Title of Invention

PROCESS FOR THE PERPARRATION OF AMINOTHIZAOLE DERIVATIVE

Abstract

A. process for the preparation of the formula (1), comprising the steps of i) reacting the compound of formula (XIII) with prop an aldehyde in the presence of a base and a solvent at a temperature in the range of 40 to 10C to produce a compound of formula (XTV>. ii) cyolizing the compound of formula (XIV) with mono acetyl thiourea in the presence of a solvent al a temperature in the range of O to 90 °C to produce Ihiazole compound of formula (XV). iii) de-esterifying the compound of formula (XV) in the presence of a base and water at rooni temperature to yield compound of formula (XVI) and iv) deacylating the compound of formula (XV) in the presence of a base and water at a temperature in the range of O to 75ºC to produce compound of formula (I).

Full Text

Field of the invention The present invention relates to a process for the preparation of amino thiazole derivative of the formula (I). More particularly, the present invention relates to a process for the preparation of (Z)-2-(2-aminothiazol-4-yI)pent-2-enoic acid of the formula (I). wherein R2 represents halogen atom, hydroxy, -0-C(=0)CH3, -0-(C=0)-NHR, wherein R represents hydrogen, haioalkyl or alkyl; R3 represents hydrogen, carboxylic acid ester, easily cleavable carboxylic protecting group or a counter ion which forms a salt. Background of the invention EP 467647 and EP 1000939 discloses a process for preparing Z-2-(2-aminothiazol-4-yl)-2-pentenoic acid alkyl ester as a hydrogen halide salt which is unstable, difficult to isolate and handle. US patent No. 4,416,880 discloses a process for the preparation of l-{2-aminothiazol-4-yl)-l-propenecarboxyIic acid which involves chromatographic separation and the process suffers from very low yield. The process comprises reacting ethyl-4-haloacetoacetate with aldehyde, followed by cyclization with thiourea and subsequent alkali hydrolysis resulting in a highly impure compound because of the free amino group. The reaction is shown in scheme 1 Scheme - 1 wherein X represents halogen atom and R represents alkyl group. Thus, for example, in the above case in which R denotes an isopropyl radical, the cyclized product after reaction with thiourea contains following compounds as the major products in addition to the desired compound. US patent No. 4,500,716 discloses the use of 2-aminothiazole-4-yl-acetic acid, to prepare the derivative of the aminothaizole intermediate by the reaction as shown in scheme 2 below. Scheme - 2 wherein R and Ri represents alkyl group. This method also suffers from a very low yield. US patent No. 4,943,568 discloses the preparation of ethylidene derivatives of 5-alkyl as well as 5-chloro substituted amino thiazole compounds having acetyl substitution at the amino position from ethyl 3-oxovalerate. We have during our sustained effort to develop a process for the preparation of (2)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I) found that ethyl-2-propylidene-4-haloacetoacetate can be reacted with mono acetylthiourea to obtain the E + Z isomers of the cyclized product from which selective isolation of the Z-isomer is achievable without resorting to any chromatographic separation. Objective of the invention The main objective of the present invention is to produce a stable (Z)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I) in high purity and yield. Another objective of the present invention is to provide a stable intermediate ethyl (Z)-2-(2-acetamidothiazol-4-y!)pent-2-enoate of the formula (XV) and its isolation with high purity for the subsequent synthesis of (Z)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I). Yet another objective of the present invention is to provide a process for the preparation of (Z)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I) without using chromatographic separation at any stage. Summary of the invention Accordingly, the present invention provides a process for the preparation of (2)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I), comprising the steps of i) reacting the compound of formula (XIII) wherein X represents halogen atom and R1 represents (C1-C3alkyl group with propanaldehyde in the presence of a base and a solvent at a temperature in the range of—40 to 10 °C to produce a compound of formula (XIV) wherein X and R, are as defined above, ii) cyclizing the compound of formula (XIV) with mono acetyl thiourea in the presence of a solvent at a temperature in the range of 0 to 90°C to produce thiazole compound of formula (XV) wherein R1 is as defined above, iii) de-esterifying the compound of formula (XV) in the presence of a base and water at room temperature to yield compound of formula (XVI) and iv) deacylating the compound of formula (XVI) in the presence of a base and water at a temperature in the range of 0 to 75 °C to produce compound of formula (I). The reaction process is shown in scheme —3 below : Detailed description of the invention In yet another embodiment of the present invention the group represented by R1 is selected from (C1-C3)alkyl such as methyl, ethyl, propyl or isopropyl. In yet another embodiment of the present invention the group represented by X is selected from halogen atom such as chlorine or bromine. In yet another embodiment of the present invention the alkylation in step (i) is carried out using propanaldehyde in the presence of a base selected from organic base such as piperidine, pyridine, triethylamine, diethylamine and the like and a solvent such as methylene chloride, chloroform, THF and the like or mixtures thereof The reaction is carried out at a temperature in the range of-40 to 10 °C. In yet another embodiment of the present invention the cyclization of compound of formula (XIV) with mono acetyl thiourea is carried out in the presence of a solvent selected from DMF, water, THF, ethanol and the like or mixture thereof. The reaction is carried out at a temperature in the range of 0 to 90 "C. In another embodiment of the present invention the de-esterification in step (iii) is carried out in the presence of base selected from sodium hydroxide, KOH and the like. In another embodiment of the present invention, the deacetylation in step (iv) is carried out in the presence of a base selected from NaOH, KOH and the like. The reaction is carried out at a temperature in the range of 0 to 75 °C, for a period in the range of 2 to 8 hrs. In yet another embodiment of the present invention the de-esterification and deacetylation of compound of formula (XV) are carried out simultaneously to obtain compound of formula (I) by carrying out the reaction at a temperature in the range of 60 - 80 °C in the presence of base selected from sodium hydroxide, KOH and the like. Both the above processes produce the compound of formula (I) in good purity as exemplified in examples. The only advantage of carrying out deesterification and deacylation in a single step is reduction in number of steps thereby reduction in reaction time. In another embodiment of the present invention, there is provided a process for the preparation of cephalosporin derivatives of the formula (II) m wherein R2 represents halogen atom, hydroxy, -0-C(=0)CH3, -0-(C=0)-NHR, wherein R represents hydrogen, haloalkyl or alkyl; R3 represents hydrogen, carboxylic acid ester, easily cleavable carboxylic protecting group or a counter ion which forms a salt, comprises condensing the compound of formula (I) wherein R2 and R3 are as defined above and R4 represents hydrogen or silyl group. In another embodiment of the present invention, the carboxylic acid ester group is selected from proxetil, axetil, pjvoxil and the like. In another embodiment of the present invention, easily cleavable carboxylic protecting group is selected from methoxybenzyl, p-nitrobenzyl, diphenylmethyl, t-butyl and the like. In another embodiment of the present invention, the counter, which forms a salt, is selected from sodium, potassium and the like. In another embodiment of the present invention, the compound of formula (XV) is selectively obtained in syn form. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. Example-1 Step(i) Preparation of ethvl-2-propvlidene-4-bromoacetoacetate (XIV) Ethyl-4-bTomoacetoacetate was prepared by reacting ethyl acetoacetate (250 g)and bromine at 10-15°C in the presence of catalytic amount of p-toluene sulphonic acid in methylene chloride (350 ml). This was added slowly into a precooled mixture of piperidine (25 gm) in methylene chloride (250 ml) at -30 °C. Propanaldehyde (140 gm) was added at -30 to -25 °C over 10-15 minutes and the reaction mass was stirred for 2 hours at -20 to -15 °C. Anhydrous sodium sulphate (50 gm) was added and stirred for 10 minutes and filtered. The reaction mass was concentrated to give 450 gm of residue which was a mixture of Z- and E- isomers. Step (ii) Preparation of ethy(Z)V2-(2-acetamidotfaiazol-4-vn)pent-2-enQate (XV) Acetylthiourea (183 gm) was suspended in a mixture of DMF (125 ml) and water (125 ml) at 0 °C. The residue (450 gm) of the step (i) was added and the resulting reaction mass was stirred at 10°C for 10 minutes. External cooling source was removed whereupon the temperature rises of its own to 55°C. The temperature was maintained at 55°C for 5 minutes and then cooled and maintained at 5°C for 15 minutes. Water (1.5 It) was added, stirred for 10 minutes, filtered and sucked dry. The crude compound so obtained was stirred in methanol (500 ml) at 0-5 °C for 1 hour and filtered to give 182 gm of the (Z)-isomer with chromatographic purity of 99%. 'H-NMR (DMS0-d6) 5(ppm) : 12.19 (IH, s); 7.02 (lH,s); 6.43(1H, t); 4.23-4.29 (2H,q); 2.27-2.3 (2H, quintet); 2.13 (3H,s); 1.27 (3H, t); 1.03 (3H, t) The corresponding E-isomer, viz. ethyl-(E)-2-(2-acetamidothiazol-4-yl)pent-2-enoate was isolated by concentration of the methanolic mother liquor. 'H-NMR (CDCI3) 8(ppm) : 7.04 (IH, t); 6.84 (IH, s); 4.12-4.19 (2H, q); 2.17-2.24 (2H, quintet); 2.16 (3H, s); 1.21 (3H, t); 0.98 (3H, t). Step am Preparation of (Z)2-(2-acetamidothiazol-4-yl)pent-2-enoic acid (XVI) Ethyl-(Z)-2-(2-acetamidothiazol-4-yl)pent-2-enoate (50 gm) obtained in step (ii) was suspended in a solution of sodium hydroxide (18.65 gm) in 200 ml water at room temperature. The reaction mixture was stirred at 30-35°C for 4 hours and then washed with methylene chloride (2 x 100 ml). pH of the aqueous layer was brought down to 3.5, stirred at 2-4 °C for 1 hour, filtered and dried to give 41.4 gm of the title compound with chromatographic purity of 97%. 'H-NMR (DMSO-d6) -. S (ppm)-12.19 (IH, s); 7.03 (IH, s); 6.59 (IH, l); 2.29- 2.51 {2H, quintet); 2.13 (3H, s); 1.039 (3H, t). The E-isomer was prepared in a similar manner from ethyl-E-2-(2- acetamidothiazol-4-yl)pent-2-enoate. 'H-NMR (Methanol-d4) : 6(ppm) - 7.08 (IH, t); 7.00 (IH, s); 2.29-2.33 (2H, quintet); 2.21 (3H, s); 1.063 (3H, t). Step (iv) Preparation of (Z)-2-(2-aminothiazol-4-y)pent-2-enoic acid (l) (Z)-2-(2-Acetamidothiazol-4-yl)pent-2-enoic acid (25 gm) obtained in step (iii) was added to a solution of NaOH (12.5 gm) in water (100 ml) at 65°C and further stirred for 4 hours. The reaction mass was cooled to 10°C, pH adjusted to 3.8 with 15% hydrochloric acid, stirred for 1 hour, filtered and dried under nitrogen atmosphere to give 10.8 gm of the title compound with chromatographic purity of 97%. 'H-NMR (dmso-dfe) : 6 (ppm) 7.0 (2H, s, D2O exchangable); 6.45 (IH, t); 6.40 (IH, s); 2.2-2.3 (2H, quintet); 1.01 (3H,t). The E-isomer was prepared in a similar manner 'H-NMR (Methanol-d4) : 6(ppm) 7.06 (IH, t); 6.46 (IH, s); 2.2-2.3 (2H, quintet); 1.07 (3H,t). Example-2 Step (i) Preparation of ethvl-2-proDvlidene-4-chIoroacetoacetate (XIV) Ethyl-4-chloroacetoacetate (250 g) was added slowly to a solution of piperidine (2.5 gm) in methylene chloride (500 ml) at -25°C. Propanaldehyde (105 gm) was added slowly to this at -25°C. The reaction mass was stirred for 4 hours at -25 to -20°C and subsequently washed with IN hydrochloric acid (250 ml x 2). The organic layer was separated, dried over sodium sulphate and concentrated to give 282 gm of residue which is a mixture of Z and E isomers. Step (ii) Preparation of ethy(Z)2-(2)-acetamidothiazQl-4-yl)pent-2-enoate (XV) Acetyl thiourea (143.5 gm) was suspended in a mixture of DMF (250 ml) and water (250 ml) at room temperature to which the residue from step (i) was added. Temperature was slowly raised to 85°C when it becomes a clear solution, stirred for 15 minutes at this temperature and then cooled to 5°C. Filtered and washed with water and sucked dry. The crude compound so obtained was stirred in methanol (250 ml) at 0-5°C for 1 hour and filtered and dried to give 76 gm of the title compound (Z-isomer) with chromatographic purity of 99%. Step fiin Preparation of (Z)-2-(2-acetainidothiazol-4-yl)pent-2-enoic acid (Xvi) Ethyl-(Z)-2-(2-acetamidothiazol-4-yl)pent-2-enoate (50 gm) obtained in step (ii) was suspended in a solution of sodium hydroxide (18.65 gm) in 200 ml water at room temperature. The reaction mixture was stirred at 30-35°C for 4 hours and then washed with methylene chloride (2 x 100 ml). pH of the aqueous layer was brought down to 3.5, stirred at 2-4 °C for 1 hour, filtered and dried to give 41.4 gm of the title compound with chromatographic purity of 97%. 'H-NMR (DMS0-d6) : 5 (ppm)=12.19 (IH, s); 7.03 (IH, s); 6.59 (IH, t); 2.29-2.51 (2H, quintet); 2.13 (3H, s); 1.039 (3H, t). The E-isomer was prepared in a similar manner from ethyl-E-2-(2-acetamidothiazol-4-yI )pent-2 -enoate. 'H-NMR (Methanol-d4) : 6(ppm) = 7.08 (IH, t); 7.00 (IH, s); 2.29-2.33 (2H, quintet); 2.21 (3H, s); 1.063 (3H, t). Step (i\) Preparation of fZ)-2-(2-aminothiazol-4-yl)pent-2-enoic acid (l) (Z)-2-(2-Acetamidothiazol-4-yl)pent-2-enoic acid (25 gm) obtained in step (iii) was added to a solution of NaOH (12.5 gm) in water (100 ml) at 65°C and further stirred for 4 hours. The reaction mass was cooled to 10°C, pH adjusted to 3.8 with 15% hydrochloric acid, stirred for 1 hour, filtered and dried under nitrogen atmosphere to give 10.8 gm of the title compound with chromatographic purity of 97%. 'H-NMR (dmso-dg) : 6 (ppm) 7.0 (2H, s, D2O exchangable); 6.45 (IH, t); 6.40 (lH,s); 2.2-2.3 (2H, quintet); 1.01 (3H,t). The E-isomer was prepared in a similar manner 'H-NMR (Methanol-d4) : 8(ppm) 7.06 (IH, t); 6.46 (IH, s); 2.2-2.3 (2H, quintet); 1.07 (3H,t). Example-3 Step (i) Preparation of ethvl-2-propvlidene-4-chloroacetoacetate (XIV) Ethy]-4-chloroacetoacetate (250 g) was added slowly to a solution of piperidine (2.5 gm) in methylene chloride (5O0 ml) at -25°C. Propanaldehyde (105 gm) was added slowly to this at -25°C. The reaction mass was stirred for 4 hours at -25 to -20°C and subsequently washed with IN hydrochloric acid (250 ml x 2). The organic layer was separated, dried over sodium sulphate and concentrated to give 282 gm of residue which is a mixture of Z and E isomers. step (ii) Preparation of ethyl-(Z)-2-(2-acetamidothiazol-4-yl)pent-2-eDoate (XV) Acetyl thiourea (143.5 gm) was suspended in a mixture of DMF {250 ml) and water (250 ml) at room temperature to which the residue from step (i) was added. Temperature was slowly raised to 85°C when it becomes a clear solution, stirred for 15 minutes at this temperature and then cooled to 5°C. Filtered and washed with water and sucked dry. The crude compound so obtained was stirred in methanol (250 ml) at 0-5°C for 1 hour and filtered and dried to give 76 gm of the title compound (Z-isomer) with chromatographic purity of 99%. Step fiii) Preparation of (Z)-2-f2-amiDothiazol-4-ynpent-2-enoic acid (l) Ethyl-(Z)-2-(2-acetamidothiazol-4-yl)pent-2-enoate (XV) (100 gm) was added to a solution of KOH (83.5 gm) in water (500 ml) at 65 °C and stirred at 65-70°C for 5 hours. The reaction mass was cooled to 25 °C and washed with methylene chloride (2 x 150 ml). Aqueous layer was further cooled to 5 °C, acidified to pH 6.0 with 15% HCl and charcolised. The reaction mass was further cooled to 0-2 °C and finally acidified to pH 3.8 and stirred at 0-2 °C for 2 hours, filtered and dried under nitrogen atmosphere at 30-35 °C to yield the title compound with chromatographic purity of 99%. 'H-NMR (DMS0-d6) : 5 (ppm) 7.0 (2H, s, D2O exchangable); 6.45 (IH, t);6.40 (IH, s); 2.2-2.3 (2H, quintet); 1.01 (3H, t). We claim : I. A process for the preparation of (Z)-2-(2-aminothiazol-4-yl)pent-2-enoic acid of the formula (I), comprising the steps of i) reacting the compound of formula (XIII) wherein X represents halogen atom selected from chlorine or bromine, Ri represents {C1-C3)alkyl group with propanaldehyde in the presence of a base and a solvent at a temperature in the range of -40 to 10 °C to produce a compound of fonnula (XIV) wherein X and R| are as defined above, ii) cyclizing the compound of formula (XIV) with mono acetyl thiourea in the presence of a solvent at a temperature in the range of 0 to 90 °C to produce thiazole compound of formula (XV) wherein R| is as defined above, iii) de-esterifying the compound of formula (XV) in the presence of a base and water at room temperature to yield compound of formula (XVI) and iv) deacylating the compound of formula (XV) in the presence of a base and water at a temperature in the range of 0 to 75 °C to produce compound of formula (I). 2. The process as claimed in claim 1, wherein the base used in step (i) is piperidine, pyridine, triethylamine or diethylamine. 3. The process as claimed in claim 1, wherein the solvent used in step (i) is selected from methylene chloride, chloroform or THF. 4. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from DMF, water, THF or ethanol. 5. The process as claimed in claim 1, wherein the base used in step (iii) is selected from sodium hydroxide or KOH. 6. The process as claimed in claim 1, wherein the base used in step (iv) is selected from NaOH or KOH. 7. The process as claimed in claim 1, wherein the compound of formula (XV) is selectively obtained in syn form. 8. A process for the preparation of (Z)-2-(2-aminothia2ol-4-yl)pent-2-enoic acid of the formula (I), comprising simultaneously de-esterification and deacetylation of compound of the formula (XV) 10. The process as claimed in claim 9, wherein the easily cleavable carboxylic protecting group is selected from methoxybenzyl, p-nitrobenzyl, diphenylmethyl or t-butyl. 11, The process as claimed in claim 9, wherein the carboxylic acid ester group is selected from proxetil, axetil or pivoxil. 12. The process as claimed in claim 9, wherein the counter, which forms a salt, is selected from sodium or potassium.

Documents:

689-mas-2002 abstract.pdf

689-mas-2002 claims.pdf

689-mas-2002 correspondence others.pdf

689-mas-2002 correspondence po.pdf

689-mas-2002 description (complete).pdf

689-mas-2002 form-1.pdf

689-mas-2002 form-19.pdf