Title of Invention

IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL FOR THE PREPARATION OF ZONISAMIDE

Abstract

An improved process for the preparation of l,2-benzisoxazoIe-3-methane sulfonate which is an intermediate useful for the preparation of zonisamide Which comprises (1) reacting methylsalicylate with methane sulfonyl chloride to get sulfonyl derivatives (2) treating it with a strong base to get the corresponding cyclocondensation product (3) treating the cyclocondensation product with hydroxylamine hydrochloride in the presence of sodium acetate to yield a novel intermediate and treating the resulting novel compound of the formula (3) with a base.

Full Text

BACKGROUND The present invention relates an improved process for the preparation of 1,2-benzisoxazole-3-methane suifonates . The invention also provides novel compounds 4-oximino-2,3-dihydrobenzoxathiin-2, 2-dioxides and a process for their preparation . These compounds are crucial and important intermediates for the preparation of Zonisamide. Zonisamide having the formula (1) given below is an anticonvulsant/antiepileptic drug. l,2-benzisoxazole-3-methane suifonates and 4-oximino-2,3-dihydrobenzoxathtin-2/ 2-dioxides prepared by the process of the present invention have the formulae (2) & (3) respectively. In the formulae 2 & 3 Rl to R4 - may be the same or different and represents hydrogen, alkyl, (with carbons, 2-5), chloro, bromo, S- alkyl, o- alkyl, NO2/ N- Me2, CF3. and X represents Na or K Zonisamide having the formula &) is a serendipitous discovery drug of Dainippon Pharmaceuticals Company ,Japan. Zonisamide was launched in Japan during 1979 and USFDA approved in 1998 to launch in USA. The synthesis of Zonisamide of the formula (1) has been described in the US Pat. No 4172896 (Dianippon pharmaceutical co.. Ltd). This Process disclosed in US patent No 4172896 involves the reaction of 3-bromomethyl-l,2-benztsoxazole of the formula (10) with sodium sulphite in methanol giving sodium sulfonate derivatives of the formula (11). The compound of the formula (11) on reaction with phosphorous oxychloride gives the compound of the formula (fi) which on treatment with anhydrous ammonia gives the Zonisamide of the formula (1) as shown in the Scheme-1 It is known from the literature references Chem. Pharm.Bull. (1976), 24, 1976,632 Chem.Ber., (1913), 46, 3816 and Chem.Ber., (1909), 42, 2523 that the compound of the formula (U) is prepared from the 4-hydroxycoumarln of the formula (21- The process involves the reaction of the formula (Z) with hydroxylamine hydrochloride in presence of pyridine gives l,2-benzisoxazole-3-acetic acid of the formula (fi)which on bromination in acetic acid to get the bromoderlvatives of the formula (ft). The bromo derivatives of the formula (2) on decarboxyiation using aqueous suphric acid to get the 3-bromomethyl-l,2 benzisoxazole (1ft) which on treatment with sodium sulfite yield the l,2-benzisoxazole-3-methanesufonatesodium salt (H) as shown in Scheme-2 The above method has the disadvantage of handling the 3-bromomethy!-l,2 benzisoxazole of the formula (10), which is highly lacrimatory. Therefore is very difficult to handle this compound of the formula (10) during the commercial production. The overall yields are also unsatisfactory of 30-35%.Therefore this process is not economical for the production of Zonisamide on an industrial scale. To overcome the handling of lacrymatory intermediate of the formula (10), DIANIPPON disclosed an improved method for the preparation of the compound of the formula (H) in their JP patent 53-77057. This process involves starting from the compound of the formula (fi) using chlorosulfonic acid-dioxane mixture to get the 1,2-benzisoxazoie -3-methane sulfonate sodium salt (ll)as shown in scheme- 3. The synthetic pathway for preparing the compound of the formula (11) through sulfonation has been modified recently by TEVA PHARMACEUTICAL in their WO patent No 03/020708 . The process disclosed involves reacting the compound of the formula (10) with concentrated suphuric acid and acetic anhydride mixture to get the product of the formula (HI thereby avoiding the environmentally hazardous dioxane in the reaction waste as per their claim . The reaction sequence is shown in scheme-4 Although the sutfonation methods could able to avoid the preparation and handling of the lacrymatory product of the formula (1ft), there is a continuous need to improve the process for preparing Zonisamide of the formula (1) because of its growing importance not only in the field of antepileptic and anticonvuteant properties but it is also found to be useful in headache particularly migraine headache (US pat 6,489350). Therefore, the main objective of the present invention is to provide an improved process for the preparation of l#2-benzisoxa2ole-3-methane sulfonates of the formula (2) as defined earlier which is useful as an intermediate for the preparation of zonisamide of the formula (D. Another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazote-3-methane suifonates of the formula (2) as defined earlier which is useful as an Intermediate for the preparation of zonisamide of the formula (1) by avoiding the formation of lacrymatory product of the formula Still another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazole-3-methane suifonates of the formula (2) as defined earlier which is useful an intermediate for the preparation of zonisamide of the formula (1) by avoiding the use of chlorosulfonic acid. Another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazole-3-methane suifonates of the formula (2) as defined earlier starting from methylsallycylate which is very cheap and easily available thereby making the process simple and economical Yet another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazo!e-3-methane suifonates of the formula (2) as defined earlier wherein the intermediates formed are crystalline solids which can be handled easily thereby making the process simple. Yet another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazole-3-methane sulfonates (2) as defined earlier which avoids the use of hazardous reagents tike bromine, chlorosulphonic acid-dioxane and sulfuric acid-acetic anhydride thereby making the process not only simple but also safe and industrially applicabte. Yet another objective of the present invention is to provide an improved process for the preparation of l,2-benzisoxazole-3-methane sulfonates of the formula (2) as defined earlier which is useful as an intermediate for the preparation of Zonisamide of the formula 1, the yield of the intermediate being 70-75% as compared to 30-35% to the reported methods. Still another objective of the present invention is to provide novel 4-oximino-2, 3-dihydrobenzoxathlin-2r 2-dloxldes of the formula (2) as defined earlier which Is also useful as an important intermediate for the preparation of Zonisamide of the formula (10). To achieve the above objectives of the present invention ,we carried out extensive Research & Development which has resulted In our devising an entirely different strategy for the preparation of the compound of the formula (2). The process developed is shown in scheme 5 step may be selected from toluene, dimethylsulfoxide, dimethylformamide and tetrahydrofuran or the like, which can be used alone or in a mixture of two or more thereof. The temperature for this reaction may be between 25 to 90°C preferably between 70-85°C. The solvents which can be employed for making the intermediate (1) in step (3) may be selected from methanol, ethanol ,isopropyl alcohol tetrahydrofuran and acetic acid or the like, which can be used alone or in a mixture of two or more thereof. The reaction may be carried out at a temperature between 25-80°C and preferably between 60-65°C. The base employed in the step (4) for making the intermediate of the formula (2) is very critical and the bases used may be selected from sodium hydroxide, potassium hydroxide, sodium methoxide and potassium methoxide. The solvents used may be selected from methanol, ethanol, isopropyl alcohol, monoethylene glycol and toluene or the like, which can be used alone or in a mixture of two or more thereof and particularly in methanol. The important aspect of this invention is that all intermediates of the formulae (2) & (1) which are produced according to the process are stable crystalline solids and can be stored for long time and no need to handle the lacrimatory bromo intermediate as per the earlier reported method of synthesis. All these intermediates can be isolated with a purity of greater than 98% and characterized using spectral data and elemental analysis. The production of the intermediate l,2-benzisoxazole-3-methane sulfonates of the formula (2) by the process of the present invention has been confirmed by spectral characteristics and also comparing with authentic sample made form the earlier reported route. The production of the compound of the formula 2 is further confirmed by converting it to 1,2-benzisoxazole -3-methanesulfonyl chloride (6) followed by ammonia treatment to get the Zonisamide of the formula (1) with 55-60% overall yield from the compound of the formula (2) with purity HPLC of 99.90%. The details of process of the present invention are described in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention. EXAMPLE -1: STEP (1): PREPARATION OF 2 - METHANE SULPHONYLOXY - METHYL BENZOATE. To a stirred solution of methyl salicylate (100 gm, 0.6578 M) in 300 ml of Methylene chloride was charged triethyl amine (80 gm,Q»792M).The mixture is cooled to -5 to 0°C and methane sulfonyl chloride(H3 gm, 0.9868 M) in Methylene chloride (100 ml) is added at 0-5° C over a period of 1 hour maintained at 0° C for 1 hour and raised to 22- 25° C and maintained for 3 hours. TLC showed the conversion >98 % , water 200 ml is added and stirred at 22 - 25° C for 1 hour. The organic layer is separated and the aqueous layeris extracted with 100 ml of Methylene chloride. The combined organic layer were washed with 100 ml of water and the solvent is evaporated to give 160 - 162g of 2 -Methane sulphonyloxy - methyl benzoate of the formula (4). The 2-Methane sulphonyloxy - methyl benzoate so produced is recrystallized from toluene to give 137 gm (yield 90 %). This product is suitable for use in the next of the process. Melting point: 48.2 - 51° C Gc purity : > 99 % IR, u max (KBr): 1731.73 cm-l(-COOMe), 1607.09 cm-1 (-SO2-) cm"1 1HNMR (CDCI3) 5, 3.28(s, 3H), 3.92(s, 3H), 7.38-7.46(m, 2H), 7.54-7.59(m, 1H), 7.97(dd,lH) "CNMR (CDCI3) δ, 38.39(q), 52.39(q), 124.03(d), 124.33 (s), 127.06(d), 131.95(d), 133.68 (d),147.67(s), 164.57(s). MS (m/z) = 231.1 (M+l) STEP-2: PREPARATION OF 3.4 -DIHYDRO -1.2-BENZOXATHIIN -4- ONE -2.2- DIOXIDE. The dimethylsulfoxide (250ml) and sodium hydride (60 % ) (13gm, ,0.326M) heated to 70 - 80° C under Nitrogen and maintained at 75° C for 3-4 hours. The reaction mixture is cooled to +15° C and the Methane sulphonyloxy - methyl benzoate prepared by the process described in step (i) above (50 gm, 0.2173 M) in 50 ml of dimethylsulfoxide is added over a period of 1 hour. Raise the temperature to 20 -25° C and maintained for 2-3 hours. Reaction mass is slowly quenched into 2.5 Lts of water and is extracted with toluene (2x 800ml). Aqueous layer pH is adjusted to 5-6 with cone HCI (25 -30 ml) and is extracted with ethyl acetate (2x1 L and 750 ml). The combined ethyl acetate layer was distilled to get 34 gm of 3,4 -Dihydro -1,2-Benzoxathiin -4- one -2,2-dioxide of the formula (5). Yield: 76 % .Melting point: 88.8 - 91.4° C GC Purity: > 99 %. IR: umax (KBr): 1696.76 (-C=O), 1610.26(-SO2-) cm1 1H NMR (CDCI3) δ, 4.71(s, 2H), 7.29-7.46(m, 2H), 7.70-7.79(m, 1H), 8.13(dd, 1H) 13CNMR(CDCI3) δ, 59.67(q), 119.45(d), 120.45(s), 126.44(d), 128.84(d), 137.49(d), 153.78(s), 182.11(s). MS (m/z) = 197 (M-l) STEP-3: PREPARATION OF 4 -QXIMINQ-3.4-DIHYDRQ -1.2-BENZOXATHIIN -4- ONE - 2.2-DIOXIDE. To a stirred solution of Hydroxylamirve Hydrochloride(17.6 gm, 0.2532M), anhydrous sodium acetate (22 gm, 0.2681M) and acetic acid (125ml) was added compound obtained from the step II(1)(25 gm, 0.1262M) at room temperature (20 - 25° C). The reaction temperature is raised to 100° C and maintained for 5 hours. TLC showed the absence of starting material. The reaction mixture is cooled to 20 -25° C and charged water (l00ml) with stirring. Extracted with methylene chloride (3x500 ml) and the combined organic layers were evaporated to give crude novel product of the formula( 3 ) .The crude novel product of the formula 1 is recrystallized from methanol to give 24 gm of novel - 4 -Oximino-3,4-Dihydro -1,2-Benzoxathiin -4- one -2,2-dioxide of the formula (3.) (Yield: 92.93%) HPLC Purity: >99 % Melting Range: 167 -170°: umax (KBr): 3276.68cm"1 and 1609 cm-1 (-SO2-) cm"1 1H NMR (DMSO-d6) δ : 5.06(s,2H), 7.28-7.37(m,2H), 7.48-7.56(m,lH), 7.98 (distorted,dd, 1H) 13C NMR ( DMSO-d6) δ: 46.68(t), 118.98(s), 119.35(d), 124.41(d),126.22(d), 131.82(d), 141.38(d),150.12(s) . MS (m/z) = 214(M+1) To a stirred solution of 4 -Oximino-3,4-Dihydro -1,2-Benzoxathiin -4- one -2,2-dioxide) prepared by the process described above (10 gms .0469 M) in 50 ml of methanol at room temperature was added 22% sodium methoxide in methanol solution (4.43gm, 0.082M) at 25 -30°C over the period of 30-40 minutes. The color of the solution changes to yellow and the solid start precipitates from clear solution.Stirred the solution at room temperature 25-30° for 9-10 hours. After the reaction completion evaporate the methanol completely under vacuum to obtain a residue after drying (14.6g) of the compound of the formula (2). To the resudue obtained after removal of solvents is charged with methanol (300ml) and heat to 50-60° to get clear solution . The clear solution was treated with Ig of activated carbon and filtered and the filtrate concentrated to get the residual volume of about 65-70ml and cool to 0-5°. The cooled solution is filtered and washed with chilled methanol to get the title compound of the formula 2. 1H NMR (D2O) 8, 4.64(s,2H), 7.41-7.47(m, 1H), 7.66-7.69(m, 2H), 7.91(distorted doublet, 1H), "CNMR (D2O) δ, 47.00a), 109.56(d), 120.31(s), 122.44(d), 124.08(d), 130.78(d),151.82(s), 162.82(s) EXAMPLE -2: STEP -1: PREPARATION OF 2 - METHANE SULPHONYLOXY - METHYL BENZQATE To a stirred solution of methyl salicylate (100 gm, 0.6578 M) in 300 ml of Methylene chloride was charged triethyl amine (80 gm,0.792M).The mixture is cooled to -5 to 0°C and methane sulfonyl chlorlde(113 gm, 0.9868 M) in Methylene chloride (100 ml) is added at 0-5° C over a period of 1 hour maintained at 0° C for 1 hour and raised to 22- 25° C and maintained for 3 hours. TLC showed the conversion >98 % , water 200 ml is added and stirred at 22 - 25° C for 1 hour. The organic layer Is separated and the aqueous layeris extracted with 100 ml of Methylene chloride. The combined organic layer were washed with 100 ml of water and the solvent is evaporated to give 160 - 162g of 2 -Methane sulphonyloxy - methyl benzoate of the formula (4). The 2-Methane sulphonyloxy - methyl benzoate so produced is recrystallized from toluene to give 137 gm (yield 90 %). This product is suitable for use in the next stage of the process. STEP-2: PREPARATION OF 3,4 -DIHYDRO -1,2-BENZOXATHIIN -4- ONE -2,2- DIOXIDE. The dimethytsulfoxide (12m!) and DBU (1.98g, 0.013M) heated to 75 - 80° C under Nitrogen and maintained for one hour. The reaction mixture is cooled to +15° C and the Methane sulphonyloxy - methyl benzoate prepared by the process described above (2gm, 0.086M). Raise the temperature to 20 -25° C and maintained for 2-3 hours. Reaction mass is quenched into l00mt of water and is extracted with toluene (2x 30mt).Aqueous layer pH is adjusted to 5-6 with cone HCI (25 -30 ml) and is extracted with ethyl acetate (3x40ml). The combined ethyl acetate layer was distilled to get 0.6gm (34.8%) of 3,4 -Dihydro -1,2-Benzoxathiin -4- one -2,2-dioxide of the formula (5).GC purity 98.78%. STEP-3: PREPARATION OF 4 -OXIMINO-3.4-DIHYDRO -1.2-BENZOXATHIIN -4- ONE - 2,2-DIOXIDE. To a stirred solution of Hydroxylamine Hydrochtoride (14.04 gm, 0.202M), triethtylamine (21,4 gm, 0.212M) and methanol (l00mi) was added compound obtained from the step -2 above (l0gm, 0..0505M) at room temperature (20 - 25° C). The reaction temperature is raised to 60-65° C and maintained for 3 hours. TLC showed the absence of starting material. The solvent Is distilled to get the residue. The residue is dissolved in toluene 200ml and washed with water and distillled to get the crude product which on crystallisation using methanol 200ml gives 2.4g of 4 -Oximino-3,4-Dihydro -1,2-Benzoxathiin -4- one -2,2-dioxide of the formula &) (Yield:22.32%) HPLC Purity: 98.52%. STEP-4: PREPARATION OF SODIUM 1.2-BENZIOXAZOLE-3-METHANE SULFONATE. To a stirred solution of 4 -Oxrmfno-3,4-Dthydro -1,2-Benzoxathiin -4- one ~2,2-dioxide) prepared by the process described in step - 3 above (55gms .2582 M) in 550 ml of monoethylene glycoi and sodium hydroxide (10.3g, 0.2582) and at room temperature and heated to 85-90° and maintained for 3 hours. After the reaction completion evaporate the monoethyleneglycol completely under vacuum to obtain a residue (7g) of the compound of the formula (2)- The residue purified in methanol following the method described in the example-1 (step4) to get the pure product l.35g with a purity of 93.26% Advantages of the invention 1. The process is simple and economical 2. The intermediate of the formula (2) and the novel intermediate of the formula (3L) formed in the process are crystalline solids and therefore can be handled easily. 3. The process avoids the usage of hazardous raw materials like bromine, chlorosulphonic acid-dioxane and sulphuric acid-acetic anhydride besides handling of the highly lacrimatory intermediate of the formula (10) thereby making the process not only safe but also simple and economical. 4. The process can be employed commercially for the production of zonisamide wherein the symbols R1 to R 4 have the meanings given above (3) treating the resulting cydocondensation product of the formula (£) with hydroxylamine hydrochloride in the presence of sodium acetate to yield a novel intermediate of the formula (3) Wherein the symbols Rl to R 4 have the meanings given above. (4) treating the resulting novel compound of the formula (S) with a base to get the product of the formula (2 ) wherein the symbols R1 to R 4 and X have the meanings given above. wherein the symbols R1 to R 4 and X have the meanings given above .. 2. An improved process as claimed in claims wherein the step (1) is carried out using methane sutphonyl chloride, the strong base employed in step (2) being selected from lithium diisopropylamide( LDA), butyllithium, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tertiary butoxide and potassium tertiary butoxide or their mixtures and the solvents used in the step (2) being =selected from toluene, dimethyisulfoxide, dimethylformamide and tetrahydrofuran, preferably dirnethylsulfoxide or thefr mixtures. 3 .An improved process as claimed in claims 1 & 2 wherein the temperature used for the reaction in step (2) is between 25 to 90°C preferably between 70-85°C and the solvents employed for the reaction in step (4) is selected from methanol, ethanol, isopropyl alcohol and monoethylene glycol or their mixtures and the reaction in step (4) is carried out at a temperature between 25-80°C and preferably between 60-65°C. 4.An improved process as claimed in claims 1 to 3 wherein the base employed in the step (4) selected from sodium hydroxide, sodium methoxide and potassium hydroxide, sodium methoxide and potaasium methoxide especially sodium methoxide or their mixtures. 5.An improved process as claimed in claims 1 to 4 wherein the solvents used in step (v) is selected from methanol, ethanol, isopropyl alcohol, monoethylene glycol and toluene Or their mixtures, most preferebly in methanol. 6. Novel intermediates, 4-oximimino-2,3-dihydrobenoxathiin-2,2- dioxides of the formula wherein R1 to R4 have the meanings given earlier Which is useful for the preparation of zonisamide having the formula 1 (Hi) treating the resulting cyclocondensation product or the formula (5) with hydroxylamine hydrochloride in presence of sodiumacetate gives a novel intermediate of the formula (3) Wherein the symbols R1 to R 4 have the meanings given above 7. An improved process as claimed in claim 6 wherein the step (1) is carried out using methane sulphonyt chloride , the strong base employed in the step (2) is selected from lithium diisopropylamide( LDA), butyllithium, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tertiary butoxide and potassium tertiary butoxide Or their mixtures ,the solvents used in the step (2) is selected from toluene, dimethylsulfoxide, dimethylformamide and tetrahydrofuran, preferably dimethylsulfoxide Or their mixtures and the temperature used for the reaction in step (2) is between 25 to 90°C preferably between 70-85°C . 8. An improved process for the preparation of l,2-benzisoxazole-3-methane sulfonates of the formula (g) as defined in claim 1 substantially as herein described with reference to the Example 9- A process for the preparation of novel intermediate 4 -oximimtno-2,3- dihydrobenoxathttn-2,2- dioxides of the formula 3 as defined earlier substantially as herein described with reference to the steps (1) to (3) of the Example

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