HU194844B - Process for production of derivatives of tiazolil acetic acid - Google Patents

Abstract

Prodn. of 1-sulphoazetidine derivs. of formula (I) in racemic and 35 enantiomeric form, and their easily hydrolysed esters or pharmaceutically acceptable salts comprises reacting the 3-aminoazetidine derivs. (II) with thioesters (III). (Het is an opt. amino substd., 5 or 6 membered aromatic heterocycle, contg. 1 or 2N and opt. also an O or S atom. R1 is H, alkyl (opt. substd. by phenyl, alkenyl, alkoxycarbonyl, phenylalkoxycarbonyl, nitrophenylalkoxycarbonyl or carboxy), alkanoyl or alkoxy carbonyl. R2 is H, alkyl (opt. substd. by alkanoyloxy or carbamoyloxy), alkenyl (opt. substd. by alkoxycarbonyl or carbamoyl), alkynyl, or hydroxy- or alkoxy-iminomethyl, and =NOR1 exists at least partly in the syn-form. R20 is as R2 or also 2,2-dimethyl-1,3-dioxolan-4-yl. R3 is H or sulpho. R10 is as R1 but not carboxyalkyl, or can also be trialkylsilyl-alkoxycarbonylalkyl or an easily hydrolysed esterified carboxyalkyl. All alkyl etc. have upto 7C). The reaction prod. having R3 as H is sulphonated and if necessary R20 and R10 converted conventionally. (I) have broad-spectrum antimicrobial activity and are esp. useful against gram negative species such as E. coli, Proteus and Serratia spp. and Pseudomonas aeruginosa. The usual daily dose is 10-600 mg per kg. Specifically claimed are 11 cpds. (I) and 7 cpds. (III), e.g. 3-((Z)-2-(2A4T)-2-(methoxyimino) acetamido- 4-((E)-carbamoylvinyl or methoxyiminomethyl)- 2-oxo-1-azetidine sulphonic acid and benzothiazol-2-ylthio 2-(2A4T)--2-((Z)- (p-nitrobenzyloxy- or tert. butoxy-carbonyl) methoxyimino)acetate (2A4T is 2-amino-4-thiazolyl).

Description

SUMMARY OF THE INVENTION The present invention relates to a novel process for the preparation of the carboxylic acids of formula IVa

Seven is 2-amino-4-thiazolyl and

R is C 1-3 alkyl; wherein the group = NOCH2COOC (R) ₃ is a color-configured quaternary N-allyl ammonium salt with a tertiary amine, characterized in that an allyl ester of formula (X) wherein: above, triphenylphosphine or a tri- (lower alkyl) phosphite and a tertiary amine in the presence of a palladium compound and isolating the product in the form of the free acid or quaternary N-allyl ammonium salt corresponding to the tertiary amine.

In the process described for the preparation of compounds of formula IVa (British Patent No. 1,600,736), the appropriate methyl or ethyl ester is used instead of the allyl ester of formula (X). However, the corresponding saponification of the said methyl or ethyl ester does not directly produce the desired acid of formula IVa, since the group -COOC (R) 3 is also saponified. It is an object of the present invention to overcome the above disadvantage. The present invention has successfully accomplished this task.

Preferably R is methyl.

Preferred compounds of formula IVa are 2- (2-amino-4-thiazolyl) -2 - ([(Z) tert-butoxycarbonyl) methoxy] imino} acetic acid. A preferred quaternary N-allyl ammonium salt is the quaternary N-allyl-N-methylmorpholine lumine salt.

The term "lower alkyl," as used herein, alone or in combination, refers to straight or branched aliphatic hydrocarbon groups having up to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl).

According to the process of the present invention, the allyl ester group is catalytically cleaved. The ester cleavage can be accomplished using a palladium compound in the presence of triphenylphosphine or a tri-lower alkyl phosphite (e.g. triethyl phosphite). Tri (lower alkyl) phosphite is preferably triethyl phosphite. The palladium compound is palladium / black or palladium salts, especially with hydrogen halides, such as, for example. hydrochloric acid or hydrobromic acid; or lower alkanecarboxylic acids, e.g. salts with acetic acid or propionic acid - can be used. In addition, triphenylphosphine or tri- (lower alkoxy) II phosphates, e.g. organic palladium complexes formed with triethyl phosphate can also be used. The reaction may then be carried out in the absence of separately added triphenylphosphine or tri- (lower alkyl) phosphate. The palladium compound clone is preferably palladium chloride or palladium acetate. An additional reaction component is a tertiary amine (e.g., triethylamine or N-methylmorpholine). The tertiary amine is preferably N-methylmorpholine. The reaction was carried out for ca. Playable at temperatures of 0-100 ° C; preferably at room temperature - while with palladium / carbon at slightly higher temperatures, approx. 50-80 ° C. The reaction is preferably carried out in an inert organic solvent such as ethyl acetate or methylene chloride.

The allyl ester of formula (X) may be prepared from diketone, chlorine gas and allyl alcohol. The resulting 4-chloroacetacetic acid allyl ester is nitrosated with salic triacid and then reacted with tlocarbamide. The resulting Het-2- (Z) -hydroxyiminoacetacetic acid allyl ester in the presence of a base (e.g., an alkali metal carbonate, triethylamine or N-ethyldiisopiopylamine) with a compound of formula XI (a) wherein Hal is chloro, bromo or iodo (R as hereinbefore defined) is reacted to give the allyl ester of formula (X).

Compounds of formula (IVa) are valuable pharmaceutical intermediates that are 1-sulfo-2-oxo-azetidine derivatives of formula (I) in racemic or 3 S-enantiomeric form

Seven has the meaning given above;

R 'is hydrogen or a group -C / (R ₃ );

R ² is hydrogen, lower alkyl, lower alkenyl, lower alklnil-, lower alkoxycarbonyl, lower word atomic number alkanoyloxy (lower word atoms alkyl) -, lower the Ikox t-butoxycarbonyl / small lower alkoxyiminomethyl, carbamoyl, carbamoyl (lower alkenyl) or carbamoyloxy (lower alkyl); and

R is C 1-3 alkyl; in addition, the = NOr 'group (R = CH 2 COOR') is at least partially colored in configuration, and is also useful in the preparation of their readily hydrolyzable esters and their pharmaceutically acceptable salts.

The compounds of formula (I) have antimicrobial activity and can be used in medicine in the form of suitable organic or inorganic inert pharmaceutical carriers suitable for parenteral administration.

The preparation of compounds of formula (I) from compounds of formula (IVa) is described in Hungarian Patent Application No. 1952/83, Publication No. T / 29165.

Further details of our process are set forth in the following example without limiting the invention to this example.

/. example

Diketone Q is dissolved in 250 ml of carbon tetrachloride and cooled to -2.1 ° C. A cloudy solution was obtained. Chlorine gas (71 g) was slowly added to the solution with stirring over 5 hours while the temperature was maintained at -20 ° C to -30 ° C by cooling. The resulting clear solution was slowly added over one hour to a solution of 58 g of allyl alcohol, 250 ml of oral tetrachloride and 80.5 ml of pyridine at 0 ° C to -5 ° C. The reaction mixture was stirred without cooling for an additional 15 minutes, then the precipitated pyridine hydrochloride was filtered off and washed with 100 ml of carbon tetrachloride. The sodium tetrachloride solution was washed with water (2 x 300 mL), dried over sodium sulfate and evaporated in vacuo. The residue is distilled off. 136 g (77%) of 4-chloroacetacetic acid allyl ester are obtained, m.p. 61-69 ° C / 0.1 mm Hg, colorless liquid.

To a solution of allyl ester of 4-chloroacetacetic acid (35.2 g) and acetic acid (34 ml) was added dropwise a solution of sodium nitrite (14.6 g) in water (21 ml) under stirring and cooling over 45 minutes. During the addition, the temperature drops from 0 ° C to -15 ° C.

The reaction mixture was stirred for 2 hours at -15 ° C. The resulting solution was then mixed with a solution of thiourea (15.2 g) and water (120 mL) preheated to 30 ° C, at a rate such that the temperature of the reaction thermoset was ca. Stay at 30-35 ° C. After stirring for a further 7 hours, the precipitated crystalline precipitate was filtered, washed successively with water, acetonitrile and ether, and then crystallized from acetonitrile. 21.8 g (48%) of 2- (2-amino-4-thiazolyl) -2- (Z) -hydroxyimino-acetic acid allyl are obtained; mp 184-185 'C.

To a solution of 20.4 g of 2- (2-amino-4-thiazolyl) -2- (Z) -hydroxylminoacetic acid in 100 ml of dimethyl sulfoxide and 100 ml of acetone was added 30 g of potassium carbonate and 19.5 ml of bromine. Acetic acid tert-butyl ester was added and the reaction mixture was stirred at room temperature for 5 hours. The acetone was evaporated in vacuo (bath temperature 50 ° C), 600 ml of ethyl acetate were added to the residue, the solution was washed neutral with ice water, dried and concentrated in vacuo. The crystalline yellowish residue was dispersed in diisopropyl ether, filtered and dried in vacuo. 20.1 g (65.5 g) of allyl 2- (2-amino-4-thiazolyl) -2 - {[(Z) - (tert-butoxycarbonyl) methoxy] imino} acetic acid are obtained. %, m.p. 135-136 ° C.

3.41 g of 2- (2-a ml of no-4-1-thiazolyl) -2 - {[(Z) - (tert-butoxycarbonyl) methoxy] imino} acetic acid allyl ester 100 Dispersed in ethyl acetate (18 mL), palladium chloride (18 g) and triethyl phosphite (0.084 mL) were added. N-methylmorpholine (1.2 ml) was added and the reaction mixture was stirred at room temperature for 48 hours. Crystallization begins slowly. After standing for 4 days, the precipitate was filtered off, washed with ethyl acetate and dried in vacuo. 3.52 g of the N-allyl-N-methyl-morpholinium salt of 2- (2-amino-4-thiazolyl) -2 - {[(Z) - (tert-butoxycarbonyl) methoxy] imino} acetic acid are obtained. .

From the above salt, 2- (2-amino-4-thiazolyl) -2 - {[(Z) - (tert-butoxycarbonyl) methoxyl] -1mino) acetic acid is obtained, m.p. 175-176. “C (decomposition).

The salt was taken up in water and the solution was washed with ethyl acetate and adjusted to pH 3 with 3N hydrochloric acid. The precipitated product is filtered off with water and then washed with acetone and ether and dried under high vacuum at 70 ° C for 16 hours.

Example 2

3.4 g of 2- (2-aminothiazolyl) -2 - [[(Z) - (tert-butoxycarbonyl) methoxy] imino] acetic acid allyl ester are suspended in 70 ml of acetonitrile at 0 ° C, then, under stirring, under nitrogen, 22.4 mg of palladium acetate, 0.068 ml of triethylphosphite and 1.60 ml of N-methylpyrrolidone are successively added. After 4.5 hours, the precipitated salt is filtered off and dried. The N-allyl-N-methylpyrrolidium salt of 2- {2-amino-4-thiazolyl) -2 - [[(Z) - (tert-butoxylcarbonyl) methoxy] imino] acetic acid is obtained. Yield: 1.8 g, m.p. 155-157 ° C (dec).

Claims (7)

PATENT CLAIMS A process for the preparation of a carboxylic acid of formula IVa Seven is 2-amino-4-thiazolyl and R is C 1 -C 3 alkyl; wherein the group = NOCH2COOC (R) 3 has a color configuration and a quaternary N-allyl ammonium salt with tertiary amines, characterized in that one of the allyl esters of formula (X) wherein with a palladium compound in the presence of the above -5-triphenylphosphine or a tris (lower alkyl) phosphite and a tertiary amine, and the product in the form of the free acid or quaternary N-allyl ammonium salt corresponding to the tertiary amine isolated. 2. A process according to claim 1 wherein the palladium compound is a palladium on carbon or palladium salt with hydrogen halide or lower alkane carboxylic acid. 3. The process of claim 2, wherein the palladium compound is used in palladium chloride or palladium acetate. 4. The process according to any one of claims 1 to 3, wherein the tri (lower alkyl) phosphite is triethyl phosphite. The process according to any one of claims 1-4, wherein the tertiary amine is N-methylmorpholine. 6. Process according to any one of claims 1 to 3, characterized in that the starting material is an allyl ester of the general formula (X) wherein R is methyl. The process of claim 1, which is 2- (2-amino-4-thiazolyl) -2 - {[(Z) - (tert-butoxycarbonyl) methoxy] imino} acetic acid or N-allyl-N for the preparation of the methylmorpholinium salt thereof -3194844 wherein the allyl ester of formula (X) is 2- (2-amino-4-thiazolyl) -2 - ([(Z) - {tertiary) butoxycarbonylmethoxy] imino} acetic acid allyl ester.