AN IMPROVED PROCESS FOR THE PREPARATION OF BIOTIN
Field of the invention
The present invention relates to an improved process for the preparation of optically active (+) biotin of formula (I) in pure form.
(I)
Description of the prior art
Though (+) biotin is a human vitamin, which is known as vitamin H, it is also used as a pharmaceutical agent for the treatment of dermatosis and as a feed additive with growth increasing action for domestic animals.
U.S pat. No 2,489,232 discloses a process for the preparation of racemic biotin. Since (+) biotin is biologically active. Resolution is required to prepare (+) biotin. U.S
Pat No 2,489,235 discloses a process in which resolution of racemates is performed in intermediate stage. In both process the undesirable enantiomer resulting from this resolution practically no longer racemizes and can no longer be fed back to the process.
U,S Pat No 3,740,416; 4,014,895, 3,876,656; 4,403,096; JP 61254590 discloses various processes for the preparation (+) biotin and its intermediates.
The prior art literature suggests the use of phosgene or alkyl chloroformate, for the following conversion:
(I)
The use of phosgene is highly toxic and potentially explosive under the influence of other gases. Thus, its use is extremely dangerous when carelessly handled, or supervised, and special precautions are required in its transport, storage and use, e.g., the use of safety devices is essential in any apparatus that comes into contact with phosgene. Thus biotin obtained from known processes suffers in terms of optical purity, quality, color and quantity.
The biotin obtained from the known literature is impure or crude biotin. Hence there is a need to develop a technique to isolate or purification of biotin, which meet all the requirements specified in BP, USP, and JP pharmacopoeia. With our continued search and intense investigation, we finally achieved identifying a clean process for producing the title compound of the invention of the formula (I), which employs solid triphosgene, and yields biotin in good purity.
Objectives of the invention The main objective of the present invention , is to provide a process for the preparation of compound of general formula (I).
(I) Another objective of the present invention is to provide a process for the preparation of biotin of formula (I), which avoid use of hazardous chemicals such . as phosgene and would be easy to implement on commercial scales, which meet all the requirements specified in BP, USP, and JP pharmacopoeia.
Still another objective of the present invention is to provide a process for the purification of compound of formula (I) in good yield and high purity.
Summary of the invention:
Accordingly, the present invention provides an improved process for the preparation of biotin of formula (I), the said process comprising the steps of: (i) converting diester of formula (II), wherein R is the same or different and represents a lower alkyl group, an alkenyl group, an aryl group, an arylalkyl group all of which may be substituted and Ri represents (Cι-C ) alkyl, into diamine of formula (N), by saponificating the formula (II) to produce the compound of formula (III) and decarboxylating the resulting dicarboxylic acid of formula (III) with a suitable reagent at a temperature in the range of 30°C to 100°C, and
(ii) reacting the diamine of formula (N), with triphosgene in a solvent system in the presence of alkali/alkali earth metal hydroxide solution at a temperature in the range of - 50°C to 150°C, to produce the crude biotin of formula (I).
The process is shown in scheme-I as given below,
t
(I)
Scheme-I
In another embodiment of the present invention there is provided a process for purification of crude biotin using a solution of alkali/alkali earth metal hydroxide in a solvent at a temperature in the range of -10°C to 150°C, charcoalising the layer, acidifying the reaction mass to pH 0.5 to 2.0 with an acid to precipitate pure biotin and isolating the product by conventional methods.
Detailed description of the invention
In an embodiment of the present invention the group R is selected from lower alkyl group such as methyl, ethyl; an alkenyl group, an aryl group such as phenyl; an arylalkyl group such as benzyl all of which may be substituted; preferably benzyl group.
In still another embodiment of the present invention, the suitable reagent used in step (i) is selected from hydrobromic acid, acetic acid, or mixtures thereof.
In an embodiment of the present invention, the solvent used in step (ii) is selected from toluene, xylene, benzene, acetic acid and the like or mixtures thereof.
In an embodiment of the present invention, the alkali/alkali earth metal hydroxide used in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like.
In an embodiment of the present invention, the alkali/alkali earth metal hydroxide used in purification step is selected from sodium hydroxide, potassium hydroxide and the like.
In an embodiment of the present invention, the solvent used in purification step is selected from water, methanol, and the like.
In yet another embodiment of the present invention the purification process disclosed in the present invention can be used to purify crude biotin obtained by any process.
In another embodiment of the present invention the starting material of formula (II) can be prepared from the literature known in the prior art.
The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.
Example-1;
Step (i): Preparation of diamine. 2HBr (V).
To diester (II) (130 g), hydrobromic acid (700 ml) and acetic acid (100 ml) were added at 30°C. The reaction mass was refluxed till completion of reaction. The reaction mass
was cooled to 50°C, toluene was added (200 ml) and stirred for 30 min. The layers were separated and to the aqueous layer hydrobromic acid (200 ml) was added and heated to reflux for 24 hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 40° C, toluene was added and stirred for 30 min. The aqueous layer was separated and washed with toluene (100 ml) and distilled off the hydrobromic acid under vacuum to yield the title compound.
Step (iii): Preparation of crude biotin (I).
To diamine obtained according to step (i) water (75 ml) was added and adjusted the pH to 11.5 to 12 with 40% NaOH. Triphosgene solution (100 gm in 160 ml toluene) was added to the reaction mass and maintained the pH with 40% NaOH and stirred at 60° C for 60 min. After completion of the reaction, the reaction mass was cooled to 50° C, and separated the layers. The aqueous layer was washed with toluene (200 ml). To this activated carbon (10 g) and EDTA (0.25 g) was added and stirred for 60 min. at RT. Filtered and washed with water and pH of the filtrate was adjusted to 1-0.9 using cone. HC1 and stirred for 60 min. at RT. The reaction mass was filtered and washed with water and acetone (100 ml) and dried to yield the title compound (38 g), purity by HPLC (92%). Example-2
Purification of crude (+) biotin
The crude biotin (100 gm), obtained according to the process known in the prior art, was taken in water (1000 ml) and heated to 60°C. IN sodium hydroxide solution (450 ml), carbon (10 gm) were added at 60°C. Stirred and then carbon was filtered. Methanol (100 ml) was added and pH of the filtrate was adjusted to 1-0.9 using cone. HC1 and stirred for 60 min. at RT. The reaction mass was filtered and washed with water and acetone (100 ml) and dried to yield pure (+) biotin (92 gm).