Field of the Invention:
The present invention is in the field of process chemistry. More particularly the invention deals with a process for the preparation of Sultamicillin Tosylate of the formula (I)
(Formula Removed)
Background of the Invention:
Sultamicillin Tosylate is chemically known as [[[(2S,5R)-3,3-Dimethyl-4,4-dioxido-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-yl]carbonyl]oxy]methyl (2S,5R,6R)-6-[[(2R)-Aminophenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate monotosylate of formula (I).
(Formula Removed)
US Patent No. 4,488,994 discloses penicillanic acid 1,1-dioxide and esters thereof which can be used as antibacterial agents.
US Patent No. 4,342,772 discloses the process for the preparation of Sultamicillin salts, wherein anhydrous Ampicillin react with methyl acetoacetate in the presence of a base in organic solvent followed by reaction with Iodomethyl penicillanate 1,1-dioxide at aqueous alkali metalhalide and followed by hydrolyses with p-toluenesulfonic acid monohydrate in organic solvents to give the Sultamicillin tosylate.

US Patent No. 4,831,025 discloses reaction of anhydrous Ampicillin with methylacetoacetate in organic solvents in the presence of base followed by reaction with iodomethylpenicillanate-1,1-dioxide in organic solvent. After dilution with organic solvent, the mixture was extracted with water and saturated aqueous sodium chloride to give a solution of the intermediate, 6ß-[N-(l-methoxycarbonyl-propen-2-yl)-D-α-amino-a-phenylacetamido]penicillanoyloxy methyl penicillanate 1,1-dioxide, in organic solvent. This is hydrolyzed with 4-toluensulfonic acid at aqueous media in organic solvents to form the Sultamicillin tosylate.
In the prior art the methods for the preparation of Sultamicillin tosylate is from anhydrous Ampicillin. To avoid the process of converting Ampicillin trihydrate to Ampicillin anhydrous the team of inventors developed the process for the preparation of Sultamicillin tosylate directly from Ampicillin trihydrate.
Objects of the Invention:
The object of the present invention is to provide a simple, sustainable and environment friendly process for the preparation of Sultamicillin tosylate of the formula (I) using economical process with miniature techniques, good yield, high purity and acceptable color, which is efficient and commercially viable.
Statement of the Invention:
Accordingly, the present invention relates to a process for the preparation of Sultamicillin tosylate of formula (I)
(Formula Removed)

from Ampicillin trihydrate of formula (II),
(Formula Removed)

wherein the process comprises
a) treating the compound of formula (II) with methylacetoacetate in presence
of a base in a suitable solvent or mixture of solvents, to form an ester
compound of formula (III),
(Formula Removed)

b) treating the compound of formula (III) with iodomethylester of sulbactam
acid to obtain the compound of formula (IV),
(Formula Removed)
c) treating the compound of formula (IV) with p-tolenesulphonic acid in an
organic solvent to yield substantially pure compound of formula (I).
Detailed Description of the Invention:
Accordingly, the present invention relates to an improved process for the preparation of Sultamicillin Tosylate from Ampicillin Trihydrate (formula II). The invention in particular avoids the preparation of anhydrous Ampicillin and completes the reaction in aqueous condition and comprises only few steps. The scheme of reactions followed in the instant invention is stated hereunder:

(Formula Removed)
For the purpose of this invention, compound of Formula (II) is treated with methylacetoacetate, in the presence of a base in a suitable solvent or mixture of solvents to form a ester compound of Formula (III), which is further treated with iodomethylester of sulbactam acid to give the compound of Formula (IV), followed by treating with p-tolenesulphonic acid in the presence of suitable organic solvent to yield substantially pure compound of Formula (I). The preparation of the compound of Formula (I) using above reaction condition results in "substantially pure" compound. "Substantially pure" as used herein

means at least 98% pure, preferably 99% pure, more preferably 99.5% pure and most preferably 99.9% pure.
The term "suitable solvent" as used herein refers various solvents known to a person skilled in the art that may be used for the extraction procedure. These include but are not restricted to N,N-dimethylformamide, Dimethylacetamide, tetrahydrofuran, dioxane, alcohols such as ethanol, methanol, propanol and mixture thereof, dichloromethane, ethyl acetate, aromatic hydrocarbon, acetone, dioxane, acetonitrile, dialkylethers, water or mixtures thereof. N,N-dimethylformamide, dimethyl acetamide, ethyl acetate and water or mixture are most preferred solvents of the invention. The solvent is preferably N,N-dimethylformamide, dimethylacetamide, ethyl acetate and water or mixture thereof.
The term "base" as used herein refers to alkali metal carbonates such as sodium or potassium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate or alkali metal hydroxides such as sodium hydroxide. For the present invention the most preferred alkali metal carbonate is potassium carbonate and the like. The base is preferably alkali metal carbonates like sodium or potassium carbonate.
The invention is illustrated further by the following examples which are only meant to illustrate the invention and not act as limitations. The embodiments which may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.
Example-1
Preparation of [[[(2S,5R)-3,3-Dimethyl-4,4-dioxido-7-oxo-4-thia-l-azabicyclo[3.2.0] hept-2-yl]carbonyl]oxy]methyl (2S,5R,6R)-6-[[(2R)-Aminophenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate monotosylate (Sultamicillin Tosylate).

1. Adding 22.2g of Ampicillin trihydrate, 8g of potassium carbonate, 9g of methyl acetoacetate, 5g of sodium thiosulfate, and 50ml of dimethyl formamide in a round bottom flask and obtaining the reaction mixture;
2. Stirring the reaction mixture at 25-27°C for 3hrs;
3. Cooling the reaction mixture to 0°C;
4. Adding 20g of iodomethyl penicillanate 1,1-dioxide followed by stirring at 20°C for 120-150 min;
5. Transferring the reaction mixture to 600ml of chilled mixture (0-5°C) of ethylacetate and water, wherein the ratio of ethyl acetate and water is 1:2;
6. Stirring the reaction mixture for 20 min., followed by separating the layers and extracting aqueous layer with 50ml ethylacetate;
7. Combining the organic layer and washing with 2 x 100ml saturated NaCl aqueous solution and obtaining layer;
8. Adding drop wise solution of 15g of p-toluene sulphonic acid in 60 ml water to the resulting organic layer solution at 20-25 °C and stirring slowly for 2hrs at 0-5°C;
9. Filtering and washing with 90ml of chilled ethyl acetate and 25ml of chilled water separately;
10. Drying at 45-50°C to get 35g of the compound of Formula I as white crystals with a m.p.: 143 to 145°C and HPLC purity: >99%.
Example-2
Preparation of [[[(2S,5R)-3,3-Dimethyl-4,4-dioxido-7-oxo-4-thia-l-azabicyclo[3.2.0]
hept-2-yl]carbonyl]oxy]methyl (2S,5R,6R)-6-[[(2R)-Aminophenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate monotosylate (Sultamicillin Tosylate).
1. Adding 22.2g of Ampicillin trihydrate, 8g of potassium carbonate, 9g of methyl acetoacetate, 5g of sodium thiosulfate, and 50ml of dimethyl acetamide in a round bottom flask and obtaining the reaction mixture;
2. Stirring the reaction mixture at 25-27°C for 3hrs;
3. Cooling the reaction mixture to 0°C;

4. Adding 20g of iodomethyl penicillanate 1,1-dioxide followed by stirring at 20°C for 120-150 min;
5. Transferring the reaction mixture to 600ml of chilled mixture (0-5°C) of ethylacetate and water, wherein the ratio of ethyl acetate and water is 1:2;
6. Stirring the reaction mixture for 20 min., followed by separating the layers and extracting aqueous layer with 50ml ethylacetate;
7. Combining the organic layer and washing with 2 x 100ml saturated NaCl aqueous solution and obtaining layer;
8. Adding drop wise solution of 15g of p-toluene sulphonic acid in 60 ml water to the resulting organic layer solution at 20-25°C and stirring slowly for 2hrs at 0-5°C;
9. Filtering and washing with 90ml of chilled ethyl acetate and 25ml of chilled water separately;
10. Drying at 45-50°C to get 35g of the compound of Formula I as white crystals with a m.p.: 143 to 145°C and HPLC purity: >99%.
Example-3
Preparation of [[[(2S,5R)-3,3-Dimethyl-4,4-dioxido-7-oxo-4-thia-l-azabicyclo[3.2.0]
hept-2-yl]carbonyl]oxy]methyl (2S,5R,6R)-6-[[(2R)-Aminophenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-l -azabicyclo [3.2.0] heptane-2-carboxylate monotosylate (Sultamicillin Tosylate).
1. Adding lllg of Ampicillin trihydrate, 47g of potassium carbonate, 47g of methyl acetoacetate, 10g of sodium thiosulfate, and 300ml of dimethyl acetamide in a round bottom flask and obtaining the reaction mixture;
2. Stirring the reaction mixture at 25-27°C for 60-90 min;
3. Cooling the reaction mixture to 20°C;
4. Adding 100g of iodomethyl ester of sulbactam followed by stirring at 20°C for 120-150 min;
5. Transferring the reaction mixture to 3000ml of chilled mixture (0-5°C) of ethylacetate and water, wherein the ratio of ethyl acetate and water is 1:2;

6. Stirring the reaction mixture for 20 min followed by separating the layers . and extracting aqueous layer with 200ml ethylacetate;
7. Combining the organic layer and washing with 2 x 500ml saturated NaCl aqueous solution and obtaining layer;
8. Adding drop wise solution of 50g of p-toluene sulphonic acid in 300 ml water to the resulting organic layer solution at 20-25°C and stirring slowly for 2hrs at 0-5°C;
9. Filtering and washing with 450ml of chilled ethyl acetate and 100ml of chilled water separately;
10. Drying at 45-50°C to get 35g of the compound of Formula I as white crystals with a m.p.: 143 to 145°C and HPLC purity: >99%

WE CLAIM;
1. A process for the preparation of sultamicillin tosylate of formula (I)
(Formula Removed)

from ampicillin trihydrate of formula (II),
(Formula Removed)

wherein the process comprises
a) treating the compound of formula (II) with methylacetoacetate in presence
of a base in a suitable solvent or mixture of solvents, to form an ester
compound of formula (III),
(Formula Removed)

b) treating the compound of formula (III) with iodomethylester of sulbactam
acid to obtain the compound of formula (IV),
(Formula Removed)

c) treating the compound of formula (IV) with p-tolenesulphonic acid in an
organic solvent to yield substantially pure compound of formula (I).

2. The process as claimed in claim 1, wherein the solvent is preferably N,N-dimethylformamide, dimethylacetamide, ethyl acetate and water or mixture thereof.
3. The process as claimed in claim 1, wherein the base is preferably alkali metal carbonates like sodium or potassium carbonate.
4. The process as claimed in claim 1, wherein substantially pure means at least 98% pure, preferably 99% pure, more preferably 99.5% pure and most preferably 99.9% pure.
5. Sultamicillin tosylate of formula I obtained by the process as claimed in claim 1.
6. Sultamicillin tosylate as claimed in claim 5, wherein the Sultamicillin tosylate is at least 99% pure.
7. The process for preparing sultamicillin tosylate of formula (I) and the Sultamicillin tosylate of formula (I), substantially as herein describe with reference to the forgoing examples.