FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL AND ONE POT PROCESS FOR THE
PREPARATION OF BIS(3-METHYL-2-
THIENYL)METHANONE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAIDESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.


A NOVEL AND ONE POT PROCESS FOR THE
PREPARATION OF BIS(3-METHYL-2-
THIENYL)METHANONE
TECHNICAL FIELD
The present invention relates to a novel and one pot process for the preparation of bis(3-methyl-2-thienyl)methanone, an important intermediate needed in the synthesis of a potent anticonvulsant drug tiagabine hydrochloride.
BACKGROUND OF THE INVENTION
Chemically, tiagabine hydrochloride is (R)-l-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-
piperidinecarboxylic acid hydrochloride and is disclosed in US5010090 (Novo Nordisk,
Oct. 7, 1988). Tiagabine hydrochloride is an amino acid derivative exhibiting GABA (y)-
aminobutyric acid, a neurotransmitter in the central nervous system) uptake inhibitory
properties.
Tiagabine is represented by the following formula (I).

(I)
In prior art tiagabine hydrochloride is prepared by using a key chemical compound viz.
bis(3-methyl-2-thienyl)methanone, represented by the following formula (II),



However the literature search reveals that there are very few methods reported for the synthesis of bis(3-methyl-2-thienyl)methanone.
Tetrahedron Letters, (Uri Michael, et. al.; 1970), 60, 5219-5222, discloses the synthesis of bis(3-methyl-2-thienyl)methanone by a reaction between (3-methyl-2-thienyl)lithium and carbamic acid derivatives of formula R1R2NCOX (where Rl and R2 are alkyl groups; X is OET, OPh, SEt or CI). However in this reaction a side product viz. N,N-dialkyl-3-methyl-2-thienylcarboxamide is also formed, further the isolation of the required product is also difficult.
J. Med. Chem., (Lars J. S. Knutsen, et al; 1993), 36, 1716-1725, discloses the synthesis of bis(3-methyl-2-thienyl)methanone by a reaction between 3-methyl-2-thiophene magnesium bromide and 3-methylthiophene-2-carboxaldehyde to afford bis(3-methyl-2-thienyl)methanol, which is further oxidized with magnesium dioxide. However this reaction involves use of costly 3-methylthiophene-2- carboxaldehyde.
Thus in the light of the above prior art, an improved and cost effective method for the synthesis of bis(3-methyl-2-thienyl)methanone is highly desired.
The present invention provides a novel method for the synthesis of bis(3-methyl-2-thienyl)methanone, which is cost effective and the final product is obtained with good purity and it is free of side products and thus advantageous over prior art processes.
OBJECT OF THE INVENTION
The object of the present invention is to provide a one pot, scalable, short and effective process for the preparation of bis(3-methyl-2-thienyl)methanone.


SUMMARY OF THE INVENTION
Accordingly the present invention provides a one pot, scalable, short and effective process for the preparation of bis(3-methyl-2-thienyl)methanone, of formula (II), an important intermediate needed for the synthesis of a potent anticonvulsant drug tiagabine hydrochloride.

(II)
The one pot, scalable, short and effective process for the preparation of bis(3-methyl-2-thienyl)methanone, of formula (II), comprises the steps of:



a) reacting the compound of formula (III) with magnesium metal in a solvent to afford insitu corresponding Grignard complex of formula (IV); and

b) reacting the in-situ formed complex of formula (IV) in the same vessel with BTC {bis-(trichloromethyl)carbonate} to afford the bis(3-methyl-2-thienyl)methanone, of formula (II).


DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a one pot, scalable, short and effective process for the preparation of bis(3-methyl-2-thienyl)methanone, an important intermediate needed for the synthesis of a potent anticonvulsant drug tiagabine hydrochloride.
According to the present invention, the said process for the preparation of bis(3-methyl-2-thienyl)methanone involves treating 2-bromo-3 -methyl thiophene with magnesium metal in a solvent optionally in the presence of an initiator. After the in-situ formation of the corresponding Grignard intermediate, a solution of bis(3-methyl-2-thienyl)methanone (BTC) in a solvent is added.
The process according to the present invention, wherein the said solvent used is an organic solvent selected from the group consisting of tetrahydrofuran (THF), methyl tert-butyl ether, 1,4-dioxane, di-isopropyl ether, benzene, toluene or xylene; preferably the solvent used is THF.
The process according to the present invention, wherein the reaction is carried out optionally in the presence of an initiator, wherein the initiator used is iodine crystal or UV light; preferably the initiator used is iodine crystal.
The said process for the synthesis of bis(3-methyl-2-thienyl)methanone, wherein the solution of BTC in tetrahydrofuran is added at a temperature of 0 to 30°C, preferably at 10 to 15°C, and the said reaction is completed within 0.5 to 2 hours, preferably within an one hour.
After completion of the reaction, the final product is worked up in usual manner. The final product i.e. bis(3-methyl-2-thienyl)methanone is obtained in good yield and good purity.


Thus the said process for the preparation of bis(3-methyl-2-thienyl)methanone according to the present invention has the several advantages such as the process according to present invention is one pot, scalable, short and cost effective process as it reduces the time required for the completion of the reaction and number of steps; and provides the final product with good purity and free from any side products.
The starting material viz. 2-bromo-3-methyl thiophene, the compound of formula (III), can be easily prepared from the readily available 3-methyl thiophene by a procedure described in the literature (J. Org. Chem., (1968), 33(7), 2902-2909).
Further and other modifications of the invention will be realized by those skilled in the art from the summary of the invention and the detailed description of the embodiments thereof.
EXAMPLE
The following example is presented for illustration only, and is not intended to limit the scope of the invention or appended claims.
Bis(3-methyl-2-thienyl)methanone (II):
To a 100ml round bottom flask magnesium turnings (0.66g, 0.027 mole) were charged under a nitrogen atmosphere. Then 1-2 small iodine crystals and tetrahydrofuran (2 ml) were successively charged to the reaction vessel and the reaction mixture was stirred for 10 min. Then a solution of 2-bromo-3-methyl thiophene (5g, 0.0280 mole) in tetrahydrofuran (15 ml) was slowly added to the reaction mixture in about 10 min. and the reaction mixture was further stirred for 45 min. Reaction mixture was then cooled to 10-15°C and a solution of BTC (1.25g, 0.004 mole) in tetrahydrofuran (15 ml) was slowly added to the reaction mixture in about 30 min. After the completion of the addition, the reaction mixture was further stirred for 60 min. The reaction progress was monitored by TLC (thin layer chromatography). On reaction completion, reaction


mixture was quenched with saturated ammonium chloride solution below 10°C. It was further acidified with dilute sulphuric acid and then extracted using methylene dichloride. The methylene dichloride layer was separated and washed using saturated potassium carbonate solution followed by brine. Finally the methylene dichloride layer was dried over anhydrous sodium sulphte. Methylene dichloride was then removed under the reduced pressure to afford an oily compound, bis(3-methyl-2-thienyl)methanone, 2.2g, 70% yield. [M+l]+ is 223; IR (cm-1) 1620;
PMR (CDCl3) 5 2.45 (s, 6H), 6.90 (d, 2H), 7.40 (d, 2H).


We Claim:
1. A one pot process for the preparation of bis(3-methyl-2-thienyl)methanone, of formula
(II), comprising the step of
a) reacting 2-bromo-3 -methyl thiophene of formula (III)

with magnesium metal in a solvent to afford an in-situ Grignard complex of formula (IV); and



b) reacting the said in-situ formed Grignard complex with BTC {bis-
(trichloromethyl)carbonate}.
2. The one pot process as claimed in claim 1, wherein the solution of BTC in solvent is added to the Grignard complex at temperature 0 to 30°C, preferably at 10 to 15°C.
3. The one pot process as claimed in claim 1, wherein the said reaction is completed in 0.5 to 2 hours, preferably in about one hour.
4. The one pot process as claimed in claim 1, wherein the said solvent is selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, di-isopropyl ether, benzene, toluene or xylene.
5. The one pot process as claimed in claims 1 and 4, wherein preferably the solvent used is tetrahydrofuran.


6. The one pot process as claimed in claim 1, wherein the said in-situ Grignard complex of formula (IV) is formed, optionally in the presence of an initiator.
7. The one pot process as claimed in claim 6, wherein the said initiator is Iodine or UV light.
8. The one pot process as claimed in claims 6 and 7, wherein preferably the said initiator is Iodine crystal.
9. A one pot process substantially as herein described.
10. A process for the preparation of compound of formula (II), substantially as herein
described and illustrated with reference to the accompanying examples


ABSTRACT:
The present invention relates to a novel and one pot process for the preparation of bis(3-methyl-2-thienyl)methanone an important intermediate needed for the synthesis of a potent anticonvulsant drug tiagabine hydrochloride from 2-bromo-3-methyl thiophene.