Field of the Invention
The present invention relates to a process for the preparation of anhydrous form of benfotiamine.
Background of the Invention
Benfotiamine, chemically is 5-[2-[[(4-amino-2-methyI-5-pyrimidinyI)methyl]formyI amino]-l-[2-(phosphonooxy)ethyIJ-l-propenyl]ester, represented by Formula I.
Benfotiamine is a synthetic S-acyl derivative of thiamine (Vitamin Bl) indicated for the treatment of painful diabetic neuropathy in adults only.
U.S. Patent No. 3,064,000 discloses benfotiamine and its process. Benfotiamine obtained as per the process disclosed in this patent has melting point about 165°C. The inventors of the present invention reproduced the process and have observed that benfotiamine obtained is highly hygroscopic and water contents reaches to a value of about 8%.
Japanese Patent No. JP 37-16042B discloses crystalline forms; crystalline form a having melting point about 165°C; crystalline form p having melting point about 150°C and crystalline form 8 having melting point about 195°C of benfotiamine. Japanese Patent No. JP 37-16042B further discloses that the crystalline forms a and p of benfotiamine are hydrated forms whereas crystalline form § is without crystal of water.
Japanese Patent No. JP 37-11040 discloses a preparation of crystalline form 8 of benfotiamine which involves treating benfotiamine with 30% ethanol.

U.S. Patent No. 9.718.846 discloses five crystalline forms of bcnfotiamine A, B, C, D and E. US '846 allegedly discloses that the crystalline form A is free of crystal water, crystalline form B contains one crystal water, crystalline form C is a solvate, crystalline form D has half of one crystal water, and crystalline form E has one crystal water.
There is a need in the art to develop an improved process for the preparation of anhydrous form of benfotiamine.
Summary of the Invention
The present invention relates to a process for the preparation of anhydrous form of benfotiamine using water.
The present invention provides an efficient, cost-effective and commercially viable process for the preparation of anhydrous form of benfotiamine. The present invention provides anhydrous form of benfotiamine having purity more than 99%. The anhydrous form of the present invention is stable even after exposing to atmosphere for about 24 hours and shows water contents below 1% having melting point range between 195°C -197°C.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature." as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The term "reaction mixture", as used herein, refers to suspension, solution, emulsion, or precipitate.
The term "contacting", as used herein refers to dissolving, slurrying, stirring, heating. suspending, or combinations thereof.
The term "anhydrous", as used herein, refers to a crystalline form that does not have water bound in the crystal lattice. Hydrates and anhydrates may show different physical properties like stability, dissolution rate and bioavailability as known for polymorphs.
The term "seed crystal," as used herein, refers to a small piece of single crystal/polycrystal material, which is used for addition to a crystallization system for the

purpose of initiating or enhancing nucleation or acting as a substrate for further crystallization.
A first aspect of the present invention provides a process for the preparation of anhydrous form of benfotiamine comprising contacting benfotiamine with water. Benfotiamine used for the preparation of anhydrous form may be prepared by any method provided in the art, for example, the method as disclosed in U.S. Patent No. 3,064,000.
In an embodiment, benfotiamine is treated with water at a temperature of about 85°C to about 110°C. In another embodiment, benfotiamine is treated with water at a temperature of about 90°C to about 105°C. In another embodiment, benfotiamine is treated with water at a temperature of about 95°C to about 100°C.
In an embodiment, benfotiamine is treated with water for about one hour to about 5 hours. In another embodiment, benfotiamine is treated with water for about 2 hours to about 4 hours.
Anhydrous form of benfotiamine may optionally be isolated by filtration, decantation. extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. Anhydrous form of benfotiamine may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, tray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, the process provides anhydrous form of benfotiamine of Formula I of greater than 99% chromatographic purity. In another embodiment, the process provides anhydous form of benfotiamine of Formula I of greater than 99.5% chromatographic purity.
A second aspect of the present invention provides a process for the preparation of anhydrous form of benfotiamine of Formula I.

a) treating thiamine chloride hydrochloride with polyphosphoric acid to obtain compound of Formula II;
Formula II
b) hydrolyzing the compound of Formula II of step a) with water to obtain compound of Formula III;
c) treating the compound of Formula III of step b) with benzoyl chloride in water to obtain benfotiamine;
d) optionally seeding the reaction mixture of step c) with seed crystal of anhydrous form of benfotiamine; and
e) isolating and drying to obtain anhydrous form of benfotiamine of Formula I. Thiamine chloride hydrochloride may be prepared by any method known in the art or
is commerically available.
In an embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid to obtain the compound of Formula II at a temperature of about 70°C to about 110°C. In another embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid at a temperature of about 75°C to about 100°C. In another embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid at a temperature of about 80°C to about 95°C. In still another embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid at a temperature of about 85°C to about 90°C.

In an embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid to obtain the compound of Formula II for about 16 hours to about 24 hours. In another embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid for about 12 hours to about 18 hours. In another embodiment, thiamine chloride hydrochloride is treated with polyphosphoric acid for about 10 hours to about 16 hours.
The reaction mixture containing the compound of Formula II may be used as such or isolated.
The compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula II may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, the hydrolysis of the compound of Formula II is carried out with water at an ambient temperature.
In an embodiment, the hydrolysis of the compound of Formula II is carried out for about 12 hours to about 18 hours. In another embodiment, the hydrolysis of the compound of Formula II is carried out for about 8 hours to about 10 hours.
The reaction mixture containing the compound of Formula III may be used as such or isolated.
The compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula III may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, the treatment of the compound of Formula III with benzoyl chloride in water to obtain benfotiamine is carried out in the presence of a base. The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide.
In an embodiment, the treatment of the compound of Formula III with benzoyl chloride in water is carried out at an ambient temeprature.

In an embodiment, the treatment of the compound of Formula III with benzoyl chloride in water is carried out for about 30 minutes to about 6 hours. In another embodiment, the treatment of the compound of Formula III with benzoyl chloride in water is carried out for about one hour to about 4 hours. In another embodiment, the treatment of the compound of Formula III with benzoyl ehloride in water is carried out for about 2 hours to about 4 hours.
The reaction mixture containing benfotiamine may be used as such or isolated.
Benfotiamine of Formula I may optionally be isolated by nitration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration. crystallization, centrifugation. and recrystallization. Benfotiamine of Formula I may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, benfotiamine is treated with water to obtain anhydrous form of benfotiamine at a temperature of about 85°C to about 110°C. In another embodiment, benfotiamine is treated with water at a temperature of about 90°C to about 105°C. In another embodiment, benfotiamine is treated with at a temperature of about 95°C to about 100°C.
In an embodiment, benfotiamine is treated with water for about one hour to about 5 hours. In another embodiment, benfotiamine is treated with water for about 2 hours to about 4 hours.
In an embodiment, the seed crystal of anhydrous form of benfotiamine is optionally added to the reaction mixture of benfotiamine in water.
In an embodiment, the seed crystal of anhydrous form of benfotiamine is added at an ambient temperature.
Anhydrous form of benfotiamine may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. Anhydrous form of benfotiamine may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
In an embodiment, the process provides anhydrous form of benfotiamine of Formula I of greater than 99% chromatographic purity. In another embodiment, the process provides anhydous form of benfotiamine of Formula I of greater than 99.5% chromatographic purity.

While the present invention has been deseribed in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparaent to those skilled in the art, and are intended to be included within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Method
Chromatographic Purity was determined using an Agilent 1260 Infinity (HPLC-01). The column used was an Inertsil® ODS 3V (250 x 4.6 mm) 5p.m.
EXAMPLES
Example 1: Preparation of thiamine monophosphate dihydrate chloride of Formula II
Polyphosphoric acid (200 g) was added to a round bottomed flask and heated to 85°C to 90°C. Thiamine chloride hydrochloride (100 g) was continously added in small lots over a period of 2 hours to 2.5 hours to obtain a reaction mixture. The reaction mixture was stirred for 60 minutes at 90°C to 95°C. The reaction mixture was cooled to 75°C to 80°C and then water was added slowly while controlling the temperature. The reaction mixture was again stirred for 120 minutes. The reaction mixture was cooled to 20°C to 25°C and a mixture of n-butanol (160 mL) and methanol (373 mL) was added. The reaction mixture was heated to 45°C to 50°C and stirred for 4 hours. The reaction mixture was then cooled to 20°C to 25°C and stirred for 8 hours. The reaction mixture was further cooled to 0°C to 5°C and stirred for 2 hours to obtain a precipitate. The precipitate was washed with a mixture of n-bulanol:methanol:water (20 mL:107 mL:13 mL) and sucked dried under vacuum to obtain a wet solid. The wet solid was dried at 45°C under vacuum lor 12 hours to obtain title compound. Yield: 120-125 g Example 2: Preparation of thiamine monophosphate dihydrate of Formula III
Methanol (400 mL) was added to thiamine monophosphate dihydrate chloride of Formula II (100 g; obtained in Example 1) at an ambient temperature to obtain a suspension. The suspension was stirred for 15 minutes to 20 minutes. Tricthylamine was added to the suspension over a period of 3 hours to 4 hours till the pH was adjusted to neutral and then

stirred for 12 hour to obtain a precipitate. The precipitate was washed with methanol (100
mL) and suck dried under vacuum to obtain a wet solid. The wet solid was dried under
vacuum at 60°C for 6 hours to 10 hours to obtain title compound.
Yield: 60-65 g
Example 3: Preparation of benfotiamine of Formula I
A reaction mixture of thiamine monophosphate dihydrate of Formula III (100 g; obtained in Example 2) and water (300 mL) was cooled to 10°C to 15°C. Sodium hydroxide (15%) solution was added to the reaction mixture until the pH was 11 to 12 and stirred for 20 minutes to 30 minutes. Benzoyl chloride (43.4 g to 46.7 g) and sodium hydroxide (15% to maintain the pll 11 to 12) were added simulaneously to the reaction mixture. Activated carbon was added to the reaction mixture at ambient temperature and stirred for 20 minutes to 30 minutes. The reaction mixture was filtered through Hyflo® and washed with dimineralised water (DM) (1.5 mL). Dichloromethane (300 mL) was added to the reaction mixture and stirred vigorously. Dilute hydrochloric acid was then added until the pFI was between 5 to 5.5 and stirred for 30 minutes. Dilute hydrochloric acid was further added until the pH was between 3.5 to 4.0 and stirred for 16 hours to 18 hours to obtain precipitate. The precipitate was filtered, washed with a mixture of dichloromethane:water (IV: IV) and sucked dried under vacuum to obtain a wet cake. The wet cake was dried at 70°C for 16 hours to 18 hours to obtain title compound. Yield: 110-120 g Example 4: Preparation of anhydrous benfotiamine
Demineralized water (DM) (650 mL) was added to benfotiamine (100 g; obtained in Example 3) at an ambient temperature to obtain a reaction mixture. The reaction mixture was heated to 95°C to 100°C and stirred at same temperature for 2 hours to obtain precipitates. The hot precipitates were filtered under vacuum, washed with water and dried in vacuum tray drier (VTD) at 75°C lo 80°C till moisture content is not more than 0.6% to obtain title compound. Yield: 92-95 g Purity: 99.79% Melting point: 195°C-197°C Example 5: Preparation of anhydrous benfotiamine using seed crystal

A reaction mixture of thiamine monophosphate dihydratc of Formula III (100 g; obtained in Example 2) and water (300 mL) was cooled to 0°C to 5°C. Sodium hydroxide solution (10%) was added to the reaction mixture until the pH was 11 to 12. Benzoyl chloride (45 g) was added dropwise to the reaction mixture with stirring over a period of 4 hours while maintaining the reaction mixture alkaline by addition of aqueous sodium hydroxide (25%) solution. After completion of reaction, activated carbon was added to the reaction mixture and stirred for 20 minutes to 30 minutes. The reaction mixture was filtered over Celite1M and washed with water to obtain a filtrate. Dichloromethane was added to the filtrate and pH was adjusted to neutral by addition of dilute hydrochloric acid. The reaction mixture was seeded with anhydrous benfotiamine (obtained in Example 4) followed by addition of dilute hydrochloric acid to adjust pH to 5.0 and stirred for 12 hours to 14 hours. Dilute hydrochloric acid was again added to adjust pH to 3.5 to 4.0 and stirred for 4 hours. The reaction mass was then cooled to 0°C to 5°C and stirred for 2 hours to obtain a solid. The solid was filtered. washed with water and dried at 70°C under vacuum till water content is not more than 1.0% to obtain the title compound. Yield: 105-110 g Purity: 99.86% Melting point: 196-198°C

Claims
1. A process for the preparation of anhydrous form of benfotiamine comprising contacting benfotiamine with water.
2. A process for the preparation of anhydrous form of benfotiamine of Formula I,
Formula I
comprising
a) treating thiamine chloride hydrochloride with polyphosphoric acid to obtain compound of Formula II;
b) hydrolyzing the compound of Formula II of step a) with water to obtain compound of Formula III;
KT¥T
c) treating the compound of Formula III of step b) with benzoyl chloride in water to obtain benfotiamine;
d) optionally seeding the reaction mixture of step c) with seed crystal of anhydrous form of benfotiamine; and

e) isolating and drying to obtain anhydrous form of benfotiamine.
3. The process according to claim 2, wherein the hydrolysis of the compound of Formula II with water to obtain the compound of Formula III is carried out at an ambient temperature.
4. The process according to claim 2, wherein the hydrolysis of the compound of Formula II with water to obtain the compound of Formula III is carried out for 12 hours to 18 hours.,
5. The process according to claim 2, wherein the treatment of the compound of Formula III with benzoyl chloride in water to obtain benfotiamine is carried out in the presence of a base.
6. The process according to claim 2 or claim 5, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide.
7. The process according to claim 2, wherein the treatment of the compound of Formula III with benzoyl chloride in water to obtain benfotiamine is carried out at an ambient temperature.
8. The process according to claim 2, wherein the treatment of the compound of Formula III with benzoyl chloride in water to obtain benfotiamine is carried out for 30 minutes to 6 hours.
9. The process according to claim 2, wherein the seed crystal of anhydrous form of benfotiamine is added at an ambient temperature.
10. Anhydrous benfotiamine of Formula I having greater than 99% chromatographic purity obtained according to process claimed in claims 1 to 9.