WO2004108732A1 - PROCESS FOR THE PREPARATION OF 2,3:4,5-BIS-O(1-METHYLETHYLIDENE)-ß-D-FRUCTOPYRANOSE SULFAMATE - Google Patents
PROCESS FOR THE PREPARATION OF 2,3:4,5-BIS-O(1-METHYLETHYLIDENE)-ß-D-FRUCTOPYRANOSE SULFAMATE Download PDFInfo
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- WO2004108732A1 WO2004108732A1 PCT/IN2004/000131 IN2004000131W WO2004108732A1 WO 2004108732 A1 WO2004108732 A1 WO 2004108732A1 IN 2004000131 W IN2004000131 W IN 2004000131W WO 2004108732 A1 WO2004108732 A1 WO 2004108732A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
Definitions
- the present invention relates to a process for the preparation of 2,3:4,5-bis-O(l- methylethylidene)- ⁇ -D-fructopyranose sulfamate.
- 2,3:4,5-bis-O(l-methylethylidene)- ⁇ - D-fructopyranose sulfamate commonly known as topiramate (INN Name), compound of formula 1, is used as an anti-epileptic.
- United States patent number 4513006 assigned to M/S McNeil Laboratories Inc., (Indian reference not available, referred to herein as '006) discloses preparation of compound of formula I from its corresponding alcohol, 2,3:4,5-bis-O(l- methylethylidene)- ⁇ -D-fructopyranose using three different routes: (i) by reacting with sulfamyl chloride using a strong alkali viz. sodium hydride in
- step (a) of the process - reaction of 2,3:4,5-bis-O(l-methylethylidene)- ⁇ -D-fructopyranose with sulfuryl chloride is carried out in toluene and step (b) - treatment with amine RNH 2 in tetrahydrofuran.
- step (b) - treatment with amine RNH 2 in tetrahydrofuran At the end of the reaction with sulfuryl chloride in toluene the organic layer is sequentially washed with 10% citric acid, demineral water, sodium bicarbonate solution, saturated sodium chloride solution and then subjected to vacuum distillation.
- the object of the present invention is to provide a simple and efficient process for the preparation of compound of formula I which utilizes different solvent.
- a more particular object of the present invention is to provide a simple and efficient process for the preparation of compound of formula I which utilizes different single solvent in the penultimate and ultimate steps.
- Formula II consisting of ketones, nitriles, esters and their mixtures to yield the compound of formula I.
- Formula DI selected from the group consisting of ketones, nitriles, esters and their mixtures to give compound of formula II;
- formula II b) treating compound of formula II with an amine RNH 2 , wherein R is selected from hydrogen and Ci to C alkyl, in solvent selected from the group consisting of ketones, nitriles, esters and their mixtures to yield compound of formula I.
- the solvent that may be used may be selected from the group consisting of ketones, nitriles, esters and their mixtures.
- Suitable ketones may be selected from acetone, methylethylketone, methylisobutylketone, 2- propanone, 4-methly-2 pentanone , cyclohexanone and the like;
- suitable nitriles may be selected from propionitrile, acetonitrile, benzonitrile and the like;
- suitable esters may be selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, methyl propionate, methyl butanoate, ethyl butanoate and the like; the most preferred being ethylacetate.
- amine RNH 2 is anhydrous ammonia.
- the process of the present invention may be carried out at temperature ranging from 0 to 50°C for 1 to 8 hours.
- Formula HI selected from the group consisting of ketones, nitriles, esters and their mixtures;
- the solvents that may be used in steps 'a' or 'b' or both may be selected from group consisting of ketones, nitriles , esters and their mixtures.
- Suitable ketones may be selected from acetone, methylethylketone, methylisobutylketone, 2-propanone, 4-methly-2 pentanone , cyclohexanone and the like;
- suitable nitriles may be selected from propionitrile, acetonitrile, benzonitrile and the like;
- suitable esters may be selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, methyl propionate, methyl butanoate, ethyl butanoate and the like; the most preferred being ethylacetate.
- the solvent used in both steps 'a' and 'b' is the same solvent.
- the use of a single solvent in both the steps is not only convenient but it obviates the need to distill out the solvent of step 'a' which results in degradation of the product.
- Step (a) of the process of the present invention may be carried out at temperature ranging from 0 to 50°C for 0.5 to 4 hours.
- step (b) amine RNH 2 is anhydrous ammonia.
- Step (b) of the process of the present invention may be carried out at temperature ranging from 0 to 50°C for 1 to 8 hours.
- Compound of formula I may be recrystallized from recrystallizing media which may be solvent or their mixtures.
- the solvent or their mixtures may be selected from aliphatic or cyclic or aromatic hydrocarbons, alcohols, ketones, nitriles, esters, water etc. Preferably mixtures of absolute alcohol and cyclohexane.
- compound of formula I According to the process for the preparation of compound of formula I may be carried out by reacting compound of formula HI with sulfuryl chloride in ethylacetate optionally in the presence of a base which will yield compound of formula H.
- compound of formula H in ethylacetate when treated with an amine RNH 2 affords the compound of formula I.
- the process is carried out by adding a solution of compound of formula HI and pyridine in ethylacetate to a solution of cooled sulfuryl chloride reacted at ambient temperature, quenched and phase separated.
- the organic phase is washed with demineral water till pH 1.5-2.5 and thereafter with saturated solution of sodium chloride.
- solvent ethylacetate may be partly removed by vacuum distillation.
- the compound of formula H is reacted with anhydrous ammonia, worked up and ethyl acetate removed by distillation under vacuum to obtain crude compound of formula I.
- Crude compound of formula I may be purified with absolute alcohol and cyclohexane mixture to get pure compound of formula I.
- Reaction mass is cooled to 5-10°C and stirred at 5-10°C for 2 hrs. Material filtered and washed with 40 lit of toluene, suck dried and dried the material. Dry wt: 64.0 kg [ HPLC purity 99.0%, Starting material : 0.8% (Formula HI)].
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Abstract
A process for the preparation of 2,3:4,5-bis-O(1-methylethylidene)-ß-D-fructopyranose sulfamate, compound of formula (I), comprising reacting 2,3:4,5-bis-O(1-methylethylidene)-ß-D-fructopyranose sulfonyl chloride, compound of formula (II) with an amine RNH2, wherein R is selected from hydrogen and C1 to C4 alkyl, in a solvent selected from the group consisting of ketones, nitriles, esters and their mixtures to yield the compound of formula (I).
Description
PROCESS FOR THE PREPARATION OF 2,3:4,5-BIS-O(l- METHYLETHYLIDENE)-β -D-FRUCTOPYRANOSE SULFAMATE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2,3:4,5-bis-O(l- methylethylidene)-β-D-fructopyranose sulfamate. 2,3:4,5-bis-O(l-methylethylidene)-β- D-fructopyranose sulfamate, commonly known as topiramate (INN Name), compound of formula 1, is used as an anti-epileptic.
BACKGROUND OF THE INVENTION
United States patent number 4513006, assigned to M/S McNeil Laboratories Inc., (Indian reference not available, referred to herein as '006) discloses preparation of compound of formula I from its corresponding alcohol, 2,3:4,5-bis-O(l- methylethylidene)-β-D-fructopyranose using three different routes: (i) by reacting with sulfamyl chloride using a strong alkali viz. sodium hydride in
DMF. Compound of formula I is isolated from the reaction mixture by extracting with toluene, vacuum distillation and recrystallization with ethylacetate/hexane. This process utilizes strong alkali in DMF which could lead to a runaway reaction which is a potential disaster. Further, preparation of commercially unavailable sulfamyl chloride uses highly toxic and corrosive chlorosulfonyl isocyanate;
(ii) by reacting with sulfuryl chloride in the presence of pyridine or triethylamine in diethylether or methylene dichloride @ -40 to 25°C to yield chlorosulfate, compound of formula II;
followed by reacting with an amine RNH2 at about -40 to 25°C in dichloromethane or acetonitrile. This process produces relatively low yields, (about 30 to 60%) of compound of formula I; (iii) by reacting with sulfuryl chloride to yield chlorosulfate, compound of formula π, which is reacted with metal azide in dichloromethane or acetonitrile to prepare azidosulfate. Azidosulfate is reduced by catalytic hydrogenation to yield compound of formula I. The drawback of this process is occurrence of explosion while handling azido compounds,
United States patent number 5387700, assigned to M/S McNeil Laboratories Inc., (Indian reference not available) claims the process of preparation of compound of formula I by utilizing the route (ii) of '006 with specific solvents. The step (a) of the process - reaction of 2,3:4,5-bis-O(l-methylethylidene)-β-D-fructopyranose with sulfuryl chloride is carried out in toluene and step (b) - treatment with amine RNH2 in tetrahydrofuran. At the end of the reaction with sulfuryl chloride in toluene the organic layer is sequentially washed with 10% citric acid, demineral water, sodium bicarbonate solution, saturated sodium chloride solution and then subjected to vacuum distillation.
This patented process utilizes two solvents hence, one needs to ensure complete removal of the first solvent before the addition of the second solvent. Toluene and tetrahydrofuran are removed by vacuum distillation above room temperature. This results in some degradation of the product. Tetrahydrofuran distillation needs to be carefully carried out
as peroxide explosions can occur. When we carried out the patented process the step (a) product is obtained in lower yield (about 70 - 75%) and purity (about 85-90%).
We have now found a process which utilizes a different single solvent in the two steps of the process for the preparation of compound of formula I which obviates the use of two different solvents used in the prior art process. Further, we find that the process of the present invention does not require sequential washings. Ordinary washing with demineralized water results in substantially pure compound of formula II.
OBJECT OF THE INVENTION
The object of the present invention is to provide a simple and efficient process for the preparation of compound of formula I which utilizes different solvent.
A more particular object of the present invention is to provide a simple and efficient process for the preparation of compound of formula I which utilizes different single solvent in the penultimate and ultimate steps.
SUMMARY OF THE INVENTION
A process for the preparation of 2,3:4,5-bis-0(l-methylethylidene)-β-D-fructopyranose sulfamate, compound of formula I, comprising
Formula I reacting compound of formula II with an amine RNH2, wherein R is selected from hydrogen and to C4 alkyl, in a solvent selected from the group
Formula II consisting of ketones, nitriles, esters and their mixtures to yield the compound of formula I.
Specifically, process for the preparation of 2,3:4,5-bis-O(l-methylethylidene)-β-D- fructopyranose sulfamate, compound of formula I, comprising
Formula I a) reacting compound of formula HI with sulfuryl chloride in a solvent
Formula DI selected from the group consisting of ketones, nitriles, esters and their mixtures to give compound of formula II; and
DETAILED DESCRIPTION OF THE INVENTION
In our endeavour for a simpler process which can use a single solvent for the penultimate and ultimate steps in the process for the preparation of compound of formula I we have found that it is not necessary to use two different solvents in the two steps. We have found different solvent that can be used in both the steps.
Accordingly in the present invention compound of formula I is prepared by a process comprising
I.
According to the process of the present invention the solvent that may be used may be selected from the group consisting of ketones, nitriles, esters and their mixtures. Suitable
ketones may be selected from acetone, methylethylketone, methylisobutylketone, 2- propanone, 4-methly-2 pentanone , cyclohexanone and the like; suitable nitriles may be selected from propionitrile, acetonitrile, benzonitrile and the like; suitable esters may be selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, methyl propionate, methyl butanoate, ethyl butanoate and the like; the most preferred being ethylacetate.
According to the process of the present invention amine RNH2 is anhydrous ammonia.
The process of the present invention may be carried out at temperature ranging from 0 to 50°C for 1 to 8 hours.
In preferred embodiment of the present invention compound of formula I is prepared by a process comprising
Formula I a) reacting compound of formula HI with sulfuryl chloride in solvent
Formula HI selected from the group consisting of ketones, nitriles, esters and their mixtures; and
Formula II b) treating compound of formula II with an amine RNH2, wherein R is selected" from hydrogen and d to C alkyl, in solvent selected from the group consisting of ketones, nitriles, esters and their mixtures to yield the compound of formula I.
According to the process of the present invention the solvents that may be used in steps 'a' or 'b' or both may be selected from group consisting of ketones, nitriles , esters and their mixtures. Suitable ketones may be selected from acetone, methylethylketone, methylisobutylketone, 2-propanone, 4-methly-2 pentanone , cyclohexanone and the like; suitable nitriles may be selected from propionitrile, acetonitrile, benzonitrile and the like; suitable esters may be selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl propionate, methyl propionate, methyl butanoate, ethyl butanoate and the like; the most preferred being ethylacetate.
Preferably, the solvent used in both steps 'a' and 'b' is the same solvent. The use of a single solvent in both the steps is not only convenient but it obviates the need to distill out the solvent of step 'a' which results in degradation of the product.
Step (a) of the process of the present invention may be carried out at temperature ranging from 0 to 50°C for 0.5 to 4 hours.
According to the process of the present invention step (b) amine RNH2 is anhydrous ammonia.
Step (b) of the process of the present invention may be carried out at temperature ranging from 0 to 50°C for 1 to 8 hours.
Compound of formula I may be recrystallized from recrystallizing media which may be solvent or their mixtures. The solvent or their mixtures may be selected from aliphatic or cyclic or aromatic hydrocarbons, alcohols, ketones, nitriles, esters, water etc. Preferably mixtures of absolute alcohol and cyclohexane.
According to the process for the preparation of compound of formula I may be carried out by reacting compound of formula HI with sulfuryl chloride in ethylacetate optionally in the presence of a base which will yield compound of formula H. Compound of formula H in ethylacetate when treated with an amine RNH2 affords the compound of formula I.
For instance, the process is carried out by adding a solution of compound of formula HI and pyridine in ethylacetate to a solution of cooled sulfuryl chloride reacted at ambient temperature, quenched and phase separated. The organic phase is washed with demineral water till pH 1.5-2.5 and thereafter with saturated solution of sodium chloride. Optionally solvent ethylacetate may be partly removed by vacuum distillation. The compound of formula H is reacted with anhydrous ammonia, worked up and ethyl acetate removed by distillation under vacuum to obtain crude compound of formula I. Crude compound of
formula I may be purified with absolute alcohol and cyclohexane mixture to get pure compound of formula I.
The invention is illustrated but not restricted by the description in the following examples.
Examples Preparation of Compound of formula I :
Example 1
A solution of compound of formula HI (100.0 gm, 0.384 mol) and pyridine(48.60 gm,0.614 mol) in ethyl acetate(0.510 L) was added to the cooled sulfuryl chloride(82.87 gm, 0.61 mol) and ethyl acetate(0.51 L) solution at -10° to 5° C. within a period of 1-1.5 hours. After the addition was completed, reaction was maintained for 1.5-2.0 hours at room temperature and it was quenched by chilled water at 10-15°C, separated the organic layer, and then washed it with D.M. water until the pH was neutral. Finally washed it with saturated solution of sodium chloride. Removal of the solvent by vacuum distillation to certain extent afforded chloro sulfate in ethyl acetate which is pressurized with anhydrous ammonia to 3-4.0 Kg at ambient temperatures for 2-3 hours , after workup the ethyl acetate was removed in vacuum to afford a semi solid to solid material (topiramate) which is treated with cyclohexane to get (if required) crude compound of formula I. The material further purified to get the compound of formula I as a white solid,(HPLC purity : more than 99.50%, M.P. : 123-125° C).
Example 2
A solution of compound of formula HI (60 kg) and pyridine (29.20 kg) in ethyl acetate(305 L) was added to the cooled sulfuryl chloride(49.8 kg) and ethyl acetate(305 L) solution at -10° to -2° C. within a period of 1-1.5 hours. After the addition was completed, reaction was maintained for 1.5-2.0 hours at room temperature and it was quenched by chilled water at 10-15°C, separated the organic layer, and washed with D.M. water until the pH comes to 1.5 to 2.5 range. Finally washed the organic layer with saturated solution of sodium chloride. Removed the solvent by vacuum distillation to afford chloro sulfate compound in ethyl acetate as an oil to which fresh ethylacetate was added and is pressurized with anhydrous ammonia to 3-4.0 Kg at ambient temperatures for 4.0 hours, reaction mass was filtered to remove ammonium chloride salt and from the filtrate the ethyl acetate was removed in vacuum to afford a semi solid to solid material (crude topiramate). 85 lit of rectified spirit was added to crude topiramate and stirred for 10 min and 170 lit of DM water was added to the reaction mass at 45 to 50°C and pH adjusted to 8 to 8.5 with an alkali solution. Reaction mass is cooled to 5-10°C and stirred at 5-10°C for 2 hrs. Material filtered and washed with 40 lit of toluene, suck dried and dried the material. Dry wt: 64.0 kg [ HPLC purity 99.0%, Starting material : 0.8% (Formula HI)].
Above material was purified with absolute alcohol and cyclohexane mixture to get pure compound of formula I of having HPLC purity greater than 99.8% (actually obtained purity is 99.87 %n and starting material: 0.13% (Formula HI)).
Claims
1. A process for the preparation of 2,3 :4,5-bis-O( 1 -methylethylidene)-β-D- fructopyranose sulfamate, compound of formula I, comprising
Formula I reacting compound of formula H with an amine RNH2, wherein R is selected from hydrogen and to C4 alkyl, in solvent selected from the group
Formula E consisting of ketones, nitriles, esters and their mixtures to yield the compound of formula I.
2. A process as claimed in claim 1 wherein solvent is ethylacetate.
3. A process as claimed in claim 1 wherein amine RNH2 is anhydrous ammonia.
4. A process as claimed in claim 1 wherein the reaction is carried out at 0 to 50°C for 1 to 8 hours.
5. A process for the preparation of 2,3:4,5-bis-O(l-methylethylidene)-β-D- fructopyranose sulfamate, compound of formula I, comprising
Formula I a) reacting compound of formula HI with sulfuryl chloride in solvent
Formula HI selected from the group consisting of ketones, nitriles, esters and their mixtures to give compound of formula H; and
Formula E b) treating compound of formula H with an amine RNH2, wherein R is selected from hydrogen and to C alkyl, in solvent selected from the group consisting of ketones, nitriles, esters and their mixtures to yield compound of formula I.
6. A process as claimed in claim 5 wherein solvent in steps a) and b) is ethylacetate.
7. A process as claimed in claim 5 wherein amine RNH2 is anhydrous ammonia.
8. A process as claimed in claim 5 wherein step (a) is carried out at 0 to 50°C for 0.5 to 4 hours.
9. A process as claimed in claim 5 wherein step (b) is carried out at 0 to 50°C for 1 to 8 hours.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN472/MUM/2003 | 2003-05-12 | ||
| IN472MU2003 | 2003-05-12 |
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| WO2004108732A1 true WO2004108732A1 (en) | 2004-12-16 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007108009A1 (en) * | 2006-03-17 | 2007-09-27 | Alembic Limited | A process for purification of topiramate |
| WO2008010231A2 (en) * | 2006-05-26 | 2008-01-24 | Alembic Limited | A process for the purification of topiramate |
| JP2013518878A (en) * | 2010-02-05 | 2013-05-23 | サイノファーム タイワン リミテッド | Topiramate manufacturing method and purification method |
| CN105566405A (en) * | 2014-11-11 | 2016-05-11 | 华东师范大学 | Preparation method of high-purity topiramate |
| CN106397502A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Synthesis technology of topiramate |
| CN110655542A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0138441A2 (en) * | 1983-09-26 | 1985-04-24 | McNeilab, Inc. | Anticonvulsant sulfamate derivatives |
| EP0533483A2 (en) * | 1991-09-19 | 1993-03-24 | Mcneilab, Inc. | Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose and (1-methylcyclohexyl)methanol |
-
2004
- 2004-05-12 WO PCT/IN2004/000131 patent/WO2004108732A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0138441A2 (en) * | 1983-09-26 | 1985-04-24 | McNeilab, Inc. | Anticonvulsant sulfamate derivatives |
| EP0533483A2 (en) * | 1991-09-19 | 1993-03-24 | Mcneilab, Inc. | Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose and (1-methylcyclohexyl)methanol |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007108009A1 (en) * | 2006-03-17 | 2007-09-27 | Alembic Limited | A process for purification of topiramate |
| WO2008010231A2 (en) * | 2006-05-26 | 2008-01-24 | Alembic Limited | A process for the purification of topiramate |
| WO2008010231A3 (en) * | 2006-05-26 | 2008-05-29 | Alembic Ltd | A process for the purification of topiramate |
| JP2013518878A (en) * | 2010-02-05 | 2013-05-23 | サイノファーム タイワン リミテッド | Topiramate manufacturing method and purification method |
| CN105566405A (en) * | 2014-11-11 | 2016-05-11 | 华东师范大学 | Preparation method of high-purity topiramate |
| CN105566405B (en) * | 2014-11-11 | 2018-11-09 | 华东师范大学 | The preparation method of high-purity Topiramate |
| CN106397502A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Synthesis technology of topiramate |
| CN110655542A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate |
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