Title of Invention | "AN IMPROVED PROCESS FOR OPENING EPOXIDES BY THIOLS" |
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Abstract | The invention relates to an improved process for the preparation of 2-hydroxyalkyl sulphides and 2-hydroxy aryl sulphides involving nucleophillic ring opening of epoxides by thiols, the said process comprising steps of (a) adding thiol to an epoxide in an inert atmosphere preferably in absence of a solvent; (b) adding zirconium catalyst to the mixture of step (a), (c) stirring the mixture of step (b) at a temperature ranging between 0 o to 150° C for a time period of 1 hour to 8 hour and (d) isolating the required 2-hydroxyalkyl sulphide or 2-hydroxy aryl suiphide by conventional methods. |
Full Text | An improved process for preparation of hydroxyalkyl and hydroxyaryl sulfides Field of the invention The present invention is related to a process for opening epoxides by thiol in presence of zirconium catalysts in presence or absence of a solvent at an appropriate temperature to give 2-hydroxyalkyl sulfides or 2-hydroxy aryl sulfides, the invention also describes opening of unsymmetrical epoxide to yield regioisomeric product, the ratio of regioisomeric product is controlled by selection of an appropriate zirconium catalyst, solvent and reaction temperature. Background of the Invention • Epoxide opening reaction is a versatile transformation in organic synthesis. This unit process constitutes a key step in the synthesis of a vast number of compounds having diverse biological activities. Nucleophilic opening of epoxide in regioselective fashion is a key issue in synthetic transformation. In the synthesis of calcium channel blocker, diltiazem, the methyl 4-methoxyphenyl glycidate is treated with 2-aminothiophenol, where sulfur opens the epoxide by nucleophilic attack, thereby generating the desired 3-(2-aminophenyl)thio 3-(4-methoxyphenyl) 2-hydroxy propanoic acid methyl ester. Various processes are known for ring opening reaction of epoxides by thiol. Simply heating the epoxide and thiol together at higher temperature opens the epoxide. However, in case of unsymmetrical epoxides the selectivity is not useful. For example, in case of styrene oxide the ratio of two isomers is 45:55. (See Figure 1) (Syn. Lett. 1992, 303-305). When a base is used as promotor and the reaction is performed in protic solvent, the reaction occurs at room temperature but the selectivity remains unchanged (Syn. Lett. 1992, 303-305).Iqbal et al (Tetrahedron 1990, 46, 6423-6432) described an investigation using CoCh, wherein on of the isomer is obtained in 51% yield. Crotti et al (Syn. Lett. 1992, 673-676) described an investigation on regioselectivity employing variety of polar salts such as lithium perchlorate, magnesium perchlorate, lithium fluoroborate etc. The report describes lithium perchlorate to be the best candidate among these salts. With lithium perchlorate, the ratio 3:4 is 53:47, when the reaction is carried out at 50°C for 17 hours. The amount of thiol and the catalyst required for the reaction is 1.5 equivalents to that of epoxide. Albenese et al (Synthesis 1994, 34-36) described a method using tetrabutylammonium fluoride as catalyst. The selectivity obtained for 3:4 is 34:66. Iranpoor et al (Tetrahedron 1991, 47, 9861-9866) described a method where eerie ammonium nitrate has been used. The yield of compound 3 is 60%. No mention of amount of compound 4 was found. Yoon et al (J. Org. Chem. 1994, 3490-3493) described a process, which uses borohydride exchange resin. The selectivity 3:4 is 66:34. Nugent et al (J. Org. Chem. 1998, 6656-6666) described a process where the complex [(L*)Zr]2(OH)(02CCF3) in which L* = (+)-(S,S,S) -triisopropanolamine was used for the diastereoselective epoxide opening reaction with trialkylsilyl azide to give 2-azidoalkanol trialkylsilyl ether. Curini et al (Eur. J. Org. Chem. 2001, 4149-4152) described a process where zirconium sulfophenyl phosphate is used as heterogeneous catalyst for the synthesis of P-amino alcohols from epoxides. Whittaker et al (J. Chem. Soc. Chem. Comm. 1993, 1427-1428) had earlier described a process where crystalline polymeric zirconium phosphate was used as heterogeneous catalyst for epoxide opening reaction using methanol and acetic acid. Shibasaki et al (J. Am. Chem. Soc. 2000, 1245-1246) described a process in which Zr(0' Pr)4 was used for synthesis of P-acetoxy alcohols from olefins in presence of bis(trimethylsilyl) peroxide (BTSP) and trimethylsilylacetate. The reaction involves formation of epoxide followed by it's opening. The protocol was extended by Shibasaki et al (J. Am. Chem. Soc. 2001, 1256-1257) for synthesis of P-cyano alcohols from olefins using BTSP and trimethylsilylcyanide. Triphenylphosphine oxide was added to increase the rate of the sluggish reaction. The epoxide opening reaction, when done in presence of strong acids, bases or alkoxides, results in less yield of the desired product. In these cases the major reaction is polymerization, rearrangement or by-products. The possible rearrangement products are alcohol, aldehyde or ketone. The possible byproduct is 1,2-diol of the epoxide. Polymerization can occur when molecules of epoxides that are unreacted, get activated due to presence of promoter or catalyst and attack another epoxide molecule. Due to the presence of these products, the isolation of desired product is also a tedious job In order to obviate all the drawbacks existing with the prior art process, it was necessary to develop an efficient process for the preparation of 2-hydroxyalkyl and aryl sulfides. This has been achieved in the present invention, by reacting, an epoxide with thiol as a nucleophile in presence of a zirconium compound as a catalyst. Thus, the epoxide opening reaction with thiol as a nucleophile using any zirconium compound as catalyst as described in the invention is not known. What is needed is an efficient and improved procedure for nucleophillic ring opening of diversely functionalised epoxides which gives higher yield, reduces the formation of disulfide that is obtained from the oxidation of thiol, reduces formation of alcohol and/or carbonyl compound that are side products obtained from rearrangement of epoxide, and in case of unsymmetrical epoxides, the choice of reaction parameters can be altered to attain regioselectivity. Object of the invention The main object of the invention is directed to an improved process for epoxide opening reaction by thiols in presence of various zirconium (IV) compounds. A further object of the invention is directed to unsymmetrical epoxides where, the ratio of regioisomers in product can be controlled by use of various zirconium compounds as a catalyst. A still further object of the invention is directed to the use of various solvents to control the ratio of regioisomers in the product. The solvent for reaction is selected from a group consisting of chlorinated solvents such as methylene chloride (CH2CI2), chloroform (CHCI3), 1,2-dichloroethane (CH2CICH2CI), aprotic polar solvents such as acetonitrile (CH3CN), aromatic solvents such as toluene and ethereal solvents such as diethyl ether, THF (tetrahydrofuran). Yet, another object of the invention is directed to the use of different temperature to control the ratio of regioisomers in the product. The reaction can be carried out at temperatures from 0°C to 110°C. The epoxide is a mono-substituted epoxide, a di-substituted epoxide, a tri-substituted epoxide, or a tetra-substituted epoxide. In a preferred mode, the catalyst is present in 0.01 to 1.0 mol % overall concentration. Summary of the Invention Accordingly, the present invention provides a process for opening epoxides by thiol using a zirconium catalyst in presence or absence of a solvent at an appropriate temperature to give 2-hydroxyalkyl sulfides or 2-hydroxy aryl sulfides; the invention also describes opening of unsymmetrical epoxide to yield regioisomeric product, the ratio of regioisomeric product is controlled by selection of an appropriate zirconium catalyst, solvent and reaction temperature. Brief description of accompanying drawings Figure 1: represents reaction of styrene oxide and thiophenol Figure 2: represents reaction of styrene oxide and various thiols Figure 3: represents reaction of styrene oxide and benzylthiol Figure 4: represents various epoxides and corresponding products. Figure 5: represents methyl 4-methoxyphenyl glycidate and the reaction products with thiophenol and 2-aminothiophenol. The invention is related to a process that does not lead to any of the above-mentioned byproducts. In case of the unsymmetrical epoxides the two positions involved in epoxide ring can lead to two isomers. The invention is related to the use of catalyst and reaction conditions that can alter the ratio of isomers. More particularly, there are three aspects of controlling the ratio of regioisomers 1. Catalyst 2. Solvent 3. Reaction temperature Detailed description of the invention The present invention relates to a process for the preparation of 2-hydroxyalkyl sulphides and 2-hydroxy aryl sulphides, the said process comprising steps of: a) adding a thiophenol to an epoxide in the presence or absence of a solvent in an inert atmosphere, b) adding zirconium catalyst to step (a) mixture, c) stirring the mixture of step (b) at a temperature ranging between 0° to 150°C for a time period of 1 hr to 8 hr, and d) isolating the required product 2-hydroxyalkyl sulphide or 2-hydroxy aryl sulphide by conventional methods. In an embodiment, the present invention provides a process, wherein in step (a) the epoxide used is selected from symmetrically substituted epoxide and unsymmetrically substituted epoxide. Another embodiment, the substituted epoxide is selected from a group consisting of monosubstituted epoxide, disubstituted epoxide, trisubstituted epoxide and tetrasubstituted epoxide. Still another embodiment, the Zirconium (IV) catalyst used in step (b) is selected from an organo and inorgano zirconium (IV) compound. Still another embodiment, wherein the Zirconium (IV) compound is represented by formula ZrX4, wherein X is selected from a group consisting of Fluorine, Chlorine, Bromine, Iodine, isopropyloxy, and/or acetylacetone (CH3COCHCOCH3). Yet another embodiment, the zirconium compound used is zirconium isopropoxide. Yet another embodiment, the solvent used in step (a) is selected from a group consisting of chlorinated solvent selected from a group consisting of methylene chloride, chloroform, 1,2-dichloroethane, aprotic polar solvent selected from a group consisting of acetontrile, aromatic solvent selected from a group consisting of benzene, toluene, xylene and etheral solvent selected from a group consisting of diethylether, tetrahydrofuran. In yet another embodiment, the thiol used in step (a) may be an aliphatic thiol, aromatic thiol or alkylaryl thiol. In yet another embodiment, the thiol used is preferably selected from a group consisting of thiophenol, 4-methyl thiophenol, 4-methoxy thiophenol, 2-amino thiophenol or benzylthiol. Still another embodiment, the inert atmosphere in step (a) is provided by flushing nitrogen gas. Yet another embodiment, the concentration of the catalyst used is in the range of 0.01 to 1.0 mol % of overall concentration and the preferred temperature is in the range of 0° to 110° C. Yet another embodiment on the invention provides a process, in which use of unsymmetrical epoxide provides a mixture of regioisomeric product. In another embodiment, the ratio of regioisomers formed is controlled by the nature of catalyst, catalyst concentration, solvent used and/or reaction temperature. One more embodiment of the invention provides an improved process for the preparation of 3-(4-methoxyphenyl)-3-(2-aminophenylthiol)-2-hydroxy propionic acid methyl ester. Another embodiment of the present invention provides a process of a type wherein a reaction mixture formed by mixing an epoxide and a thiol in presence or absence of a solvent at an appropriate temperature is treated under inert atmosphere with organo or inorgano Zr(IV) compound to give 2-hydroxyalkyl sulfides. Still another embodiment of the present invention provides that cyclohexene oxide and thiophenol were used as substrate for the invention of catalytic activity of zirconium (IV) compounds. Brief description of examples As shown in example 1, the yield of the desired product was found to be excellent. The earlier mentioned by-products like the ketone or alcohol related to cyclohexene oxide was not obtained. In case of entry 1 and 3 the starting materials were recovered as unreacted. In example 2, the effect of equivalents of catalyst is discussed. In example 3, the reaction of other thiols with Zr(acac)4 as catalyst is given. Styrene oxide was used as substrate to study the effect on regioselectivity. In example 4, various catalysts are used for the reaction of styrene oxide and thiophenol. In example 5, various thiols used for reaction with styrene oxide to establish generality. Benzylthiol is considered to be less reactive as compared to other aromatic thiols. In example 6, the reaction of benzylthiol is given with styrene oxide in presence of various catalysts. In example 7, effect of reaction temperature on regioselectivity has been discussed. In example 8, various solvents have been used for the reaction of styrene oxide and thiophenol. In example 9, the reaction is done with other epoxides (figure 4) and thiophenol. Finally in example 10, reaction of methyl 4-methoxyphenylglycidate is performed with thiophenol and 2-aminothiophenol (figure 5). With the later thiol, the reaction product is the intermediate in the synthesis of diltiazem. The present invention is illustrated with following examples and should not construed to limit the scope of the invention. EXAMPLES Example 1: The reaction of cyclohexene oxide (1 equivalent) and thiophenol (1 equivalent) in presence of a zirconium catalyst was carried out in an inert atmosphere in absence of a solvent for 2 hours. The results are summarized in table 1. (Table Removed) 1H-NMR (CDC13, δ): 1.3 (m, 4H), 1.7 (m, 2H), 2.1 (m, 2H), 2.7 (m, 1H), 3.0 (bs, 1H, D20 exchangeable), 3.3 (m, 1H), 7.3 (m, 5H) IR (neat, cm"1): 1067 (s), 1447 (m), 1477 (w), 1583 (w), 2856 (m), 2932 (s), 3056 (w), 3429 (m) Example 2: The reaction of cyclohexene oxide (1 equivalent) and thiophenol (1 equivalent) was carried out in presence of Zr(acac)4 in inert atmosphere in absence of a solvent for 2 hours. The results are summarized in table 2. (Table Removed) IR and NMR are identical to those of compound obtained in the example 1. Example 3: The reaction of cyclohexene oxide (1 equivalent) and various thiols (1 equivalent) was carried out in presence of Zr(acac)4 (0.05 equivalent) in inert atmosphere in absence of any solvent for 2 hours. (Table Removed) Entry 1: 1H NMR (CDC13,δ): 1.25-1.32 (m, 4H), 1.68-1.71 (m, 2H), 2.05-2.13 (m, 2H), 2.33 (s, 3H), 2.64-2.71 (m, 1H), 3.06 (bs, 1H), 3.25-3.31 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H) IR (neat, cm-1): 1068 (m), 1447 (m), 1492 (s), 1597 (w), 2856 (m), 2931 (s), 3018 (w), 3453 (broad, m) Entry 2: 1H NMR (CDC13,δ): 1.14-1.32 (m, 4H), 1.67-1.71 (m, 2H), 2.02-2.13 (m, 2H), 2.55-2.61 (m, 1H), 3.14 (bs, 1H, D2O exchangeable), 3.20-3.28 (m, 1H), 3.80 (m, 3H), 6.84 (d, J= 8.7 Hz, 2H), 7.42 (d, 7 =8.7 Hz, 2H) IR (neat, cm-1): 1032 (s), 1245 (s), 1284(s), 1447 (m). 1462 (m), 1493 (s), 1592 (m), 2856 (m), 2933 (s), 3000 (w), 3453 (broad, m) Example 4: Styrene oxide (1 equivalent) was treated with thiopenol (1 equivalent) in presence of the catalyst (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 1.5 h., the results are summarized below. (Table Removed) 1H NMR (CDC13,δ): 3.85-3.95 (m,2H), 4.31 (t, 7= 6.8 Hz, 1H), 7.22-7.42 (multiplate, 10H) IR (neat, cm-1): 1024 (m), 1055 (s), 1384 (w), 1438 (m), 1479 (m), 1582 (w), 2873 (w), 2933 (m), 3028 (w), 3058 (w), 3495 (broad, s) 4a: lH NMR (CDC13,δ): 3.04- 3.12 (dd, 7= 9.4,13.8 Hz, IH), 3.28- 3.34 (dd, 7= 3.4, 13.8 Hz, 1H), 4.69- 4.73 (dd, 7= 3.4, 9.4 Hz, 1H), 7.22-7.42 (multiplate, 10H) IR (neat, cm-1): 1022 (m), 1056 (s), 1448 (m), 1475 (m), 1581 (w), 2857 (w), 2925 (m), 3027 (w), 3059 (w), 3386 (broad, s) Example 5: Styrene oxide (1 equivalent) was treated with different thiols (1 equivalent) in presence of Zr(acac)4 (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 2 h. The results are summarized below. (Table Removed) Entry 1: Compound 3 1H NMR (CDC13,δ): 2.29 (s, 3H), 3.85-3.88 m, 2H), 4.19-4.24 (t, J = 6.8 Hz, 1H), 7.02-7.31 (m, 9H) IR (neat, cm-1): 1055 (s), 1451 (m), 1491 (s), 1599 (w), 2871 (w), 2922 (m), 3026 (m), 3060 (w), 3403 (broad, s) Compound 4: 1H NMR (CDC13,δ): 2.32 (s,3H), 2.98-3.05 (dd, J= 9.5, 13.7Hz, 1H), 3.22-3.28 (dd, J= 3.5, 13.7Hz, 1H), 4.64-4.68 (dd, J= 3.5,9.5 Hz, 1H), 7.02-7.31 (m, 9H) IR (neat, cm"1): 1054 (s), 1451 (m), 1492 (s), 1601 (w), 2919 (m), 3027 (m), 3061 (w), 3425 (broad, s) Entry 2 Compound 3: 1H NMR (CDC13, δ): 2.09 (bs, 1H, D2O exchangeable), 3.75 (s, 3H), 3.85-3.88 (m, 1H), 4.03- 4.13 (t, J = 6.8 Hz), 6.72-7.40 (m, 9H) IR (neat, cm"1): 1055 (s), 1410 (s), 1582 (w), 2882 (w), 3022 (m), 3060 (w), 3410 (broad, s) Compound 4: 1HNMR (CDCl3, δ): 2.92-3.00 (dd,J= 9.7,13.7Hz, 1H), 3.15-3.21 (dd,7= 3.2, 13.7Hz, 1H), 3.79 (s, 3H), 4.59-4.64 (dd, J= 3.2, 9.7 Hz, 1H), 6.75-7.42 (multiplate, 9H) IR (neat, cm-1): 1054 (s), 1411 (s), 1580 (w), 2901 (m), 3047 (m), 3445 (broad, s) Example 6: Styrene oxide (1 equivalent) was treated with benzylthiol (1 equivalent) in presence of the catalyst (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 4 h. the results are summarized below. (See figure 3) (Table Removed) Compound 3d: 1H NMR (CDC13, δ): 3.53 (d, J= 13.4 Hz, 1H), 3.66 (d, J= 13.4 Hz, 1H), 3.78-3.87 (multiplate, 3H), 7.20-7.36 (multiplate, 10H) IR (neat, cm"1): 1024 (m), 1057 (s), 1452 (m), 1492 (m), 1600 (w), 2873 (m), 2922 (m), 3027(s), 3059 (m), 3394 (broad, s). Compound 4d: 1H NMR (CDCI3, δ): 2.64 (dd, 7=5.9, 13.9 Hz, 1H), 2.79 (dd, J=4.0, 13.9 Hz, 1H), 3.72 (s, 2H), 4.66 (dd, J=4.0, 8.9Hz, 1H), 7.24-7.34 (multiplate, 10H) IR (neat, cm-1): 1051 (s), 1449 (m), 1490 (w), 2851 (w), 2913 (m), 3027 (m), 3058 (m), 3367 (broad, s). Example 7: Styrene oxide (1 equivalent) was treated with thiophenol (1 equivalent) in presence of the Zr(acac)4 (0.05 equivalent) at different temperatures under nitrogen in absence of solvent. The results are summarized below. (Table Removed) Example 8: Styrene oxide (1 equivalent) was treated with thiophenol (1 equivalent) in presence of the Zr(acac)4 (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 1.5 hours. The results are summarized below. (Table Removed) Example 9: Epoxide (1 equivalent) was treated with thiophenol (1 equivalent) in presence of Zr(acac)4 (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 2 h. The results are summarized below. (Table Removed) Entry 1 1H NMR (CDC13, δ): 3.10-3.27 (multiplate, 2H), 3.98-4.04 (multiplate, 2H), 4.1 (multiplate, 1H), 6.8-7.5 (multiplate, 10H) IR (neat, cnV1): 1040 (m), 1079 (m), 1172 (w), 1242 (s), 1296 (w), 1493 (s), 1593 (s), 2874 (m), 2926 (s), 3060 (s), 3417 (broad, s) Entry 2 'H NMR (CDCh, 5): 3.10-3.27 (multiplate, 2H), 3.95-4.01 (multiplate, 2H), 4.05-4.12 (multiplate, 1H), 6.78-7.41 (multiplate, 10H) IR (neat, cm-1): 824 (m), 1031 (s), 1091 (s), 1171 (w), 1242 (s), 1284 (m), 1489 (s), 1588 (m), 2875 (m), 2927 (s), 3062 (m), 3423 (broad, s) Entry 3 1H NMR (CDC13, δ): 1.17 (s, 9H), 3.00-3.14 (multiplate, 2H), 3.37-3.49 (multiplate, 2H), 3.78- 3.88 (multiplate, 1H), 7.12-7.41 (multiplate, 5H) IR (neat, cm-1): 1022 (m), 1085 (s), 1194 (m), 1366 (m), 1477 (m), 1582 (w), 2870 (m), 2927 (s), 2973 (s), 3057 (w), 3427 (broad, s) Entry 4 1H NMR (CDCI3, δ): 3.03-3.19 (multiplate, 2H), 3.65-3.71 (multiplate, 2H), 3.85-3.97 (multiplate, 1H), 7.19-7.50 (multiplate, 5H). IR (neat, cm"1): 1043 (broad, s), 1297 (m), 1433 (m), 1477 (m), 1581 (m), 2922 (w), 2954 (w), 3057 (w), 3419 (broad, s) Example 10: Methyl-3-(4-methoxyphenyl)glycidate (1 equivalent) was treated with thiophenol (1 equivalent) in presence of Zr(acac)4 (0.05 equivalent) at room temperature under nitrogen in absence of solvent for 6 h. The results are summarized below. (Table Removed) Entry 1: 1H NMR (CDCI3, δ): 3.61 (s, 3H), 3.79 (s, 3H), 4.51- 4.54 (multiplate, 1H), 4.58- 4.61 (multiplate, 1H), 6.84 (d, 7= 8.8 Hz, 2H), 7.20-7.33 (multiplate, 4H), 7.37 (d, 7= 8.8 Hz, 2H) IR (neat, cm-1): 1031 (s), 1110 (s), 1178 (s), 1252 (broad, s), 1440 (s), 1510 (s), 1608 (s), 1738 (s), 2837 (m), 2953 (s), 3002 (m), 3057 (m), 3475 (broad, s) Entry 2: 1H NMR (CDCI3, δ): 3.77 (s, 3H), 3.90 (s, 3H), 4.25 (d, 7=4.2 Hz, 1H), 4.41 (d, J=4.1 Hz, 1H), 6.54-7.35 (multiplate, 8H) IR (neat, cm-1): 692 (m), 742 (s), 1043 (s), 1297 (m), 1433 (m), 1608 (m),1716 (s), 2834 (w), 2961 (w), 3355(s), 3455 (broad, s) We claim: 1. An improved process for the preparation of 2-hydroxyalkyl sulphides and 2-hydroxy aryl sulphides involving nucleophillic ring opening of epoxides by thiols, the said process comprising steps of: a) adding thiol to an epoxide in an inert atmosphere in absence of a solvent; b) adding zirconium catalyst to the mixture of step (a); c) stirring the mixture of step (b) at a temperature ranging between 0 ° to 150° C for a time period of 1 hour to 8 hour; and d) isolating the required 2-hydroxyalkyl sulphide or 2-hydroxy aryl sulphide by conventional methods. 2. The process as claimed in claim 1, wherein the step (a) is optionally performed in the presence of solvents such as herein described. 3. The process as claimed in claim 1, wherein in step (a) the epoxide used is selected from symmetrically substituted epoxide and unsymmetrically substituted epoxide. 4. The process as claimed in claim 3, wherein the substituted epoxides is selected from the group of monosubstituted epoxides, disubstituted epoxides, trisubstituted epoxides or tetrasubstituted epoxides. 5. The process as claimed in claim 1, wherein the Zirconium catalyst is selected from an organo and inorgano zirconium (IV) compound. 6. The process as claimed in claim 5, wherein the Zirconium (IV) compound is represented by formula ZrX4, wherein X is selected from a group consisting of Fluorine, Chlorine, Bromine, Iodine, isopropyloxy, and/or acetylacetone (CH3COCHCOCH3). 7. The process as claimed in claim 6, wherein the zirconium compound used is zirconium isopropoxide. 8. The process as claimed in claim 1, wherein the solvent is selected from a group consisting of chlorinated solvent, aprotic polar solvent, aromatic solvent and etheral solvent. 9. The process as claimed in claim 8, wherein the chlorinated solvent is selected from methylene chloride, chloroform, or 1,2-dichloroethane. 10. The process as claimed in claim 8, wherein the aprotic polar solvent is selected from acetonitrile. 11. The process as claimed in claim 8, wherein the aromatic solvent is selected from benzene, toluene or xylene. 12. The process as claimed in claim 8, wherein the etheral solvent is selected from diethyl ether or tetrahydrofuran. 13. The process as claimed in claim 1, wherein the thiol used may be an aliphatic thiol, aromatic thiol or alkylaryl thiol. 14. The process as claimed in claim 13, wherein the thiol used is selected from a group consisting of thiophenol, 4-methyl thiophenol, 4-methoxy thiophenol, 2-amino thiophenol or benzylthiol. 15. The process as claimed in claim 1, wherein in step (a) the inert atmosphere is provided by flushing nitrogen gas. 16. The process as claimed in claim 1, wherein the concentration of the Zirconium catalyst used is in the range of 0.01 to 1.0 mol % of overall concentration. 17. The process as claimed in claim 1, wherein the preferred temperature is in the range of 0 ° to110°C. 18. The process as claimed in claim 3, wherein the use of unsymmetrical epoxide provides a mixture of regioisomeric product. 19. The process as claimed in claim 18, wherein the ratio of regioisomers formed is controlled by the nature of catalyst, catalyst concentration, solvent and/or reaction temperature used. 20. The process as claimed in claim 1, wherein the said process is an improved process for the preparation of 3-(4- methoxyphenyl)-3-(2-aminophenylthiol)-2-hydroxy propionic acid methyl ester. |
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1209-DEL-2002-Abstract-(25-05-2011).pdf
1209-DEL-2002-Claims-(25-05-2011).pdf
1209-del-2002-correspondence-others.pdf
1209-del-2002-correspondence-po.pdf
1209-del-2002-description (complete).pdf
1209-DEL-2002-Form-1-(25-05-2011).pdf
1209-DEL-2002-Form-2-(25-05-2011).pdf
1209-DEL-2002-GPA-(25-05-2011).pdf
Patent Number | 248681 | |||||||||
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Indian Patent Application Number | 1209/DEL/2002 | |||||||||
PG Journal Number | 31/2011 | |||||||||
Publication Date | 05-Aug-2011 | |||||||||
Grant Date | 04-Aug-2011 | |||||||||
Date of Filing | 03-Dec-2002 | |||||||||
Name of Patentee | NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER) | |||||||||
Applicant Address | SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA. | |||||||||
Inventors:
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PCT International Classification Number | B01J 31/38 | |||||||||
PCT International Application Number | N/A | |||||||||
PCT International Filing date | ||||||||||
PCT Conventions:
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