-oxa-zolebutanoates of the general formula [Tj:

wherein Ar is an aromatic radical and R is an alkyl radical, which comprises the addition of an amine or a mixture of amines to a mixture of 2-aryl-5-oxa--;olone of the formula [ II ]:

r

╬ô╬áJ and an alkyl succinyl chloride of the formula [ HI ]:

[mi in the presence of a pyridine derivative as a catalyst and optionally in the presence of an inert solvent

2. A process according to Claim 1 wherein said amines are tertiary amines or sterically hindered secondary amines or a mixture thereof.

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

4. A process according to Claim 2 wherein said sterically hindered secondary amines are selected from diisopropylamine, dicyclohexylamine, 2,2,6,6- tetramethylpiperidine or mixture thereof.

5. A process according to Claim 1 wherein 4-dimethylaminopyridine,

4-(4-methylpiperidino)pyridine and 4-pyrrolidinopyridine or mixture thereof are used as catalysts.

6. 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 [ ╧Ç ] and a compound of formula [ III ] or to their solution in an inert solvent, in the presence of a pyridine derivative as a catalyst.

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