CLIAMS:WE CLAIM:

1. A process for the preparation of a thiamine derivative and salt thereof, the process comprising the steps of:

reacting thiamine chloride hydrochloride with phosphoric acid in the presence of a catalyst to produce a reaction mass of thiamine polyphosphates;
isolating said thiamine derivative from said reaction mass of thiamine polyphosphates; and
preparing salt of said thiamine derivative.

2. The process according to claim 1, wherein said thiamine derivative includes, not being limited to, thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate.

3. The process according to claim 1, wherein said isolated thiamine derivative is thiamine monophosphate dihydrate.

4. The process according to claim 1, wherein salt of said thiamine derivative is salt of said S-benzoyl thiamine monophosphate.

5. The process according to claim 1, wherein the thiamine polyphosphates includes, not being limited to, thiamine monophosphate, thiamine diphosphate (cocarboxylase), thiamine tetraphosphate.

6. The process according to claim 1 and claim 3, wherein the step of isolating said thiamine derivative from said reaction mass of thiamine polyphosphates, further comprising the steps of:

hydrolysing said reaction mass of thiamine polyphosphates;
adding Tri-n-butyl amine and chloroform to said reaction mass of thiamine polyphosphates resulting in formation of an aqueous layer; and
recovering said thiamine monophosphate dihydrate by separation of the aqueous layer by adding methanol by filtration.

7. The process according to any one of the preceding claims, wherein the step of preparing salt of said thiamine derivative, further comprising the steps of:

converting said isolated thiamine monophosphate dihydrate into said S-benzoyl thiamine monophosphate; and
preparing salts of said S-benzoyl thiamine monophosphate.

8. The process according to claim 7, wherein the step of converting said isolated thiamine monophosphate dihydrate into said S-benzoyl thiamine monophosphate, further comprising the steps of:

treating said thiamine monophosphate dihydrate in water with a solution of benzoyl chloride forming a reaction mixture;
maintaining said reaction mixture alkaline by addition of aqueous sodium hydroxide;
drying said reaction mixture; and
isolating said S-benzoyl thiamine monophosphate from the dried reaction mixture by adding acetone.

9. The process according to claim 7, wherein the step of preparing salt of said S-benzoyl thiamine monophosphate, further comprising the steps of:

treating S-benzoyl thiamine monophosphate in water with a solution of metal salts of hydroxide to form a resulting solution;
filtering and adding acetone to the resulting solution to precipitate crystals of metal salt of S-benzoyl thiamine monophosphate;
filtering and dissolving crystals of metal salt of S-benzoyl thiamine monophosphate in a small amount of water; and
adding acetone to the resulting solution to produce a recrystallization of purified product of metal salt of S-benzoyl thiamine monophosphate.

10. The process according to claim 1, wherein said reaction is carried out at temperature ranging between 500C - 1300C, preferably between 850C -1250C.

11. The process according to claim 6, wherein said hydrolysis reaction is carried out at temperature ranging between 500C - 1000C, preferably between 550C -950C.

12. The process according to claim 1, wherein said catalyst is metal pyrophosphate catalyst, which is selected from a group, not being limited to, sodium pyrophosphate, potassium pyrophosphate, calcium pyrophosphate.

13. The process according to claim 12, wherein the content of said catalyst is preferably 1 to 10% with respect to the content of thiamine chloride hydrochloride.

14. The process according to claim 1, wherein said phosphoric acid is highly concentrated containing preferably 90% to 120% of phosphoric acid.

Dated this 20th day of November, 2014
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to a process for preparing thiamine derivatives. More particularly, the present invention relates to novel processes for preparing thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof.

BACKGROUND OF THE INVENTION

Thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof are useful as therapeutics and nutrients. Further, some of the thiamine derivatives are known to be biochemically important compounds.

There are processes known where thiamine derivatives have been prepared by reacting thiamine with polyphosphoric acid derived from phosphoric acid; heating of the two gives a mixture of thiamine phosphate comprising thiamine O-monophosphate, thiamine O-diphosphate, thiamine O-triphosphate and thiamine O-polyphosphate. Each polyphosphate may be isolated from the reaction mixture. However, the above prior process is commercially unpractical, because yields of the desired phosphates isolated are extremely poor.

In another process, orthophosphoric acid is used as phosphorylating agent to convert thiamine hydrochloride into thiamine monophosphate. The process demands heating acids like orthophosphoric acid which is considered to be highly unsafe up to 270º C. Moreover, this prior art process does not produce the desired product immediately after work up. The process requires 7 days to get all higher phosphates derivatives eq. Thiamine diphosphate (cocarboxylase) and thiamine triphosphate to convert into thiamine monophosphate. The prepared thiamine monophosphate dihydrate is converted into S-benzoyl thiamine monophosphate by reaction with benzoyl chloride or dibenzyl sulfide or Sodium benzoyl thiosulfate. Due to such drastic conditions the intermediate purity and in turn the product purity is extremely poor requiring series of purification steps.
In yet another process, compounds like P2O5 which are unsafe from operation point of view since it requires changing into orthophosphoric acid at considerably high temperature. This process gives the mixture of mono, di, tri and tetra phosphate derivatives of thiamine. The process provides that even after hydrolysis, the reaction mass contains only 61-62% desired thiamine monophosphate dihydrate along with 31-32 % cocarboxylase and 2-3 % thiamine triphosphate. Further, it requires their separation by means of techniques like Ion Exchange which is again troublesome and not advantageous from process point of view.

Thus, the processes known hitherto for the production of such thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof have cost and/or lower yield with poor quality disadvantages. The prior art processes also suffer in that the workup of reaction mass is tedious which eventually increases the manufacturing cost.

Accordingly, there exists a need for a process which possesses none of the above-discussed disadvantages and gives the desired products not only in higher yields but also in high purity. It is therefore an object of the present invention to provide a process for the production of thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof of high purities and in higher yield. Other objects will become apparent to those skilled in this art as the description proceeds.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof.

As a result of numerous studies in order to find a new and commercially viable process for preparing thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof, it has now been found that the desired thiamine derivatives and salts thereof may be prepared in excellent yields with high purity by use of highly concentrated phosphoric acid containing 90% to 120% of phosphoric acid and metal pyrophosphate catalyst in very simple way without any intermittent treatment/process/steps. The process provides for the reaction to operate at about 85 to 125º C and the subsequent hydrolysis at 55 to 95 º C to yield immediately desired product thiamine monophosphate dihydrate in high yield and higher purity.

Thus, one aspect of the present invention relates to a novel and commercially viable process for the preparation of thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof.

Accordingly, the present invention relates to a process for the preparation of a thiamine derivative and salt thereof, the process comprising the steps of: reacting thiamine chloride hydrochloride with phosphoric acid in the presence of a catalyst to produce a reaction mass of thiamine polyphosphates; isolating said thiamine derivative from said reaction mass of thiamine polyphosphates; and preparing salts of said thiamine derivative. The said reaction is carried out at temperature ranging between 500C - 1300C, preferably between 850C -1250C. The catalyst is metal pyrophosphate catalyst, which is selected from a group, not being limited to, sodium pyrophosphate, potassium pyrophosphate, calcium pyrophosphate. The content of said catalyst is preferably 1 to 10% with respect to the content of thiamine chloride hydrochloride. The phosphoric acid is highly concentrated containing preferably 90% to 120% of phosphoric acid.

The said thiamine derivative includes, not being limited to, thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate. The isolated thiamine derivative is thiamine monophosphate dihydrate and salt of said thiamine derivative is salt of said S-benzoyl thiamine monophosphate.

The said thiamine polyphosphates includes, not being limited to, thiamine monophosphate, thiamine diphosphate (cocarboxylase), thiamine tetraphosphate.

The step of isolating said thiamine derivative from said reaction mass of thiamine polyphosphates, further comprising the steps of: hydrolysing said reaction mass of thiamine polyphosphates; adding Tri-n-butyl amine and chloroform to said reaction mass of thiamine polyphosphates resulting in formation of an aqueous layer; and
recovering said thiamine monophosphate dihydrate by separation of the aqueous layer by adding methanol by filtration. The hydrolysis reaction is carried out at temperature ranging between 500C - 1000C, preferably between 550C -950C.

The step of preparing salts of said thiamine derivative, further comprising the steps of: converting said isolated thiamine monophosphate dihydrate into said S-benzoyl thiamine monophosphate; and preparing salts of said S-benzoyl thiamine monophosphate.

The step of converting said isolated thiamine monophosphate dihydrate into said S-benzoyl thiamine monophosphate, further comprising the steps of: treating said thiamine monophosphate dihydrate in water with a solution of benzoyl chloride forming a reaction mixture; maintaining said reaction mixture alkaline by addition of aqueous sodium hydroxide; drying said reaction mixture; andisolating said S-benzoyl thiamine monophosphate from the dried reaction mixture by adding acetone.

The step of preparing salts of said S-benzoyl thiamine monophosphate, further comprising the steps of:treating S-benzoyl thiamine monophosphate in water with a solution of metal salts of hydroxide to form a resulting solution;filtering and adding acetone to the resulting solution to precipitate crystals of metal salt of S-benzoyl thiamine monophosphate; filtering and dissolving crystals of metal salt of S-benzoyl thiamine monophosphate in a small amount of water; and adding acetone to the resulting solution to produce a recrystallization of purified product of metal salt of S-benzoyl thiamine monophosphate.

Another aspect of the present invention relates to the compositions/formulations produced by the processes claimed herein.
Accordingly, the primary object and advantage of the present invention is to provide a novel and commercially viable process for the preparation of thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof with higher purity and higher yield.

Another object and advantage of the present invention is to provide a process involving use of highly concentrated phosphoric acid containing 90% to 120% of phosphoric acid and metal pyrophosphate catalyst in very simple way without any intermittent treatment/process/steps.

Another object and advantage of the present invention is to provide a process involving use of safe chemicals capable of operating at low temperature which is safe from operational point of view.

Another object and advantage of the present invention is to provide a process wherein the intermediates generated have higher yield and higher purities.

Another object and advantage of the present invention is to provide a process involving use of catalysts which facilitate the O-phosphorylation of thiamine to thiamine monophosphate dihydrate with very high selectivity.

Yet another object and advantage of the present invention is to provide a process providing controlled hydrolysis of thiamine poly phosphate (mono, cocarboxylase, tri and tetra phosphate) into thiamine monophosphate dihydrate of high purity with higher yield.

DESCRIPTION OF THE INVENTION:

The invention provides a novel and commercially viable process for the preparation of thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof using highly concentrated phosphoric acid which contains 90 % to 120 % of phosphoric acid along with catalyst such as metal pyrophosphate such as, not being limited to, Sodium pyrophosphate, potassium pyrophosphate, calcium pyrophosphate etc. The process providing concentration of catalyst at 1 to 10% with respect to thiamine chloride hydrochloride. The reaction operates at 85 to 125º C yielding thiamine monophosphate dihydrate along with small amount of cocarboxylase and the subsequent hydrolysis at 55 to 95º C to yield immediately desired product with high yield and higher purity. Thus, the production of high yield with higher purity of thiamine monophosphate dihydrate is possible without any intermittent treatment/process/step due to the properly designed process of O-phosphorylation in the presence of catalyst and controlled hydrolysis of thiamine poly phosphates (mono, coacarboxylase and tetra phosphate).

The resultant thiamine monophosphate dihydrate obtained is converted into S-benzoyl thiamine monophosphate (a fat soluble form of Vitamin B2) and its metal salts which includes sodium, potassium, lithium, calcium, iron, magnesium, barium etc.

The reaction diagram of the process is depicted below:

The first step in the process of present invention comprises reacting a compound having the above Formula (I) with phosphoric acid to form a thiamine derivative having the above Formula (II). Thereafter, controlled hydrolysis of the resultant compound of Formula (II) yields immediately the desired compound having the above Formula (III).

Example

In order to more clearly describe the nature of the present invention, specific examples will hereinafter be described. It should be understood, however, that this is done solely by way of example, and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.

EXAMPLE 1

Preparation of Thiamine monophosphate

To the solution of 2500 g of Polyphosphoric acid and 25 g sodium pyrophosphate was added 700 g thiamine hydrochloride chloride and the mixture was heated slowly at 120 Deg C. After the ceasing of HCl gas evolution, which generally takes 3-4 hours. It was maintained for 2 hours and was further cooled to 50 Deg C. HPLC analysis shown the following analysis

7% of cocarboxylase ( thiamine diphosphate)
88.0% of thiamine monophosphate
1.0% of thiamine triphosphate
1.5% of thiamine chloride

After cooling hot demineralized water was added and the reaction mass heated to 90 Deg C. The reaction mass was maintained at this temperature for 5-6 hours.

HPLC analysis of reaction mass shown the following analysis.
1% of cocarboxylase
95% of thiamine monophosphate
1.0% of thiamine chloride

The reaction mass is allowed to cool up to 25 Deg C. To this was added 4000 ml Tri-n-butyl amine and 5000 ml chloroform. The two layer formed was separated and product was recovered from aqueous layer by adding 5000 ml methanol by filtration. Dry weight of thiamine monophosphate dihydrate was 862 g (almost 100 % yield ) of purity 99 % by HPLC. Melting point 198-200 Deg C.

EXAMPLE 2

Preparation of S-benzoyl thiamine monophosphate

100 g thiamine monophosphate dihydrate was added to 300 ml water and cooled up to 0 to 5 Deg C. 10 % caustic solution is run in to this solution to make pH 8 - 10. 75 g of benzoyl chloride was added drop wise to the mixture with stirring within 4 hours and maintained the reaction mixture alkaline by occasional addition of 25% aqueous sodium hydroxide. After the completion of reaction, the mass is concentrated to dryness and the product was isolated by adding acetone. The precipitated solid was filtered and dried. Dry weight of product was 75 g.

EXAMPLE 3

Preparation of Lithium salt of S-benzoyl thiamine monophosphate

To a mixture of 12 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of lithium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Lithium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield -9 g and MP - decomposes at about 190°C.

EXAMPLE 4

Preparation of Barium salt of S-benzoyl thiamine monophosphate

To a mixture of 15 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of Barium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Barium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield 9 g and melt with decomposition at 180 Deg C.

EXAMPLE 5

Preparation of Magnesium salt of S-benzoyl thiamine monophosphate

To a mixture of 15 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of Magnesium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Magnesium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield 9 g and melt with decomposition at 205 Deg C.

Although this invention has been disclosed in the context of certain preferred embodiments and examples, it will be understood by those skilled in the art that the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention and obvious modifications and equivalents thereof. Thus, from the foregoing description, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.

Accordingly, it is not intended that the scope of the foregoing description be limited to the description set forth above, but rather that such description be construed as encompassing all of the features of patentable novelty that reside in the present invention, including all the features and embodiments that would be treated as equivalents thereof by those skilled in the relevant art. Thus, it is intended that the scope of the present invention herein disclosed should not be limited by the particular disclosed embodiments described above but should be determined only by a fair reading of the appended claims.