DESC:Field of the Invention:
The present invention relates to an improved process for the preparation of 7 – ACCA which is a key intermediate for the preparation of Cefaclor.
Background of the Invention:
Cefaclor belongs to the family of antibiotics known as the cephalosporins (cefalosporins). The cephalosporins are broad-spectrum antibiotics that are used for the treatment of septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis, and urinary tract infections. Cefaclor is developed by Eli Lilly under the trade name Cefaclor.
7-amino-3-chloro-3-cephem-4-carboxylic acid (7-ACCA) is a key intermediate in the synthesis of Cefaclor.

The main step in the preparation of 7 – ACCA is ozonolysis. Ozonolysis reaction is usually conducted by executing two steps, i.e., the step of causing ozone to act on an organic unsaturated compound or an aromatic compound to obtain an ozonide as an intermediate and the step of subjecting the ozonide to reduction. The present invention relates to the later step. Such method is carried out using various ozonide reducing agents. However, all of these reducing agents have some problems such as catalytic hydrogenation in the presence of a metallic catalyst such as Pt, Pd, Ni or the like (J. Am. Oil Chem. Soc., 42, 236 (1965)) always entails danger of explosion, since hydrogen is passed through a solution of a peroxide in the presence of a metal which is active to the solution.
Reduction with a metal such as Raney nickel, sodium boron hydride and the like (Can. J. Chem., 48, 1105 (1962)), trivalent phosphoric compound such as triphenylphosphine, phosphorous ester and the like (J. Org. Chem., 27, 4498 (1962)), the metal remains as industrial wastes after the treatment and poses environmental problems.
Reduction with dimethylsulfide which is most commonly used in laboratories (Tetrahedron Letters, 1966, 4273), the reducing agent exhibits a very high reducing power. However, this reducing agent is difficult to use for industrial purposes, since it causes an environmental problem.
As apparent from the above, an ozonide reducing agent has not been found out yet which is satisfactory in costs, safety, yield, working atmosphere and the like. For solving the foregoing problems of conventional ozonide reducing agents in ozonolysis reaction, present process is a novel approach by the inventor towards attaining significant cost effective method by using thiourea as a reducing reagent.
Summary:
In one aspect, present invention provides an improved process for the preparation of 4-Nitrobenzyl(2E)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3.2.0)hept-2-en-6-yl)-3-hydroxybut-2-enoate (compound V).
In another aspect, the present invention provides an improved process for the preparation of 7-ACCA.
In another aspect, the present invention provides an improved process for the preparation of Cefaclor.
Detail Description of the Invention:
The term “ozonide” is an unstable, reactive polyatomic anion O3, derived from ozone, or an organic compound similar to organic peroxide formed by a reaction of ozone with an unsaturated compound.
The term “ozonolysis” is an organic reaction where the unsaturated bonds of alkenes, alkynes, or azo compounds are cleaved with ozone.
In one embodiment, present invention provides an improved process for the preparation of 4-Nitrobenzyl(2E)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo(3.2.0)hept-2-en-6-yl)-3-hydroxybut-2-enoate (compound V) comprising the steps of:
i. reacting compound of formula IV with ozone to give an ozonide compound as an in-situ;

ii. reducing ozonide compound of step (i) with thiourea to give compound of formula V;

The compound of formula IV undergoes ozonolysis to give an ozonide intermediate in-situ in step (i) which is subsequently reduced by reducing reagent in step (ii) to give the compound of formula V. The compound of formula IV can be dissolved in suitable solvent, such as mixture of dichloromethane and methanol, and is reacted with ozone gas over a period of 80-100 minutes to form an ozonide intermediate. An ozonide can be further reduced by using reducing reagent, thiourea.
The solvent used for the ozonolysis reaction of step (i) and reduction step (ii) is selected from which includes but not limited to chloroform, carbon tetrachloride, dichloromethane, ethylene dichloride, ethyl acetate, acetic acid, cyclohexane, methanol, ethanol, acetone, water, methyl ethyl ketone, diethyl ketone, tert. butyl methyl ether, diethyl ether, tert. butyl ether, hexane, pentane and heptane or mixtures thereof. Such as, mixture of dichloromethane and methanol or ethyl acetate and methanol.
In another embodiment, the present invention provides an improved process for preparation of 7-ACCA comprising the steps of:
a) reacting compound of formula I with compound of formula II to obtain compound of formula III;


b) cyclization of compound of formula III with trimethyl phosphite in a suitable solvent to give compound of formula IV;

c) reacting compound of formula IV with ozone to give an ozonide compound as an in-situ;

d) reducing ozonide compound of step (c) with thiourea to give compound of formula V;

e) cyclizing compound of formula V to give Compound of formula VI;

f) chlorinating compound of formula VI to give compound of formula VII;

g) deprotecting of compound of formula VII to give compound of formula VIII;

h) neutralizing compound of formula VIII in the presence of base to give 7-ACCA;

The synthesis begins with the compound of formula (I). In most instances this is the preferred starting material and can be prepared by any suitable means of synthesis. Thus the compound of formula I reacts with compound of formula II to give compound of formula III. The starting material can be dissolved in suitable solvent, such as dimethyl formamide, and is react with p-nitro benzyl bromide, compound of formula II in presence of peracetic acid.
The compound of formula III undergoes cyclization to give compound of formula IV. The compound of formula III can be dissolved in suitable solvent, such as toluene, and is react with trimethyl phosphite at reflux temperature. For the better yield of the reaction the water present in the reaction mixture can be removed azeotropically and then added trimethyl phosphite. The reaction was found to be completed in 2 -3 hours.
The compound of formula IV then undergoes ozonolysis to give an ozonide intermediate in-situ which is subsequently reduced by reducing agent to give the compound of formula V. The compound of formula IV can be dissolved in suitable solvent, such as mixture of dichloromethane and methanol or ethyl acetate and methanol and ozone gas was purged over a period of 60 to 80 minutes to form an ozonide intermediate which can be further reduced by using reducing agent, thiourea.
The compound of formula V undergoes cyclization to give compound of formula VI. This reaction is carried out in the presence of p-toluene sulfonyl chloride, bromine, ammonia and morpholine in any suitable solvent, such as dichloromethane.
Compound of formula VI further undergoes chlorination using triphenylphosphite dichloride. Triphenylphosphite dichloride can be prepared in-situ by passing chlorine gas into mixture of triphenylphosphite and pyridine in dichloromethane. The compound of formula VII further undergoes deprotection of benzyloxycarbamate group by using dimethyl amine & phosphorus pentachloride, to give the compound of formula VIII.
The compound of formula VIII can be neutralized by using suitable base wherein an inorganic or an organic base may be used. The compound obtained can be optionally purified by crystallization or any other purification technique to get the pure 7-ACCA.
In another embodiment, the present invention provides use of 7-ACCA as obtained above to prepare Cefaclor. 7-ACCA can be converted to Cefaclor by using conventional methods known in the art.
Examples:
Example 1: Preparation of compound III

Dimethyl formamide (200 mL) was added to compound I (100.0 g, 0.2685 moles) followed by P-nitro benzyl bromide (59.2 g, 0.2754 moles) and stirred for 1-2 h. After completion of reaction, filtered the solid and washed with dimethyl formamide (50 mL). The filtrate was cooled to -10 to -5°C, added per acetic acid (90 mL, 1.235 moles) below 5°C. After completion of the reaction water was added and filtered to obtain compound III (124.5 gm).

Example 2: Preparation of compound IV

Toluene (1000 mL) was added to compound III (100.0 g, 0.2062 moles) and water was removed azeotropically then added trimethyl phosphite (30.7 g, 0.2476 moles) & refluxed the mass for 2-3 h. After completion of reaction, cooled the mass & distilled out toluene under vacuum. Added water (500 mL) to the mass & stirred at room temperature followed by filtration to give crude compound IV which was further purified to obtain pure compound IV (83.7 g).
Example 3: Preparation of compound V

To a mixture of Dichloromethane & methanol, added to compound IV (100.0 g, 0.2215 moles) and stirred to get clear solution. Reaction mixture was cooled to -25°C. Ozone gas was purged over a period of 60 to 80 minutes. After reaction completion, aqueous thiourea solution (8.4 g, 0.1108 moles dissolved in water) was added and stirred the reaction mass. Organic layer was separated, washed with water, concentrated under reduced pressure to obtain compound V (83.8 g).
Example 4: Preparation of compound V

To a mixture of Ethyl acetate and methanol, added to compound IV (100.0 g, 0.2215 moles) and stirred to get clear solution. Reaction mixture was cooled to -25°C. Ozone gas was purged over a period of 60 to 80 minutes. After reaction completion, thiourea (8.4 g, 0.1108 moles) slurry in ethyl acetate was added and concentrated under reduced pressure to obtain compound V (84.5 g).
Example 5: Preparation of compound VI

To a solution of compound V (100.0 g, 0.22 moles) in Dichloromethane (650 mL), added to p-toluene sulfonic acid (43.0 g, 0.2255 moles), Benzyltriethylammonium chloride (2.5 g, 0.010 moles) and Catalyst-S (0.2 gm) at 0-5°C. Addition of morpholine (80 mL, 0.276 moles) & liquor ammonia (25 mL) to the above reaction mass was done below 10°C and stirred the mass for 3 hours. After completion of reaction, layers were separated, organic layer was cooled and water, followed by morpholine (19.58 g, 0.225 moles) and bromine (36.0 g, 0.225 moles) solution in DCM. After completion of the reaction, added methanol, water & conc. HCl to the reaction mass, stirred for 20-30 then added dilute sodium carbonate solution. Then filtered the reaction mass to obtain compound VI (82.0 g).
Example 6: Preparation of compound VIII

To a solution of triphenylphosphite (119.0 g, 0.3838 moles) in Dichloromethane (650 mL), was added pyridine (7.0 gm, 0.087 moles). Chlorine gas passed in reaction mass at below -15°C. Further added Triphenylphosphite (8.0 gm, 0.0256 moles) to mass followed by addition of compound VI (100.0 gm, 0.2132 moles) & stirred to get complete dissolution. Dimethyl amine (25.8 gm, 0.213 moles) was added to the reaction mass and stirred for 1.0 h. After reaction completion, again added dimethyl amine (25.8 gm, 0.213 moles) at below -10°C followed by addition of phosphorus pentachloride (35.6 gm, 0.1705 moles), cooled the mass, added iso-butanol and stirred the mass followed by filtration to obtain compound VIII (80.0 gm).
Example 7: Preparation of 7-ACCA

To a mixture of Methanol / water, added compound VIII (100.0 g, 0.2463 moles) followed by addition of sodium carbonate solution to adjust pH acidic at 25-30°C. Added sodium hydrosulphite (128.6 g, 0.7389 moles) at below 50°C. After completion of reaction, added water and adjusted acidic pH by adding dilute HCl solution. Filtration of the solid afforded 7-ACCA crude (80g). This wet cake was further purified to get pure 7-ACCA (45.6 g).
,CLAIMS:1. An improved process for the preparation of Compound V,

comprising:

i) reacting compound of formula IV with ozone to obtain an ozonide compound;

ii) reducing ozonide compound of step (i) with thiourea to give compound of formula V.

2. The process of claim 1, the reaction step i) and ii) can be done in the presence of dichloromethane and methanol solvent mixture.
3. The process of claim 1, the reaction step i) and ii) can be done in the presence of ethyl acetate and methanol solvent mixture.

4. A process for the preparation of 7-ACCA comprising:

a) reacting compound of formula IV

with ozone to give an ozonide compound,

b) reducing ozonide compound of step (a) to give compound of formula V

c) cyclizing compound of formula V to give Compound of formula VI;

d) chlorinating compound of formula VI to give compound of formula VII;

e) deprotecting the compound of formula VII to give compound of formula VIII;

f) neutralizing compound of formula VIII in the presence of base to give 7-ACCA.

5. The process according to claim 4, the reagent used for reduction in step (a) is thiourea.
6. The process of claim 4, the reaction step a) and b) can be done in the presence of dichloromethane and methanol solvent mixture.
7. The process of claim 4, the reaction step a) and b) can be done in the presence of ethyl acetate and methanol solvent mixture.
8. A process for the preparation of Cefaclor comprising use of 7-ACCA intermediate, wherein 7-ACCA is obtained by process according to claim 3.