Field of the Invention

The present invention relates to the preparation of 4-methylthiazol-5- carboxaldehyde of Formula I, and use thereof as an intermediate in prepara-tion of 3-[2-(4- methylthiazole-5-yl)vinyl] cephalosporins.

Background of the Invention

Cephalosporin antibiotics belonging to the class of 3-[2-(4-methylttiiazole-5- yl)vinyl] cephalosporins have a broad spectrum of antimicrobial activity. Cefditoren pivoxil, which belongs to this class, is highly active not only against a variety of gram- positive and gram-negative bacteria but also against some resistant strains of bacteria. 4- Methylthiazol-5-carboxaldehyde (Formula I)

FORMULA I

is an intermediate in synthesis of 3-[2-(4-methylthiazole-5-yl)vinyl] cephalosporins such as Cefditoren pivoxil of Formula II,

FORMULA II

wherein R is pivaloxymethyl group, one of the R] and R2 is hydrogen and other is a group of Formula A FORMULA A

wherein R3 is methyl and R4 is hydrogen. This compound is a third-generation cephalosporin derivative developed with the aim of producing active cephalosporins with potent and broad-spectrum activity (see EP 175 610). Cefditoren pivoxil is active not only against a variety of gram-positive and gram-negative bacteria but also against some resistant strains of bacteria.

EP 343 640 describes a process of preparation of heterocyclic aldehydes, which comprises hydrogenating the corresponding heterocyclic carboxylic acid with molecular hydrogen in the presence of catalyst containing an oxide of at least one element selected from zirconium, yttrium, zinc, cerium, titanium and hafnium. High-pressure hydrogenation with molecular hydrogen requires a specially designed pressure vessel. The catalysts described in the patent are costly and recovery after the completion of reaction can be doubtful.

An oxidative degradation of 5-(/3-hydroxyethyl)-4-methylthiazole using pyridinium dichromate in methylene chloride at room temperature to get 4-methylthiazol-5- carboxaldehyde is reported by White et al in JACS, 104, No. 18, 4934-4943 (1982). However, the reaction time is 24 hours and the work-up involves vacuum distillation of ethereal extract to get the desired product. The yield is only 52%.

U.S. Patent No. 6,277,871 describes preparation of inhibitors of protein isoprenyl transferases wherein a process for the preparation of 4-methylthiazole-5-carboxaldehyde has been disclosed. The process follows Swern oxidation of 2-hydroxymethyl-4-methyl- thiazole in anhydrous methylene chloride and oxalyl chloride under N2 atmosphere in anhydrous DMSO at -70 to -8O0C. The product is obtained in 87% yield. The reaction requires lower temperature of about -7O0C and therefore it is not commercially feasible. The intermediate 4-methyl-5-hydroxymethylthiazole has been prepared by reduction of ethyl 4-methylthiazole-5-carboxylate using sodium borohydride and calcium chloride in ethanol in 48 hours.

US Patent Appl. No. 2003/0204095 describes a process for preparation of 4- methylthiazole-5-carboxaldehyde from 4-methyl-5-hydroxymethylthiazole using 2,2,6,6- tetramethyl- 1 -pyperidinyloxy free radical (TEMPO) in presence of potassium bromide, sodium carbonate, sodium hypochlorite and methylene chloride at 0-20C and also using pyridinium chlorochromate in presence of methylene chloride at 15-3O0C. Both these processes use costly catalysts and reagents and gives yield of about 60-70%. The intermediate 4-methyl-5-hydroxymethylthiazole has been prepared by reduction of methyl or ethyl ester of 4-methylthiazole-5-carboxylic using sodium borohydride and aluminium chloride in monoglyme.

Summary of the Invention

While attempting the synthesis of 4-methylthiazol-5-carboxaldehyde, the present inventors have found that when oxidation of 5-hydroxymethyl-4-methylthiazole of Formula III

FORMULA III

is carried out in presence of an oxidizing agent, for example, manganese dioxide at relatively high temperature, the reaction proceeds efficiently and gives yields of about 80% of 4-methylthiazol-5-carboxaldehyde. The purity of the 4-methylthiazol-5- carboxaldehyde obtained is in excess of 99%, as determined, for example, by HPLC.

The intermediate 4-methyl-5-hydroxymethylthiazole can be prepared by reduction of C1-3 alkyl ester of 4-methylthiazole-5-carboxylic acid using lithium aluminium hydride in 2 to 3 hours in excellent yield and purity.

Detailed Description of the Invention

Inn one aspect, herein is provided an efficient oxidative preparation of 4- methylthiazole-5-carboxaldehyde of Formula I, FORMULA I

wherein the process comprises oxidizing 5-hydroxymethyl-4-methylthiazole of Formula III with manganese dioxide. i

FORMULA III

The reaction can be carried out in presence of an inert organic solvent at a temperature of about 50-1500C. After completion of the reaction (as monitored, for example, by TLC or by HPLC), the reaction mass can be filtered to remove the catalyst and the solution obtained can be cooled suitably to precipitate the product. The product can then be filtered and dried to obtain 4-methylthiazole-5-carboxaldehyde as light yellowish solid having purity in excess of 99% (as determined, for example, by HPLC).

The inert organic solvent can be selected from, for example, aromatic hydrocarbons, such as benzene, toluene, xylene, substituted toluenes, substituted xylenes or substituted benzenes; chlorinated hydrocarbons, such as chloroform, or ethylene chloride; ethers, such as tetrahydrofuran, 1,4-dioxane, or diisopropyl ether; aliphatic hydrocarbons, such as hexane, heptane or petroleum ether; cylohexane; ketones, such as acetone, diisobutyl ketone, methyl ethyl ketone, or methyl isobutyl ketone; polar aprotic solvents, such as dimethylacetamide, dimethylformamide or dimethylsulphoxide; or mixtures thereof. In another aspect, herein is provided a process for preparation of 5-hydroxymethyl- 4-methylthiazole of Formula III,

FORMULA III

wherein the process comprises treating 4-methylthiazole-5-caboxylate of Formula IV

FORMULA IV

wherein R5 is an esterifying residue selected from C1-3 alkyl, with lithium aluminium hydride.

The reaction of 4-methylthiazole-5-caboxylate of Formula IV with lithium aluminium hydride can be carried out in the presence of an organic solvent, such as, for example, tetrahydrofuran, diethyl ether, 1,4-dioxane, cyclohexane, hexane, heptane, toluene, benzene, xylene or mixtures thereof, at a temperature of about -50 to about 4O0C.

After conversion of the starting material, the reaction mass can be quenched with water and the entire mass filtered to remove inorganic residue. The aqueous layer can be extracted with a solvent capable of substantially dissolving the compound of Formula III. After recovering the solvent from the organic layer, the product of Formula III can be obtained having purity in excess of 99% (as determined, for example, by HPLC).

In another aspect, herein is provided a process for the preparation of 4- methylthiazol-5-carboxaldehyde of Formula I wherein the process comprises

a) reacting a compound of Formula IV (wherein R5 is an esterifying residue selected from C1-3 alkyl) with lithium aluminium hydride to get compound of Formula III, b) oxidizing the compound of Formula III with an oxidizing agent (for example, manganese dioxide), and

c) isolating the compound of Formula I.

In yet another aspect, herein is provided a process for the preparation of compound of Formula II;

FORMULA II

wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; R1 and R2 are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, an optionally substituted amino acid residue or a group of Formula A

FORMULA A

wherein R3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and R4 is hydrogen or amino protecting group, wherein the process comprises

a) oxidizing a compound of Formula III

FORMULA III with an oxidizing agent (for example, manganese dioxide) to get a compound of Formula I,

FORMULA I

b) reacting the compound of Formula I with an ylide of Formula V,

FORMULA V

wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and R1 and R2 are independently hydrogen, a monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A

FORMULA A

wherein R3 is an optionally substituted lower alkyl wherein the substituents groups are selected from, for example, carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo; and R4 is hydrogen or amino protecting group, Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from C1 to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Ci0 cycloalkyl, aryl or aralkyl, and

c) isolating the compound of Formula II. The compound of Formula I can be prepared by the oxidation of compound of Formula III using, for example, manganese dioxide as described above. The isolated product can be treated with a compound of Formula V wherein R, R1, R2, R3, R4, Y, n and R6 are as defined above in presence of an organic solvent at a temperature of about -50 to about 350C. After completion of the reaction, it can be quenched by addition of water, followed by washing of organic layer with sodium bisulphite solution to eliminate aldehydic and related impurities generated during reaction. The compound of Formula II can then be isolated from the organic layer by suitable method of isolation, which includes evaporation of organic solvent to get the product, precipitation of the product from the organic solvent by addition of anti-solvent and the like.

The organic solvent can be selected from, for example, chlorinated hydrocarbons, such as chloroform or methylene chloride; lower alkanols, such as methanol, ethanol, n- propanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran, diethyl ether, or 1,4- dioxane; esters, such as ethyl acetate, n-butyl acetate, isopropyl acetate, or the like, or ketones, such as acetone, or ethyl methyl ketone; or mixtures thereof. Chlorinated hydrocarbons containing lower alkanols can be used as a solvent mixture, for example.

hi still a further aspect, herein is provided a process for the preparation of compound of Formula II;

FORMULA II

wherein R is hydrogen, esterified residue or a metal cation capable of forming a salt; R1 and R2 are independently selected from hydrogen, an amino protecting group or combine together form a divalent amino protecting group, or a group of Formula A

FORMULA A wherein R3 is a optionally substituted lower alkyl (wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo) and R4 is hydrogen or amino protecting group; wherein the process comprises a) treating a compound of Formula IV

FORMULA IV with lithium, aluminium hydride to get compound of Formula III,

FORMULA III b) oxidizing the compound of Formula III to get a compound of Formula I,

FORMULA I c) reacting compound of Formula I with an ylide of Formula V,

FORMULA V

wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and R1 and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group or a group of Formula A

FORMULA A

wherein R3 is a optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and R4 is hydrogen or amino protecting group; Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R6 is selected from C1 to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to C10 cycloalkyl, aryl or aralkyl, and

d) isolating the compound of Formula II.

The compound of Formula III can be prepared by reducing the compound of Formula IV with, for example, lithium aluminium hydride as described above. The compound of Formula III obtained can then be converted to a compound of Formula II by a process as described above.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are within the scope of the present invention. Example 1: Preparation of 4-Methyl-5-hydroxymethylthiazole

To a stirred mixture of lithium aluminum hydride (0.25 g) in THF (100 ml) at 5- 100C was added 4-methyl thiazole-5-caboxylic acid methyl ester (10 g) over a period of 30 minutes. The reaction mixture was stirred at 10- 150C for 2 to 3 hours. Progress of reaction was monitored by TLC. After completion, the reaction was quenched by adding a aqueous solution of sodium sulfate. The resultant inorganic solids were filtered and the cake was washed with ethyl acetate. Filtrate was concentrated under reduced pressure to get a pale yellow solid (7.5 g), providing an HPLC Purity (% area) of more than 99%.

1H-NMR (300MHz): 2.36 (s, 3H), 3.98 (s broad, IH), 4.79 (s, 2H), 8.58 (s, IH).

Example 2: Preparation of 4-Methylthiazolyl-5-carboxaldehyde

To a stirred mixture of 4-methyl-5-hydroxymethylthiazole (10 g ) in toluene (100 ml) at 55-6O0C was added manganese dioxide (50 g ) in one lot. The reaction mixture was stirred at 55-6O0C for 8 to 10 hours. Progress of reaction was monitored by TLC. After completion of the reaction, manganese dioxide was filtered over celite bed and washed with toluene. Filtrate was cooled below minus 2O0C to get solid. The solid was filtered, and dried to get 7.0 g 4-methylthiazole-5-carboxaldehyde as a light yellowish solid, with an HPLC Purity (% area) of more than 99%.

1H-NMR (300MHz): 2.80 (s, 3H), 8.99 (s, IH) 10.15 (s, IH).

Example 3: Preparation of Cefditoren acid, sodium salt

Step a) Preparation of 7-Amino-3-[2-(4-methylthiazol-5-yl)vinyI]-3-cepheme-4- carboxylic acid

1 , 1 -diphenylmethyl 7-(phenylacetamido)-3-[(triphenylphoshoranylidene)methyl]- 3-cepheme-4-carboxylate (16 g) was mixed with methylene chloride (120 ml) and 1- propanol (40 ml) followed by addition of 4-methylthiazol-5-carboxaldehyde (8 g). The resultant heterogeneous mixture was stirred at 20 to 250C for 20 to 22 hours. Progress of reaction was monitored by HPLC. After completion, reaction mixture was sequentially washed with 3% sodium bisulfite (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure to get an oily residue of 1,1, -diphenylmethyl 7- (phenylacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem e-4-carboxylate. To this oily residue was added phenol (60 ml) was added to the residue to get a clear solution. This solution was stirred at 40 to 50°C for 10 to 12 hours and n-butyl acetate (150 ml) was added to the reaction mass followed by cooling to 5 to 10°C. The organic portion was extracted with sodium bicarbonate solution (0.17 Molar, 2 x 150 ml). The aqueous layer was washed with n-butyl acetate (2 x 150 ml) to remove traces of phenol. To the aqueous layer was added Pen-G amidase (8 g wet) at 20 to 250C. The pH of the reaction mixture was intermittently adjusted to 7.5 to 7.7 by slow addition of 5% sodium carbonate solution. After completion of reaction, enzyme was filtered and washed with deionized water. The filtrate was treated with activated carbon and then filtered at 30-35°C. The filtrate was cooled to 20-25°C and to it was added dilute HCl (2 M) to adjust the pH to 3.0 to 3.5 in order to affect complete precipitation of title compound. The product was filtered and sequentially washed with water and acetone and finally dried under vacuum to get 5.5 g of off-white title compound.

Step b) Preparation of Cefditoren acid, sodium salt

A suspension of the product obtained in Step a) (5.0 g, 15.4 mmol) and 2- methoxyimino-2-(2-amino thiazol-4-yl)acetic acid, S-2-benzothiazole ester (6.7 g, 18.6 mmol) in aqueous tetrahydrofuran (60 ml) was stirred at 0 to 5°C. Triethylamine (2.3 ml) was added slowly at 0-5° C over 15 to 20 minutes. The mixture was stirred at 0-50C for 2-3 hours. The reaction was quenched by addition of dichloromethane followed by layer separation. The aqueous layer was diluted with acetone to 50 ml. Sodium 2- ethylhexanoate (3.3 g, 19.8 mmol) was added to the aqueous acetone solution at 20-25°C. After stirring the mixture for sufficient time for crystallization of the sodium salt of Cefditoren, acetone was added (50 ml) slowly to the reaction mass in order to effect crystallization. Filtered the crystallized product under suction and washed with acetone (2 x 10 ml). The product was vacuum dried to get 6.5 g of off-white title compound (Yield = 75%).