Title of Invention

NOVEL (S)-2-AMINO-3(4-AMINOPHENYL) PROPANOL, PROCESS FOR ITS PREPARATION

Abstract

The invention disclosed in this application relates to novel (S)-2-amino-3-(4-amino phenyl) propanol Of the formula I . and also to a process of its preparation .The process comprises (i) Preparing the 4-nitro-(S)-phenylalaninol of formula (IV) by conventional methods.(il) Reducing the nitro compound of formula (IV) to produce a novel intermediate of the formula (I). The novel compound (I) is useful for the preparation of oxazolidinone of the formula which in turn is an intermediate for the preparation of Zolmitriptan which is a drug useful in the treatment of migraine

Full Text

INTRODUCTION The present invention provides novel (S)-2-amino-3-(4-amino phenyl) propanol. The novel (S)-2-amino-3-(4-amino phenyl) propanol has the formula I This novel compound is useful as an intermediate for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolldinone.(S)-4-(4-aminobenzyl)-2-oxazolidinone having the formula (II) The compound of the formula II prepared is useful for the preparation of zolmitriptan. Zolmitriptan is an important drug for the treatment of migraine. The invention also relates to a process for the preparation of the novel compound of the formula I BACKGROUND OF INVENTION In the literature only two processes are available to prepare (S)-4-(4-aminobenzyl)-2-oxazolidinone of formula (I). In the first route disclosed in WO 9118897 (corresponding to US 5466699), the process for the preparation of compound of formula (I) comprises (i) esterification of (S)-4-nitro-phenylalanine give (S)-methyl-4-nitro phenyl alanate of the formula (III). (2) Reducing the connpound of formula (III) with sodiumborohydride to give (S)-4-nitrophenylalanilol of the formula (IV). (3)Cyclising the compound of formula (IV) using phosgene to give (S)-4 (4-nitrobenzyl)l,3-oxazolidinone of the formula (V). (4)Hydrogenating the compound of the formula (V) with 5% Pd-C to give (S)-4- (Aminobenzyl)-l,3-oxazolidinone of the formula (I). The main draw backs in this process are : 1. Yield reported in the step No.3 is 41%. 2. Process involves use of phosgene which is dangerous and not preferable on a commercial scale. 3. Overall yield from step (1) to step (4) is 17%. The second route disclosed in [WO 97/06162, WO 97/06163] which comprises of following steps; a) Forming a carbamate from methyl-4-nitro-(L)-phenylalanate HCI represented by formula (III) by the action of sodium carbonate (or) sodium hydrogen carbonate and n-butylchloroformate to give methyl (S)-N-butoxycarbonyl-4-nitrophenyl alanate of the formula (VI). b) Reduction of the nitro group in the compound of the formula (VI) to give methyl (S)-N-butoxycarbonyl-4-aminophenylalanate of the formula(VII). c) Reduction of the methyl ester group (- CO2CH3) in the compound of formula (VII) to give (S)-N-butoxycarbonyl-4-aminophenylalaninol of the formula (VIII). d) Ring closure of the compound of the formula (VIII) with 30% sodium methoxide in methanol gives (S)-4-(Aminobenzyl)-l,3-oxazolidinone of the formula (II). This process involves relatively more expensive reagent butyl chloro formate in step (a) and step (d) needs extremely dry conditions and involves use of anhydrous sodium methoxide. These critical process parameters are very difficult to maintain consistently in a process plant, more so while taking scale up on commercial batches. Yields are not mentioned in the patent for any of the stages mentioned. However, we have found that experimentally only 20-25% overall yields are realized. Considering the importance gained of Zolmitriptan for the treatment of migraine for which the compound of the formula is an important intermediate there is a great need for developing a simple inexpensive and safe method for the commercial scale preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula 11. Therefore the main objective of the present invention is to provide a novel intermediate (S)-2-amino-3-(4-amino phenyl) propanol of the formula I which is useful for the preparation of(S)-4-(4-aminobenzyl)-2-oxazolidinone (II) which is inexpensive, scalable, high yielding and safe. Another objective of the present invention is to provide a process for the preparation of compounds of the formula I which is useful for the preparation of compounds of the formula (II) which is not only simple but also convenient and useful for commercial production. Yet another objective of the present invention is to provide a process for the preparation of the novel intermediates(S)-2-amino-3-(4-amino phenyl) propanol of the formula (I) SUMMARY OF INVENTION Keeping in view of tine difficulties in commercialization of the processes disclosed in the above mentioned prior art patents, we aimed our research work to develop a simple and convenient process for the preparation of the oxazolidinone of the formula (II) which can be utilized for the preparation of zolmitriptan of the formula (A). In our sustained research to develop a simple process for the preparation of the oxazolidinone of the formula (II), we observed that a promising approach for developing such a process would be to. a) Avoid the usage of phosgene in the ring formation step. b) Reduce the nitro group present in the compound of the formula (IV) with appropriate reducing agent before the cydisation step. c) Use of dialkylcarbonates like dimethyl carbonate, diethyl carbonate in ring formation step. Accordingly we focused our research on the above mentioned directions. Following the above directions we are successful to develop an improved process for the preparation of oxazolidinone of the formula (II). Accordingly we observed that the ring formation step can be carried out in the presence of an amino group present on benzene ring of compound of formula the (I). We also found further that dialkyi carbonates used in the ring formation step gave better yields than the phosgene method (30-35% higher overall yield). Accordingly, the present invention provides a process for the preparation of novel intermediate of the formula I useful for the preparation of oxazolidinone of the formula (II) which comprises: (I) Preparing the 4-nitro-(S)-phenylalaninol of the formula (IV) by conventional methods. (ii) Reducing the nitro compound of formula (IV) by hydrogenation in the presence of a metal catalyst in alcoholic solvents under pressure at a temperature in the range of 25-80°C, to produce a novel intermediate of the formula (II) and (iii) Isolating the reduced product of the formula (II) by filtration of catalyst The 4-nitro-(S)-phenylalaninol of formula (IV) in the step (i) may be prepared by following the method described in the US patent No. 5466699. For example 4-nitro-(S)-phenylalaninol of formula (IV) may be prepared as follows: Esterlflcation of (S)- 4-nitro phenylalanine with methanol, and thionyl chloride at -10°C yields (S)- methyl-4-nitro phenylalanate hydrochloride of the formula (III). Compound of the formula (III) on reduction with sodium borohydride in aqueous ethanol medium yields compound of the formula (IV). The metal catalyst used in step (ii) may be Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or 5% palladium on carbon. The amount of catalyst employed may range from 5% to 20% weight. The reduction step may also be carried out by using metal/acid eg. SnClz/HCI, Fe/HCI and the like. The alchoholic solvent used may be selected from methanol, ethanol, isopropanol and the like The solvent used in step (ii) may be selected from methanol, ethanol, isopropanol, etc., preferably methanol. The hydrogen pressure used in case of catalytic hydrogenation may be in the range of 20-80 psi preferably in the range of 40-60 psi. The temperature of the hydrogenation may be preferably in the range of 30-40°C. A particularly preferred reaction scheme for the preparation of the compound of the formula (II) is : The details of the invention are given in the examples given below w are provided for illustration only and therefore these examples should be construed to limit the scope of the invention. Example 1; Raw materials Qty 1. (S)-2-Annino-3-(4-nitro phenyl) propanol - 10.0 Kg 2. Methanol - 111.0 Kg 3. 5% Palladium carbon (50% water wet) - 2.0 Kg 4. Ethyl acetate - 24.0 Kg 5. n-Hexane - 20.0 Kg 6. Hydrogen - as required Procedure A methanolic solution of (S)-2-Annino-3-(4-nitro phenyl)-propanol, and 5% palladium carbon catalyst was charged to the reactor and hydrogenated at about 60 psi of hydrogen at room temperature. On completion, filtered off the catalyst through filter aid and washed with methanol. The methanol solution of novel (S)-2-Amino-3-(4-aminophenyl) propanol of the formula (I) which was formed was completely distilled under vacuum. The mixture of ethyl acetate and n-Hexane was charged to the residue. After cooling the solution to 10°C for about 2 hours filtered and washed the filtered product with n-hexane and dried it about 50°C in vacuum (7.6 Kg, 89.5%; mp 108-112°C) HPLC purity - 99%. Analysis : C9H14N2O; molecular weight : 166.0 IR spectrum - KBr disc Absence of - NO2 NH2 at 3307 and 3368 cm^^ UV spectrum - Methanol Xmax at 238.75 nm Xmin at 293.15nm Procedure Charged into the reactor (S)-2-Amino-3-(4-nitrophenyl) propanol, 95% ethanol, iron filings, DM water and cone. Hydrochloric acid at room temperature. Refluxed the reaction mass for two to three hours. After cooling the reaction mass to room temperature filtered off iron through filter aid and washed thoroughly with 95% ethanol. Distilled off the ethanol solution of (S)-2-amino-3-(4-aminophenyl) propanol completely under vacuum. Charged the mixture of ethyl acetate and n-Hexane to the residue. After cooling the solution to 10°C for about 2 hours, filtered and washed the filtered product with n-Hexane and dried it about 50°C in vacuum (6.2 Kg, 73.0%, mp : 107-111°C) HPLC purity : 98.7% Analysis : C9H14N2O, molecular weight : 166.0 IR , ^HNMR and ^^CNMR were consistent with the proposed structure. Methanol - 30.0 Kg 5. Isopropanol - 7.5 Kg Procedure Charged into the reactor (S)-2-Annino-3-(4-aminophenyl) propanol prepared by the process explained In step (A), dimethyl carbonate and potassium carbonate at 115-120°C. Distilled off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charged methanol and filtered salts through filter aid and washed with methanol. Distilled off filtered methanol completely under vacuum and charged isopropanol to the residue. Filtered and washed the product with isopropanol. Dry at 50°C In vacuum (5.5 Kg, 75.0% , mp 95-100°C) Analysis : C10H12N2O2, molecular weight : 192.0 IR , ^HNMR and ^-^CNMR were consistent with the proposed structure. Procedure Charged into the reactor cone. Hydrochloric acid and stannous chloride dihydrate at room temperature. Cool to 0°C. Added (S)-2-amino-3-(4- nitrophenyl) propanol lot wise slowly at 0-5°C during two hours. Bring reaction mass to room temperature and maintained for two hours at 25- 35°C. Chargde 200 L DM water to the reactor and adjust pH to 12-13 with 50% sodium hydroxide solution. Filtered the separated mass through filter aid. Suspended the filtered solid into reactor and charged ethyl acetate and extracted for 30 minutes. Filtered again through filter aid and water washed ethyl acetate layer with DM water till pH of last washing is neutral. Concentrated ethyl acetate solution of (S)-2-Amino-3-(4- aminophenyl)-phenylpropanol, to a residual quantity of 15-20 Kgs. Cooled to room temperature and n-hexane to the residue. After cooling the solution to 10°C for about 2 hours, filtered through filter aid and wash the filtered product with n-hexane and dry it about 50°C in vacuum (5.1 Kg, 60.0%, mp : 108-110°C) HPLC purity 99.1% Analysis : C9H14N2O, molecular weight : 166.0 IR , ^HNMR and ^-^CNMR were consistent with the proposed structure. Preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone. Raw materials Qty 1. (S)-2-Amino-3-(4-aminophenyl) propanol - 5.1 Kg 2. Dimethyl carbonate - 9.1 Kg 3. Potassium carbonate - 0.42 Kg 4. Methanol - 25.0 Kg 5. Isopropanol - 6.5 Kg Procedure Charged into the reactor (S)-2-Amino-3-(4-amlnophenyl) propanol obtained by the process explained in step(A) of Example 3, dimethyl carbonate and potassium carbonate at 135°C. Distilled off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature, charged methanol and filter salts through filter aid and washed with methanol. Distilled off filtered methanol completely under vacuum and charged isopropanol to the residue. Filtered and washed the product with isopropanol. Dry at 50°C under vacuum (4.5 Kg, 76.0% , mp 95-100°C) Analysis : C10H12N2O2, molecular weight : 192.0 IR , ^HNMR and ^^CNMR were consistent with the proposed structure. Procedure Charged into the reactor ethanolic solution of (S)-2-Amino-3-(4-nitrophenyl) propanol and Raney nickel catalyst and hydrogenate at about 60 psi of hydrogen at room temperature. On completion, filtered off catalyst through filter aid and washed with ethanol. The ethanol solution of (S)-2-Amino-3-(4-aminophenyl) propanol of the formula (I) was completely distilled under vacuum. Charged the mixture of ethyl acetate and n-hexane to the residue. After cooling tine solution to 10°C for about 2 hours, filtered and washed the filtered product with n-hexane and dry it about 50°C in vacuum (7.5 Kg, 88.3%, mp : 107-111°C) Analysis : C9H14N2O, molecular weight : 166.0 IR , ^HNMR and ^^CNMR were consistent with the proposed structure. Advantages of the process of the present invention • When the novel compound of the formula I is used for the prepartion of Oxazolidinodione of the formula (II) the yield of the compound of the formula II was found to be 40% , as compared to 17% reported in literature. • The process does not involve use of toxic reagents like phosgene which is all the more difficult when operating on a commercial scale. • The process does not involve additional steps as preparation of a carbamate as is the case with the process employing butyl chloroformate. • The process also avoids employing extremely dry conditions required while handling sodium methoxide as in the butyl chloroformate process • The process is commercially viable & safe. We have described and claimed a process for the preparation of intermediate of the formula (II) using the novel intermediate of the formula (I) defined above in our another application which is being filed simultaneously with this application. We Claim 1. Novel intermediate (S)-2-amino-3-(4-aminophenyl) propanol of formula (I) useful for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula II 2. A process for the preparation of (S)-2-amlno-3-(4-aminophenyl) propanol of formula (I) Which comprises (i) Preparing the 4-nitro-(S)-phenylalaninol of formula (IV) by conventional methods. (ii)Reducing the nitro compound of formula (IV) by hydrogenation in tlie presence of a metal catalyst in alcoholic solvents under pressure at a temperature in the range of 25-80°C, to produce a novel intermediate of the formula (I). (iii) Isolating the reduced product of formula (I) by filtration of catalyst 3. A process as claimed in claims 2 wherein the metal catalyst used in step (ii) is selected from Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or palladium on carbon. 4. A process as claimed in claims 2 to 3 wherein the amount of catalyst employed ranges from 5% to 20% by weight. 5. A process as claimed In claims 2 to 4 wherein the reduction step is carried out by using other metal/acid catalysts for example SnClz/HCI, Fe/HCI and the like. 6. A process as claimed in claims 2 to 5 wherein the solvent used in step (ii) is selected from methanol, ethanol or isopropanol etc., preferably methanol. 7. A process as claimed in claims 2 to 6 wherein the hydrogen pressure used in case of catalytic hydrogenation ranges from 20-80 psi preferably in the range of 40-60 psi. 8, A process as claimed in claims 2 to 7 wherein the hydrogenation temperature used ranges preferably from 30-40°C. 9. A process for the preparation of novel (S)-2-amino-3-(4-aminophenyl) propanol of formula (I) substantially as herein described in the Examples 1-3.

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028-che-2003-abstract.pdf

028-che-2003-claims filed.pdf

028-che-2003-claims grant.pdf

028-che-2003-correspondnece-others.pdf

028-che-2003-correspondnece-po.pdf

028-che-2003-description(complete)filed.pdf

028-che-2003-description(complete)grant.pdf

028-che-2003-form 1.pdf

028-che-2003-form 19.pdf

028-che-2003-form 5.pdf

028-che-2003-pct.pdf