CLIAMS:1. A process for preparing an intermediate or it’s salt for the synthesis of antibiotics, the process comprising
oxidizing derivative of furan in an acidic medium in the presence of an additive and nitrite salt to form α-ketocarboxylic acid; and
reacting α-ketocarboxylic acid with derivative of hydroxylamine to form the intermediate.

2. A process for preparing α-ketocarboxylic acid as claimed in claim 1, the process comprising
oxidizing derivative of furan in an acidic medium in the presence of an additive and nitrite salt to form α-ketocarboxylic acid.

3. The process as claimed in claim 1 or claim 2, wherein the derivative of furan is 2-acetyl furan.

4. The process as claimed in claim 1 or claim 2, wherein the acidic medium is selected from aqueous HCl or aqueous H2SO4.

5. The process as claimed in claim 1 or claim 2, wherein additive is selected from C1-C10alkanoic acid.

6. The process as claimed in claim 5, wherein the alkanoic acid is selected from acetic acid, propanoic acid, formic acid, butanoic acid or mixtures thereof.

7. The process as claimed in claim 1 or claim2, wherein the nitrite salt is sodium nitrite or isopropyl nitrite.

8. The process as claimed in claim 1, wherein the derivative of hydroxylamine is alkoxyamine or it’s acid salt.

9. The process as claimed in claim 8, wherein the alkoxyamine or it’s acid salt is methoxyamine base or methoxyamine hydrochloride.

10. The process as claimed in claim 1 or claim 2, wherein α-ketocarboxylic acid is furylglyoxalic acid and the intermediate is syn-2-furyl-2-methoxyimino acetic acid.

11. The process as claimed in claim 1, further comprising extracting the intermediate from an aqueous phase and purging ammonia in the organic phase to form ammonium salt of the intermediate.

12. The process as claimed in claim 11, wherein the extraction is carried out with butyl acetate, dichloromethane,ethyl acetate , ethyl butyrate ,hexyl ester.

13. A process for preparing syn-2-furyl-2-methoxyimino acetic acid or it’s salt, the process comprising
oxidizing 2-acetyl furan in aqueous HCl medium in the presence of sodium nitrite to form furylglyoxalic acid; and
reacting furylglyoxalic acid with methoxyamine hydrochloride to form syn-2-furyl-2-methoxyimino acetic acid.

14. The process as claimed in claim 13, further comprising extracting syn-2-furyl-2-methoxyimino acetic acid from an aqueous phase by using butyl acetate and purging ammonia in the butyl acetate extract to form ammonium syn-2-furyl-2-methoxyimino acetic acid.

15. The process as claimed in any of the preceding claims, wherein the process is an in-situ process.

16. The process as claimed in claim 1 or 2 or 13, wherein the unreacted derivative of furan or 2-acetyl furan is recycled to the oxidation step.
,TagSPECI:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

A PROCESS FOR PREPARING AN INTERMEDIATE OR IT’S SALT FOR THE SYNTHESIS OF ANTIBIOTICS;

DEEPAK NITRITE LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956 WHOSE ADDRESS IS 9/10 , KUNJ SOCIETY , ALKAPURI, VADODARA, GUJARAT; 390007 INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to a process for preparing intermediate or it’s salt for the synthesis of antibiotics.

BACKGROUND OF THE INVENTION
Syn-2-furyl-2-methoxyiminoacetic acid is pharmaceutical intermediate used in the preparation of antibiotics such as Cefuroxime acid and Cefuroxime axetil. The main form furan hydroxamic acid amine salt is particularly used in the preparation of Cefuroxime acid.

US4013680 discloses method of preparation of α-keto carboxylic acid wherein the corresponding methyl ketone is oxidized in aqueous solution with an inorganic nitrite salt and mineral acid. The acid is preferably hydrochloric acid. The process disclosed in this patent usesexcessof costly raw materials, isolation of intermediate (Oxidation step), multiple solvents. Also, use of various buffer solutions causes excess consumption of raw materials.

Shandong Huagong, Volume: 34, Issue: 6, Pages: 5-8, Journal, 2005 discloses synthesis of 2-methoxyimino-2-furylacetic acid from 2-furanyl oxoacetic acid by oximation with methoxyamine hydrochloride wherein 2-furanyl oxoacetic acid is prepared from 2-acetyl furan. The process involves use of excess costly raw materials, isolation of intermediate (Oxidation &oximationstep) and use of multiple solvents. The time required for the completion of the process is also high.

International Journal of Applied Chemistry, Volume: 3, Issue: 1, Pages: 19-26, Journal, 2007, discloses preparation of syn-2-furyl-2-(methoxyimino) acetic acid wherein 2-acetyl furan is oxidized in aqueous solution with an isopropyl nitrite and mineral acid preferably hydrochloric acid. The process involves use of excess costly raw materials, isolation of intermediate (oxidation & oximation step) and use of multiple solvents. The time required for the completion of the process is also high.

Various all above known processes for production of syn-2-furyl-2-methoxyiminoacetic acid from 2-acetyl furan discloses use of excess costly raw materials, isolation of intermediate, ionic liquids, multiple solvents or mixture of solvents. Also use of various buffer solutions causes excess consumption of raw materials like buffer reagents,sodium hydroxide, solvents.Also, recovery of 2-Acetyl furan at different pHand using gas purging make the processes difficult and non-economical.

There is a need for an in-situ process for preparing syn-2-furyl-2-methoxyiminoacetic acid, which aids in recovery and re-use of costly raw materials without addition of buffer solutions.

SUMMARY OF THE INVENTION
An object of the present invention is to provide a cost efficient process for producing an intermediate or it’s salt for use in the synthesis of antibiotics. The process involves recovery and reuse of expensive chemical components.

The present invention relates to a process for preparing an intermediate or it’s salt for the synthesis of antibiotics by oxidation of derivative of furan in an acidic medium in the presence of an additive and nitrite salt to form α-ketocarboxylic acid. The α-ketocarboxylic acid is reacted with derivative of hydroxylamine to form the intermediate.

The present invention also relates to a process for preparing α-ketocarboxylic acid by oxidation of derivative of furan in an acidic medium in the presence of an additive and nitrite salt to form α-ketocarboxylic acid.

 
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention relates to a process for preparing an intermediate or it’s salt for synthesis of antibiotics. The process comprises of oxidizing a derivative of furan in an acidic medium in the presence of an additive and nitrite salt to form α-ketocarboxylic acid. The α-ketocarboxylic acid formed is further reacted with derivative of hydroxylamine to form the intermediate.

Another embodiment of the present invention relates to a process for preparing α-ketocarboxylic acid by oxidizing derivative of furan in an acidic medium in the presence of an additive and nitrite salt to obtain α-ketocarboxylic acid.

The oxidation process is carried out at a temperature of 40-80°C for 8-12 hours.The second step of reacting α-ketocarboxylic acid with derivative of hydroxylamine is carried out at a temperature of 8-12°C.

Process for preparing the intermediate or it’s salt is an in-situ process. The unreacted derivative of furan is recovered and recycled back to the step of oxidation, wherein it can be further utilized in the formation of α-ketocarboxylic acid. This avoids wastage ofchemicals and makes the process more economical.The unreacted derivative of furan is recovered by the addition of solvent such as dichloromethane.
The intermediate is extracted from the reaction mass by addition of a solvent to form an aqueous and an organic phase. The intermediate is extracted from the aqueous phase. organic phase is collected and ammonia is purged in the organic phase to obtain crude intermediate, which is further purified. The extraction of the intermediate can be carried out by using solvents such as butyl acetate, dichloromethane, ethyl acetate, ethyl butyrate, hexyl ester or mixtures thereof.

The derivative of furan used in the process is 2-acetyl furan.

The acidic medium is selected from mineral acid such as 15% of aqueous HCl or aqueous H2SO4 present in the range of 14-18%.

The additive is selected from C1-C10alkanoic acid such as 1-4 moles of acetic acid, propanoic acid, formic acid, butanoic acid or mixtures thereof.

The nitrite salt is selected from 3-6 moles of sodium nitrite or isopropyl nitrite.

The derivative of hydroxylamine is an alkoxyamine or it’s acid salt selected from methoxyamine base or methoxyamine hydrochloride present in a range of 38-45%.

The α-ketocarboxylic acid formed in the aforesaid process is furyl glyoxalic acid and the intermediate is syn- 2-furyl-2-methoxyimino acetic acid.

A preferred embodiment of the present invention relates to an in situ cost effective process for preparing syn- 2-furyl-2-Methoxyiminoacetic acid. The process comprises of oxidizing 2-acetyl furan in aqueous acidic solution in the presence of an additive and sodium nitrite to form furyl glyoxlic acid. The second stage comprises of reacting furyl glyoxlic acid with methoxy amine hydrochloride to form syn-2-furyl-2-methoxyiminoacetic acid. The unreacted 2-acetyl furan can be extracted by using methylene dichloride. The recovered 2-acetyl furan is recycled to the oxidation step, thus avoiding wastage of 2-acetyl furan.

Another embodiment of the present invention relates to an in situ cost effective process for preparing ammonium salt of syn- 2-furyl-2-methoxyimino acetic acid. The process comprises of oxidizing 2-acetyl furan in aqueous acidic solution in presence of additive with sodium nitrite to form furyl glyoxlic acid. The second stage comprises of reacting furyl glyoxlic acid with methoxy amine hydrochloride to form syn-2-furyl-2-methoxyiminoacetic acid. The third stage comprises of purging of ammonia gas in extracted organic phase containing syn-2-furyl-2-methoxyiminoacetic acid at elevated pHto obtain ammonium salt of syn-2-furyl-2-methoxyiminoacetic acid. The unreacted 2-acetyl furan can be extracted by using methylene dichloride. The recovered 2-acetyl furan is recycled to the oxidation step, thus avoiding wastage of 2-acetyl furan.

The acidic medium is selected from mineral acid such as 15% of aqueous HCl or aqueous H2SO4 present in the range of 14-18%.

The additive is selected from C1-C10alkanoic acid such as 1-4 moles of acetic acid, propanoic acid, formic acid, butanoic acid or mixtures thereof.

The oxidation process is carried out at a temperature of 40-80°C for 8-12 hours. The second step of reacting α-ketocarboxylic acid with derivative of hydroxylamine is carried out at a temperature of 8-12°C.

The use of additive obviates the use of buffer reagent, which causes reduction in the consumption of sodium hydroxide solution. It alsoresults inimprovement in the overall process such as reduction in time cycle,raw material consumption, byproduct formation and helpsin maintaining required range of pHduring oxidation stage.

The intermediate or it’s prepared by the aforesaid process can be further utilized in the synthesis of antibiotics such as cefuroxime acid or cefuroxime axetil.

The following examples illustrates the invention, but is not limiting thereof.
Example 1:
Process to prepare ammonium syn-2-furyl-2-methoxyimino acetic acid
A. Oxidation
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funneland scrubber system, solution of sodium nitrite (580gm) in water (908ml) was added lot wise slowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1692gm) at 70°C over a period of 12hours. After complete addition of aqueous sodium nitrite solution, acetic acid (160gm) was added and stirred for 1hourto obtain furylglyoxalic acid. After completion of addition, reaction mixture was subjected to extraction using methylene dichloride (250gm x3) for recovery of 2-acetyl furan which was recovered by solvent evaporation and recycled to the first step.

B. Oximation
In the above reaction mass,methoxy amine hydrochloride (170gm) in water (234ml) was added by maintaining neutral pH to form 2-furyl-2-methoxyiminoacetic acid. The reaction mass was cooled at 10°C and butyl acetate (500gm) was added followed by addition of sodium chloride (500gm) at acidic pH. The organic phase was separated and collected. The reaction mass was further extracted twice with butyl acetate (500gmx2), the combined extract was subject to neutralization using anhydrous ammonia at 10°C to form 163gm wet crude ammonium salt of 2-furyl-2-Methoxyimino acetic acid .The crude ammonium salt of 2-furyl-2-Methoxyimino acetic acid was recrystallized by using methanol and dried under vacuum to give 160gmof white to beigecrystals of ammonium syn-2-furyl-2-methoxyiminoacetic acid (Purity greater than 99.0% ;product yield 48%).

Example 2:
Process to prepare ammonium syn-2-furyl-2-methoxyimino acetic acid
A. Oxidation
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funnel and scrubber system, solution of sodium nitrite (600gm) in water ( 938ml ) was added lotwiseslowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1751gm) at 70°C over a period of 12 hours . After complete addition of aqueous sodium nitrite solution,formic acid (122gm) was added and stirred for 1hourto obtain furylglyoxalic acid. After completion of addition, reaction mixture was subjected to extraction using methylene dichloride (250gm x 3) for recovery of 2-acetyl furan which was recovered by solvent evaporation and recycled to the first step.
 
B. Oximation
In the above reaction mass, methoxy amine hydrochloride (160gm) in water (220ml) was added by maintaining neutral pH to form 2-Furyl-2-methoxyiminoacetic acid. The reaction mass was cooled at 10°C and butyl acetate (500gm) was added followed by addition of sodium chloride (500gm) at acidic pH . The organic phase was separated and collected. The reaction mass was further extracted twice with butyl acetate (500gmx2), the combined extract was subject to neutralization using anhydrous ammonia at 10°c to form 170gm wet crude ammonium salt of 2-furyl-2-Methoxyiminoacetic acid .The crude ammonium salt of 2-furyl-2-Methoxyimino acetic acid was recrystallized by using methanol and dried under vacuum to give 167gm off white to beige crystals of ammonium syn-2-Furyl-2-methoxyiminoacetic acid (Purity greater than 99.0% ; product yield 50%.

Example 3:
Process to prepare ammonium syn-2-furyl-2-methoxyimino acetic acid
A. Oxidation
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funneland scrubber system, solution of sodium Nitrite (620gm) in water ( 971ml ) was added lotwise slowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1808gm) at 70°C over a period of 12hours.After complete addition of aqueous sodium nitrite solution,propionic acid (196gm) was added and stirred for 1hourto obtain furylglyoxalic acid. After completion of addition, reaction mixture was subjected to extraction using methylene dichloride (250gmx3) for recovery of 2-acetyl furan which was recovered by solvent evaporation and recycled to the first step.
B. Oximation
In the above reaction mass,methoxy amine hydrochloride (182gm) in water (250ml) was added by maintaining neutral pH to form 2-furyl-2-methoxyiminoacetic acid. The reaction mass was cooled at 10°C and butyl acetate (520gm) was added followed by addition of sodium chloride (500gm) at acidic pH. The organic phase was separated and collected. The reaction mass was further extracted twice with butyl acetate (500gmx2), the combined extract was subject to neutralization using anhydrous ammonia at 10°c to form 176gm wet crude ammonium salt of 2-furyl-2-methoxyiminoacetic acid .The crude ammonium salt of 2-furyl-2-Methoxyimino acetic acid was recrystallized by using methanol and dried under vacuum to give 173gmof white to beige crystals of ammonium syn-2-furyl-2-methoxyiminoacetic acid (Purity greater than 99.0% ;product yield 51.62%).

Example 4:
Process to prepare ammonium syn-2-furyl-2-methoxyimino acetic acid
A. Oxidation
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funnel and scrubber system, solution of sodium Nitrite (640gm) in water (1000ml) was added lotwiseslowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1868 gm) into the flask at 70°C over a period of 12 hours to obtain furylglyoxalic acid. After complete addition of aqueous sodium nitrite solution,butanoic acid (233 gm) was added and stirred for 1hour. After completion of addition, reaction mixture was subjected to extraction using methylene dichloride (250gm x 3) for recovery of 2-acetyl furan which was recovered by solvent evaporation and recycled to the first step.

B. Oximation
In the above reaction mass, methoxy amine hydrochloride (171gm)in water (234ml) was added by maintaining neutral pH to form 2-furyl-2-methoxyiminoacetic acid. The reaction mass was cooled at 10°C and butyl acetate (500gm) wasadded followed by addition of sodium chloride (500gm) at acidic pH . The organic phase was separated and collected. The reaction mass was further extracted twice with butyl acetate (500gmx2), the combined extract was subject to neutralization using anhydrous ammonia at 10°c to form 180gm wet crude ammonium salt of 2-furyl-2-Methoxyiminoacetic acid .The crude ammonium salt of 2-furyl-2-methoxyimino acetic acid was recrystallized by using methanol and dried under vacuum to give 177 gm off white to beige crystals of ammonium syn-2-furyl-2-methoxyiminoacetic acid (Purity greater than 99.0% ; product yield 53%.)
Example 5
Process to prepare syn-2-furyl-2-methoxyimino acetic acid
A. Oxidation
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funnel and scrubber system, solution of sodium Nitrite (640gm) in water (1000ml ) was added lot wise slowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1868 gm) at 70°C over a period of 12 hours . After complete addition of aqueous sodium nitrite solution, butanoic acid (233 gm) was added and stirred for 1hourto obtain furylglyoxalic acid. After completion of addition, reaction mixture was subjected to extraction using methylene dichloride (250gm x 3) for recovery of 2-acetyl furan which was recovered by solvent evaporation and recycled to the first step.

B. Oximation
In the above reaction mass, methoxy amine hydrochloride (171gm) in water (234ml) was added by maintaining neutral pH to form 2-furyl-2-methoxyiminoacetic acid. The reaction mass was cooled at 10°C and butyl acetate (500gm) was added followed by addition of sodium chloride (500gm) at acidic pH . The organic phase was separated and collected. The reaction mass was further extracted twice with butyl acetate (500gmx2) to obtain 180 gm crude 2-furyl-2-methoxyimino acetic acid. Crude 2-furyl-2-Methoxyimino acetic acid was recrystallized by using methanol and dried under vacuum to give 176gm off white to beige crystals of syn-2-Furyl-2-methoxyiminoacetic acid (Purity greater than 99.0%; product yield 53%.
Example 6
Process to prepare furylglyoxalic acid
To a reaction vessel equipped with a thermometer, mechanical stirrer, a dropping funnel and scrubber system, solution of sodium Nitrite (640gm) in water (1000ml) was added lot wise slowly to stirred mixture of 2-acetyl furan (222 gm) in 15% aqueous acidic solution (1868 gm) at 70°Cover a period of 12 hours. After complete addition of aqueous sodium nitrite solution, butanoic acid (233 gm) was added and stirred for 15-30 minutes to obtain furylglyoxalic acid.