Description:FIELD OF THE INVENTION
The present disclosure relates to a process for preparing methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
BACKGROUND OF THE INVENTION
The background information herein below relates to the present disclosure but is not necessarily prior art.
Methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate is synthesized by many conventional methods. The disadvantages of these methods are low yield of the product resulting in high production costs.
The literature is replete in various other methods for the synthesis of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate by various routes. However, these methods are associated with drawbacks such as low yield and/ or low purity of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate.
There is, therefore, felt a need to provide a process for the synthesis of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate, which mitigates the drawbacks mentioned herein above or at least provides a useful alternative.
OBJECTS OF THE INVENTION
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present disclosure is to provide a process for the synthesis of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate.
Another object of the present disclosure is to provide a simple, economical and environment-friendly process for the synthesis of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate.
Still another object of the present disclosure is to provide a process for the synthesis of methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1, 3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene] amino} oxy) acetate with high purity and high yield.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY OF THE INVENTION
The present disclosure relates to a process for preparing methyl ({[(1Z)-1-(2-amino-1, 3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy) acetate. The process comprising the following steps:
i. reacting tert-butylacetoacetate with aqueous alkali metal nitrate salt to obtain a first reaction mixture and cooling said first reaction mixture at a first pre-determined temperature followed by adding acetic acid over a first pre-determined time period to obtain tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate;
ii. reacting tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate with methyl chloroacetate in presence of a first fluid medium and an inorganic salt at a second pre-determined temperature for a second pre-determined time period to obtain tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate;
iii. hydrolyzing tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate by purging hydrochloric acid gas over a third pre-determined time period in a solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate and acetic acid cooled at a third pre-determined temperature to obtain an intermediate, followed by chlorinating an intermediate by adding sulfuryl chloride at a fourth pre-determined temperature for a fourth pre-determined time period to obtain (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid;
iv. reacting (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid with thiourea in an aqueous solution of sodium bicarbonate cooled at a fifth pre-determined temperature to obtain a second reaction mixture, followed by stirring and maintaining said second reaction mixture at a sixth pre-determined temperature for a fifth pre-determined time period, and adjusting pH of said reaction mixture between pre-determined pH by using dilute acid followed by cooling at a seventh pre-determined temperature to obtain (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino] ethanoic acid; and reacting (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino]ethanoic acid with 2,2'–dithiobisbenzothiazole in presence of a second fluid medium at an eighth pre-determined temperature, followed by adding triethyl amine and triethyl phosphite to obtain a third reaction mixture and stirring said third reaction mixture for a sixth pre-determined time period at a ninth pre-determined temperature to obtain crude product comprising methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure relates to a process for preparing methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy) acetate.
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to theperson skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises,""comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
In an aspect, the present disclosure relates to a process for preparing methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.The process comprising the following steps:
i. tert-butylacetoacetate is reacted with aqueous alkali metal nitrate salt to obtain a first reaction mixture and the first reaction mixture is cooled at a first pre-determined temperature followed by adding acetic acid over a first pre-determined time period to obtain tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate;
ii. tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate is reacted with methyl chloroacetate in presence of a first fluid medium and an inorganic salt at a second pre-determined temperature for a second pre-determined time period to obtain tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate;
iii. tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate is hydrolyzed by purging hydrochloric acid gas over a third pre-determined time period in a solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoate and acetic acid cooled at a third pre-determined temperature to obtain an intermediate, followed by chlorinating an intermediate by adding sulfuryl chloride at a fourth pre-determined temperature for a fourth pre-determined time period to obtain (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid;
iv. (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid is reacted with thiourea in an aqueous solution of sodium bicarbonate cooled at a fifth pre-determined temperature to obtain a second reaction mixture, followed by stirring and maintaining the second reaction mixture at a sixth pre-determined temperature for a fifth pre-determined time period, and adjusting pH of said reaction mixture between pre-determined pH by using dilute acid followed by cooling at a seventh pre-determined temperature to obtain (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino] ethanoic acid; and (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino]ethanoic acid is reacted with 2, 2'–dithiobisbenzothiazole in presence of a second fluid medium at an eighth pre-determined temperature, followed by adding triethyl amine and triethyl phosphite to obtain a third reaction mixture and stirring the third reaction mixture for a sixth pre-determined time period at a ninth pre-determined temperature to obtain crude product comprising methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
The process for preparing methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate is described in detail herein below.
Step (i): Preparation of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate
In a first step, tert-butylacetoacetate is reacted with aqueous alkali metal nitrate salt to obtain a first reaction mixture and the first reaction mixture is cooled at a first pre-determined temperature followed by adding acetic acid over a first pre-determined time period to obtain tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate.
In an embodiment, thealkali metal nitrate salt is sodium nitrate.
In an embodiment, the first pre-determined temperature is in the range of from 5 ? to 20 ?, preferably 10 ? to 15 ?.
In an embodiment, the first pre-determined time is in the range of from 8 hours to 20 hours, preferably 10 hours to 15 hours.
The preparation of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1 given below:

Scheme 1: Schematic representation of the preparation of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate
Step (ii): Preparation of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate
In a second step, tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate is reacted with methyl chloroacetate in presence of a first fluid medium and an inorganic salt at a second pre-determined temperature for a second pre-determined time period to obtain tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate.
In an embodiment, the first fluid medium is selected from dimethyl formamide.
In an embodiment, the inorganic salt is potassium carbonate.
In an embodiment, the second pre-determined temperature is in the range of from 20 ? to 50 ?, preferably 25 ? to 40 ?.
In an embodiment, the second pre-determined time is in the range of from 2 hours to 10 hours, preferably 4 hours to 6 hours.
The preparation of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 2 given below:

Scheme 2: Schematic representation of the preparation tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate
Step (iii): Preparation of (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid
In a third step,tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate is hydrolyzed by purging hydrochloric acid gas over a third pre-determined time period in a solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate and acetic acid cooled at a third pre-determined temperature to obtain an intermediate, followed by chlorinating an intermediate by adding sulfuryl chloride at a fourth pre-determined temperature for a fourth pre-determined time period to obtain (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid.
In an embodiment, the third pre-determined time is in the range of from 0.5 hour to 5 hours, preferably 1 hour to 2 hours.
In an embodiment, the fourth pre-determined time is in the range of from 20 hours to 35 hours, preferably 24 hours to 30 hours.
In an embodiment, the third pre-determined temperature is in the range of from 0 ? to 10 ?, preferably 0 ? to 5 ?.
In an embodiment, the fourth pre-determined temperature is in the range of from 15 ? to 40 ?, preferably 20 ? to 35 ?. The step of chlorination at this stage makes reaction environment less acidic which ultimately results in high product yield.
The preparation of (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 3 given below:

Scheme 3: Schematic representation of the preparation (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid
Step (iv): Preparation of (2Z) - (2-amino-1, 3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid
In fourth step, (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid is reacted with thiourea in an aqueous solution of sodium bicarbonate cooled at a fifth pre-determined temperature to obtain a second reaction mixture, followed by stirring and maintaining the second reaction mixture at a sixth pre-determined temperature for a fifth pre-determined time period, and adjusting pH of said reaction mixture between pre-determined pH by using dilute acid followed by cooling at a seventh pre-determined temperature to obtain (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino]ethanoic acid.
In an embodiment, the fifth pre-determined temperature is in the range of from 0 ? to 10?, preferably 0 ? to 5 ?.
In an embodiment, the sixth pre-determined temperature is in the range of from 5 ? to 20 ?, preferably 10 ? to 15 ?.
In an embodiment, the seventh pre-determined temperature is in the range of from 0 ? to 10 ?, preferably 0 ? to 5 ?.
In an embodiment, the fifth pre-determined time is in the range of from 4 hours to 15 hours, preferably 6 hours to 10 hours.
In an embodiment, the dilute acid is dilute sulphuric acid.
In an embodiment, the pre-determined pH is in the range of from 2 to 5, preferably 2 to 3.
The preparation of (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino] ethanoic acid, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 4 given below:

Scheme 4: Schematic representation of the preparation (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino]ethanoic acid
Step (v): Preparation of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate
In fifth step, (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino] ethanoic acid is reacted with 2, 2'–dithiobisbenzothiazole in presence of a second fluid medium at an eighth pre-determined temperature, followed by adding triethyl amine and triethyl phosphite to obtain a third reaction mixture and stirring the third reaction mixture for a sixth pre-determined time period at a ninth pre-determined temperature to obtain crude product comprising methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
In an embodiment, the second fluid medium is selected from acetonitrile, methylene dichloride, and mixture thereof.
In an embodiment, the eighth pre-determined temperature is in the range of from 0 ? to 10 ?, preferably 0 ? to 5 ?.
In an embodiment, the ninth pre-determined temperature is in the range of from 0 ? to 10 ?, preferably 0 ? to 5 ?.
In an embodiment, the sixth pre-determined time is in the range of from 2 hours to 10 hours, preferably 4 hours to 6 hours.
The preparation of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate, in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 5 given below:

Scheme 5: Schematic representation of the preparation methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate
The crude product is purified using an extraction solvent to obtain methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
The purity of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetateis at least 99.2%
In an embodiment, the extraction solvent is selected from methylene dichloride, methanol, cyclohexane, acetone, acetonitrile, MDC, formic acid, and mixtures of two or more thereof.
The process of the present disclosure employs inexpensive and easily available reagents. Thus, the process of the present disclosure is economical.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.

EXPERIMENTAL DETAILS
Preparation of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate in accordance with the present disclosure
Step 1: Preparation of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate
Tertbutylacetoacetate (50 g, 0.31 mole) was dissolved in 150 ml water added sodium nitrate (28.2 g, 0.40 mole) to obtain a reaction mixture. The reaction mixture was cooled at 10°C and acetic acid (26.5 g, 0.44 mole) was added over a period of 2 hours, maintained for 10 hours. After completion, reaction product was extracted in ethyl acetate. On complete distillation of solvent, gives59.8 g of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate as pale yellow colour oil, Purity 93.0 to 95.0 %.
Step 2: Preparation of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate
Example 1:
A suspension of 100 ml DMF (dimethyl formamide) in dry potassium carbonate (43.0 g, 0.31 mole) was stirred for 15 min and added solution of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate (57.7 g, 0.30 mole) dissolved in 5.5 g DMF and methyl chloroacetate (38.0 g, 0.35 mole) at 25°C. The reaction mass was heated to 35° C for 4 hours. After completion of reaction, the insoluble salt was filtered. On complete distillation of DMF, gives 75 g of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate as brown colour oil.Purity 92.0 to 93.5%.

Example 2:
A suspension of 100 ml DMF in dry potassium carbonate (43.0 g, 0.31 mole) was stirred for 15 min and added solution of tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate (57.7 g, 0.30 mole) dissolved in 5.5 g DMF and methyl chloroacetate (43.4 g, 0.40 mole) at 30° C. The reaction mass was heated to 40° C for 6 hours. After completion of reaction, the insoluble salt was filtered. On complete distillation of DMF, gives 75 g of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate as brown colour oil, Purity 94.0 to 95.2%.

Step 3: Preparation of (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid
Example 1:

A solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate (77.0 g, 0.29 mole) in 22.5 ml acetic acid was cooled to 5°C, purged HCl gas in the reaction mass for 1 hours, and checked the complete hydrolysis of ester by TLC. After completion of reaction, sulfuryl chloride (45 g, 0.33 moles) was added drop wise at 20° C and maintained the reaction mass for 24 hours. On completion of reaction 50 ml MDC was charged (methylene dichloride) and the reaction mass was cooled to 5° C. The solid observed was filtered and washed with chilled 10 ml MDC to give 46 g of (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid as off white colour powder. Purity 88-93%.
Example 2:

A solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoate (77.0 g, 0.29 mole) in 22.5 ml acetic acid was cooled to 5° C, purged HCl gas in the reaction mass for 1 hours, and checked the complete hydrolysis of ester by TLC. After completion of reaction, sulfuryl chloride (54.1 g, 0.40 moles) was added drop wise at 35° C and maintained the reaction mass for 30 hours. On completion of reaction 50 ml MDC was charged and the reaction mass was cooled to 0° C. The solid observed was filtered and washed with chilled 10 ml MDC to give 48.5 g of (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid as white colour powder. Purity 90-92%.
Step 4: Preparation of (2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid

Example-1

A solution of sodium bicarbonate (34.0 g, 0.40 mole) was dissolved in 202.5 ml water and the reaction mass was cooled to 0° C, added (40.5 g, 0.14 mole) tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoate solution followed by addition of (19.4 g, 0.25 mole) thiourea. Stirred and maintained the reaction mass at 10° C for 6 hours, then adjusted pH of reaction mass to 2 by using dil. H2SO4 solution. After pH adjustment, the reaction mass was stirred and cooled to 0° C and the solid observed was filtered and washed with 40 ml water to give 34.5 g(2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid, Purity 99.00%.
Example-2

A solution of sodium bicarbonate (34.0 g, 0.40 mole) was dissolved in 250 ml water and cool the reaction mass to 10° C, added (40.5 g, 0.14 mole) tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoate solution followed by addition of (23.3 g, 0.30 mole) thiourea. Stirred & maintained the reaction mass at 15° C for 10 hours, then adjusted pH of reaction mass to 3 by using dil. H2SO4 solution. After pH adjustment, the reaction mass was stirred and cooled to 5° C and the solid observed was filtered and washed with 40 ml water to give 36.5 g (2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid, Purity 99.5%.

Example-3

A solution of sodium bicarbonate (34.0 g, 0.40 mole) was dissolved in 250 ml water and the reaction mass was cooled to 0° C, added (40.5 g, 0.14 mole) tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoate solution followed by addition of (19.1 g, 0.25 mole) thiourea. Stirred& maintained the reaction mass at 10° C for 6 hours, then adjusted pH of reaction mass to 2 by using dil. H2SO4 solution. After pH adjustment, the reaction mass was stirred and cooled to 0° C and the solid observed was filtered and washed with 40 ml water to give 35.0 g (2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid, Purity 98.50%.
Step 5: Preparation of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate
Example-1

A suspension of (27.5 g 0.10 mole) (2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid was prepared in 137.5 ml acetonitrile and in (43.12 g, 0.12 mole) 2,2' – dithiobisbenzothiazole (MBTDS) to obtain a reaction mass. The reaction mass was cooled at 0° C. To this reaction mass, mixture of (12.8 g, 0.12 mole) Triethyl amine and Triethylphosphite (28.9 g 0.17 mole) in 8 lots were added. After complete lot addition, reaction mass was stirred for 4 hours at 0° C & filtered the solid observed, washed with chilled 27.5 ml acetonitrile to obtain 36.5 g methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate as yellow colour powder, purity 98.5%.
Example-2

A suspension of (27.5 g 0.10 mole) (2Z) - (2-amino-1,3-thiazol-4-yl) [(2-methoxy-2 oxoethoxy) imino] ethanoic acid was prepared in 137.5 ml acetonitrile, 27.5 MDC and in (43.12 g, 0.12 mole) of 2,2' – dithiobisbenzothiazole (MBTDS) to obtain a reaction mass. The reaction mass was cooled at 5° C. To this reaction mass, mixture of (12.8 g, 0.12 mole) Triethyl amine and Triethylphosphite (28.9 g 0.17 mole) in 14 lots were added. After complete lot addition, reaction mass was stirred for 6 hours at 5° C & filtered the solid observed, washed with chilled 27.5 ml acetonitrile to obtain 24.3 g methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate as yellow colour powder, purity 98.0%. On purification with mixture of MDC: Methanol gives 21. 5g methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate as orange colour powder, purity NLT 99.2%
From above, it is conclusive that the above process steps along with the process parameter such as temperature range and purification solvent played an effective role achieving higher yield and purity.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization ofa process for the synthesis of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate, which:
- is carried out at low pressure;
- is feasible for large scale manufacturing;
- is simple, economical and environment-friendly; and
- provides high yield and high purity methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3 benzothiazol-2-ylsulfanyl) -2-oxoethylidene] amino} oxy) acetate.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation. , Claims:WE CLAIM:
1. A process for preparing methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate, wherein said process comprising the following steps:
i. reacting tert-butylacetoacetate with aqueous alkali metal nitrate salt to obtain a first reaction mixture and cooling said first reaction mixture at a first pre-determined temperature followed by adding acetic acid over a first pre-determined time period to obtain tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate;
ii. reacting tert-butyl (2Z)-2-(hydroxyimino)-3-oxobutanoate with methyl chloroacetate in presence of a first fluid medium and an inorganic salt at a second pre-determined temperature for a second pre-determined time period to obtain tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate;
iii. hydrolyzing tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate by purging hydrochloric acid gas over a third pre-determined time period in a solution of tert-butyl (2Z)-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoate and acetic acid cooled at a third pre-determined temperature to obtain an intermediate, followed by chlorinating an intermediate by adding sulfuryl chloride at a fourth pre-determined temperature for a fourth pre-determined time period to obtain (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy) imino]-3-oxobutanoic acid;
iv. reacting (2Z)-4-chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid with thiourea in an aqueous solution of sodium bicarbonate cooled at a fifth pre-determined temperature to obtain a second reaction mixture, followed by stirring and maintaining said second reaction mixture at a sixth pre-determined temperature for a fifth pre-determined time period, and adjusting pH of said reaction mixture between pre-determined pH by using dilute acid followed by cooling at a seventh pre-determined temperature to obtain (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino]ethanoic acid;
v. reacting (2Z)-(2-amino-1,3-thiazol-4-yl)-[(2-methoxy-2-oxoethoxy)imino] ethanoic acid with 2, 2'–dithiobisbenzothiazole in presence of a second fluid medium at an eighth pre-determined temperature, followed by adding triethyl amine and triethyl phosphite to obtain a third reaction mixture and stirring said third reaction mixture for a sixth pre-determined time period at a ninth pre-determined temperature to obtain crude product comprising methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
2. The process as claimed in claim 1, wherein the crude product is purified using an extraction solvent to obtain methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate.
3. The process as claimed in claim 1, wherein said alkali metal nitrate salt is sodium nitrate.
4. The process as claimed in claim 1, wherein said first fluid medium is dimethyl formamide.
5. The process as claimed in claim 1, wherein said inorganic salt is potassium carbonate.
6. The process as claimed in claim 1, wherein said dilute acid is dilute sulphuric acid.
7. The process as claimed in claim 1, wherein said pre-determined pH is in the range of from 2 to 5.
8. The process as claimed in claim 1, wherein said second fluid medium is selected from acetonitrile, methylene dichloride, and mixture thereof.
9. The process as claimed in claim 2, wherein said extraction solvent is selected from methylene dichloride, methanol, cyclohexane, acetone, acetonitrile, MDC, formic acid, and mixtures of two or more thereof.
10. The process as claimed in claim 1, wherein said
- first pre-determined temperature is in the range of from 5 ? to 20 ?;
- second pre-determined temperature is in the range of from 20 ? to 50 ?;
- third pre-determined temperature is in the range of from 0 ? to 10 ?;
- fourth pre-determined temperature is in the range of from 15 ? to 40 ?;
- fifth pre-determined temperature is in the range of from 0 ? to 10 ?;
- sixth pre-determined temperature is in the range of from 5 ? to 20 ?;
- seventh pre-determined temperature is in the range of from 0 ? to 10 ?;
- eighth pre-determined temperature is in the range of from 0 ? to 10 ?; and
- ninth pre-determined temperature is in the range of from 0 ? to 10 ?.
11. The process as claimed in claim 1, wherein said
- first pre-determined time is in the range of from 8 hours to 20 hours;
- second pre-determined time is in the range of from 2 hours to 10 hours;
- third pre-determined time is in the range of from 0.5 hour to 5 hours;
- fourth pre-determined time is in the range of from 20 hours to 35 hours;
- fifth pre-determined time is in the range of from 4 hours to 15 hours; and
- sixth pre-determined time is in the range of from 2 hours to 10 hours.
12. The process as claimed in claim 2, wherein the purity of methyl ({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino}oxy)acetate obtained in step (vi) is at least 99.2%.