WO2004041830A2 - An improved process for the preparation of biotin - Google Patents

An improved process for the preparation of biotin Download PDF

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Publication number
WO2004041830A2
WO2004041830A2 PCT/IB2003/004974 IB0304974W WO2004041830A2 WO 2004041830 A2 WO2004041830 A2 WO 2004041830A2 IB 0304974 W IB0304974 W IB 0304974W WO 2004041830 A2 WO2004041830 A2 WO 2004041830A2
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Prior art keywords
formula
alkali
biotin
process according
earth metal
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Application number
PCT/IB2003/004974
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French (fr)
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WO2004041830A3 (en
Inventor
Pandurang Balwant Deshpande
Anil Ganpat Holkar
Sanjay Nivrutti Karale
Wajid Sajjad Jafri
Gautam Kumar Das
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Orchid Chemicals & Pharmaceuticals Ltd
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Priority to AU2003276510A priority Critical patent/AU2003276510A1/en
Publication of WO2004041830A2 publication Critical patent/WO2004041830A2/en
Publication of WO2004041830A3 publication Critical patent/WO2004041830A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for the preparation of optically active (+) biotin of formula (I) in pure form.
  • (+) 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.
  • 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.
  • the main objective of the present invention is to provide a process for the preparation of compound of general formula (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.
  • 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 (C ⁇ -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
  • 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.
  • the suitable reagent used in step (i) is selected from hydrobromic acid, acetic acid, or mixtures thereof.
  • the solvent used in step (ii) is selected from toluene, xylene, benzene, acetic acid and the like or mixtures thereof.
  • the alkali/alkali earth metal hydroxide used in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like.
  • the alkali/alkali earth metal hydroxide used in purification step is selected from sodium hydroxide, potassium hydroxide and the like.
  • the solvent used in purification step is selected from water, methanol, and the like.
  • the purification process disclosed in the present invention can be used to purify crude biotin obtained by any process.
  • the starting material of formula (II) can be prepared from the literature known in the prior art.
  • step (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 To diamine obtained according to step (i) water (75

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to an improved process for the preparation of optically active (+) biotin of formula (I) in pure form.

Description

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.
Figure imgf000002_0001
(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:
Figure imgf000002_0002
(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).
Figure imgf000003_0001
(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,
Figure imgf000004_0001
t
Figure imgf000004_0002
(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).

Claims

Claims:
1. A process for the preparation of (+) Biotin of formula (I),
Figure imgf000007_0001
(I) which comprising the steps of:
(i) converting diester of formula (II),
Figure imgf000007_0002
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 (Ci- C ) alkyl, into diamine of formula (V),
Figure imgf000007_0003
(V) by saponificating the formula (II) to produce the compound of formula (HI)
Figure imgf000007_0004
and decarboxylating the resulting dicarboxylic acid of formula (ILT) with a suitable reagent at a temperature in the range of 30°C to 100°C, and
(ii) reacting the diamine of formula (V), 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).
2. The process according to claim 1, wherein suitable reagent used in step (i) is selected from hydrobromic acid, acetic acid or mixtures thereof.
3. The process according to claim 1, wherein alkali/alkaline earth metal hydroxide used in step (ii) is selected from sodium hydroxide, potassium hydroxide.
4. The process according to claim 1, wherein the solvent used in step (ii) is selected from toluene, xylene, benzene, acetic acid and the like or mixtures there of.
5. A process for the preparation of (+) biotin reacting the diamine of formula (N) or its reactive derivative,
Figure imgf000008_0001
(V) 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, separating the layer, acidifyingthe aqueous layer to pH 0.5-2.0 with an acid.
6. The process according to claim 5, wherein alkali/alkaline earth metal hydroxide used is selected from sodium hydroxide, potassium hydroxide.
7. The process according to claim 5, wherein the solvent used is selected from toluene, xylene, benzene, acetic acid and the like or mixtures there of.
8. A process for the 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.
9. The process according to claim 8, wherein alkali/alkaline earth metal hydroxide used is selected from sodium hydroxide or potassium hydroxide.
10. The process according to claim 8, wherein the solvent used is selected from water, or methanol.
11. The process according to claim 8, wherein the acid used is selected from HCl, H2SO4 or phosphoric acid.
PCT/IB2003/004974 2002-11-07 2003-11-06 An improved process for the preparation of biotin WO2004041830A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101195629B (en) * 2006-12-05 2010-05-19 浙江医药股份有限公司新昌制药厂 D-biotin purification process
CN104710437A (en) * 2015-04-04 2015-06-17 富阳科兴生物化工有限公司 Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2489238A (en) * 1948-06-08 1949-11-22 Hoffmann La Roche Debenzylation of benzylated imidazolido-thiophane compounds
WO1998043979A1 (en) * 1997-03-27 1998-10-08 Merck Patent Gmbh Method for debenzylation of dibenzyl biotin
DE19962661A1 (en) * 1998-12-24 2000-06-29 Sumitomo Chemical Co Hexahydro-2-oxo-1H-thieno (3,4-d) imidazole-4-pentanoic acid preparation from benzylated analog using inexpensive sulfuric acid, used e.g. as food or feed additive

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
CN1142166C (en) * 2002-03-27 2004-03-17 复旦大学 Syhnthesis of d-biotin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2489238A (en) * 1948-06-08 1949-11-22 Hoffmann La Roche Debenzylation of benzylated imidazolido-thiophane compounds
WO1998043979A1 (en) * 1997-03-27 1998-10-08 Merck Patent Gmbh Method for debenzylation of dibenzyl biotin
DE19962661A1 (en) * 1998-12-24 2000-06-29 Sumitomo Chemical Co Hexahydro-2-oxo-1H-thieno (3,4-d) imidazole-4-pentanoic acid preparation from benzylated analog using inexpensive sulfuric acid, used e.g. as food or feed additive

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN F-E ET AL: "Synthetic Studies on d-Biotin, Part 6:An Expeditious and Enantiocontrolled Approach to the Total Synthesis of d-Biotin via a Polymer-Supported Chiral Oxazaborolidine-Catalyzed Reduction of meso-Cyclic Imide Strategy" SYNTHESIS 2003 GERMANY, no. 14, 2003, pages 2155-2160, XP002278550 ISSN: 0039-7881 *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2002, XP002278544 retrieved from STN Database accession no. 140:181254 & CN 1 374 312 A 16 October 2002 (2002-10-16) *
POPSAVIN VELIMIR ET AL: "An efficient synthesis of (+)-oxybiotin from D-arabinose" TETRAHEDRON LETTERS, vol. 43, no. 12, 18 March 2002 (2002-03-18), pages 2281-2284, XP002278543 ISSN: 0040-4039 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101195629B (en) * 2006-12-05 2010-05-19 浙江医药股份有限公司新昌制药厂 D-biotin purification process
CN104710437A (en) * 2015-04-04 2015-06-17 富阳科兴生物化工有限公司 Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation

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WO2004041830A3 (en) 2005-05-26

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