|Title of Invention||
NOVEL PROCESS FOR SYNTHESIS OF 3-(2-THIENYL THIO) BUTYRIC ACID"
|Abstract||Disclosed herein is a Process for one- pot synthesis of 3 - (2-Thienyl thio) butyric acid comprises reaction of Thiophene with n-Buty1 Lithium and Sulphur in etherial solvent to obtain 2-Mercapto Thieny1 Lithium which is reacted with Crotonic acid by Micheal reaction to obtain the title product.|
|Full Text||FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
(See section 10 and rule 13)
TITLE OF THE INVENTION: "Novel Process for Synthesis of 3-(2-Thienyl
thio) butyric acid"
(a) NAME: BAKUL FINECHEM RESEARCH CENTRE
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: Sterling Centre, 4th Floor, 16/2, Dr. Annie Besant Road, Worli, Mumbai - 400 018. Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.
The present invention relates to novel in-situ preparation of useful key intermediate of dorzolamide. The present invention particularly relates to process for preparation of 3-(2-thienyl thio) butyric acid from Thiophene. The present invention further relates to the resolution of racemic 3-(2-Thienyl thio) butyric acid by using suitable resolving agent.
Background and prior art:
Glaucoma is an ocular disorder associated with elevated intraocular pressures in the eye. This is caused by an imbalance between the formation of liquid substance in the eye and its absorption, or drainage out of the eye. Eventually, if the pressure builds up too much, the blood vessels of optic nerve become damaged. This can result in irreversible damage to the nerve and reduction in vision or even blindness. There are five main types of drugs used in the treatment of glaucoma -miotics, beta-blockers, sympathomimetic agents, carbonic anhydrase inhibitors, and latanoprost. Most of these drugs are applied directly into the eye in the form of drops, although there are a few drugs that are taken by mouth.
Dorzolamide is a generic name given to a chemical (4S-trans)-4-(ethylamino)5,6-dihydro-6methyl-4H-thieno[2,3b]thiopyran-2-sulfamide 7, 7-dioxide having the following structural formula.
Dorzolamide is a carbonic anhydrase inhibitor formulated for topical ophthalmic use and was first disclosed in US4797413 under thieno thiopyran sulfonamide derivatives. Carbonic anhydrase plays a key role in controlling the production of fluid particularly
within the eye. In turn, the amount of fluid within the eye determines the intraocular pressure within the eye. Dorzolamide blocks this enzyme, carbonic anhydrase, and is used as eye drops in the treatment of glaucoma, a condition in which the fluid and pressure in the eye is increased.
3-(2-thienyl thio) butyric acid is a key intermediate in the preparation of Dorzolamide. According to the teachings of this patent racemic modification of the 3-(3-mercaptothiophene)-3-methylpropionic acid and its homologs were prepared by the addition of 2-Mercapto thiophene and substituted acrylic acid in presence of Triethylamine and THF.
US4968815discloses a process for preparation of chiral alkyl 3(thien-2-ylthio) butyric acid. The patented process reports the condensation of thenyl-2-thiol with a chiral propiolactone in an ethereal solvent in presence of base at a temperature of 10-40°C.
Condensation of thienyl-2-thiol with (R)-3-(p-toluenesulfonyloxy) butyrate a chiral alkonte having a leaving group at 3-position to prepare methyl (S)-3-(2-Thienylthio) butyrate was disclosed in US4968814. Methyl (S)-3-(2-Thienylthio) butyrate was further hydrolyzed to get (S)-3-(2-thienylthio) butyric acid. The starting compound chiral C4-C7 alkanoate was prepared by reacting methyl (R) -3-hydroxy butyrate in pyridine with p-toluene sulphonyl chloride at 0°C for 24 hrs. However, the whole process involves multiple steps, is cumbersome and time consuming.
It is therefore an objective of the present invention to provide a simple in-situ one pot synthesis for preparation of 3-(2-Thienyl thio) butyric acid with good yields. The one-pot reaction includes the preparation of Lithium Thiophene-2-Thiolate of formula III; which is also prepared in situ by Thiophene, BuLi and Sulphur further reacted with crotonic acid by Micheal addition in-situ to obtain racemic 3(2-thienyl thio) butyric acid (IV). This racemate, 3-(2-Thienyl thio) butyric acid is further resolved by using suitable resolving agent.
Summary of the invention:
The present invention is concerned with simple insitu synthesis for preparation of 3-(2-thienyl thio) butyric acid of formula IV with good yields. The instant process reduces the reaction to a single batch process and avoids further decomposition of thiophene-2-thiolate lithium arid its dimmer formation.
In the process of the present invention, Thiophene is reacted with n-butyl lithium in tetrahydrofuran under N2 atmosphere at a temperature -5C to 0°C. Powdered Sulphur is added to this reaction mixture at -10°C stirred at -5 to 0°C for 2 hours to obtain a Lithium Thiophene-2-Thiolate (III) in the reaction mixture. The reaction mixture is diluted with Formamide /water and treated with Crotonic acid to yield 3-(2-Thienyl thio) butyric acid in racemic form. After adjusting the pH with Con HCl, extracted with Ethylacetate and distilled under high vacuum to obtain the title product. The present invention further discloses the resolution of racemic 3-(2-Thienyl thio) butyric acid by using suitable resolving agent.
Detailed description of the invention:
In the present invention, there is provided a process for synthesis of 3-(2-Thienyl thio) butyric acid of formula IV in good yields. Thiophene was reacted with n-Butyl Lithium in Tetrahydrofuran under N2 atmosphere at a temperature -5C to 0°C to form 2-Thienyl Lithium (II). Powdered Sulphur was added to this reaction mixture at -10°C stirred at -5 to 0°C for 2 hours to obtain a Lithium Thiophene-2-Thiolate (III) in the reaction mixture. The reaction mixture was diluted with Formamide /water and treated with Crotonic acid at room temperature to yield racemic 3-(2-Thienyl thio) butyric acid (IV).
In a preferred embodiment of the present invention, the nucleophile compound Lithium thiophene-2-thiolate which also formed insitu by reaction of Thiophene, BuLi and Sulphur formula III was reacted with Crotonic acid in a mixture of ethereal solvent and water.
In another preferred embodiment, formula III was reacted with Crotonic acid in a mixture of ethereal solvent and Formamide. The reaction was carried out at room temperature under stirring for 12-20 hrs.
The process of the present invention can be depicted as shown in scheme below.
The present invention is further illustrated with the following examples.
To a solution of 14 gm Thiophene (0.166 mol) in 140 ml anhydrous THF, 120 ml n-Butyl Lithium in Hexane (0.193 mol, 1.6 molar solution)was added under nitrogen, maintaining temperature -5 to 0°C for 30 minutes. To this reaction mass Sulphur powder 5.1 gm (0.159 mol) was added at -10°C stirred at -5 to 0°C for 2 hours. This reaction mixture was diluted with Formamide (250 ml) followed by Crotonic acid 18 gm (0.20 mol) and stirred, for 18 hours at RT. The progress of reaction was monitored by TLC/GC. Ethyl Acetate 60 ml and HCl (3N ; 50 ml) was added and extracted in Organic layer.
After removal of solvent, 3-2(Thienyl thio) butyric acid was distilled, 9 gm.(26.5 %; yield) under high vacuum
To a solution of 14 gm Thiophene (0.166 mol)in 150 ml anhydrous THF, 120 ml n-
Butyl Lithium (0.193 mol 1.6 molar solution) was added at -10°C and stirred for 45
minutes at -5 to -10°C. Sulphur powder was added (5.5 gm ; 0.17 mol) and stirred for 3
hours at -5° to 0°C. Reaction mixture was diluted with Water (35 ml). Crotonic acid (15
gm 0.17 mol) was added and reaction was stirred for 12 hours at RT. Organic layer was
separated and aqueous layer was extracted with Ethyl Acetate (20 ml) after treatment of
Conc. HCl 25 ml.
3-(2-Thienyl thio) butyric acid was distilled 16 gm (47% yields) at high vacuum,
identified by NMR; its assay was 80% by GC and HPLC.
Dated this 11th day of July 2005
|Indian Patent Application Number||830/MUM/2005|
|PG Journal Number||08/2013|
|Date of Filing||11-Jul-2005|
|Name of Patentee||BAKUL FINECHEM RESEARCH CENTRE|
|Applicant Address||STERLING CENTRE, 4TH FLOOR, 16/2,ANNIE BESANT ROAD, WORLI.|
|PCT International Classification Number||C07D445/04|
|PCT International Application Number||N/A|
|PCT International Filing date|