Title of Invention

A PROCESS FOR THE PRODUCTION OF 2,4-DIAMINO-5-(3,4,5-TRIMETHOXYBENZYL) PYRIMIDINE OR TRIMETHOPRIM.

Abstract

A process for the preparation of 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim) comprising of 3 steps wherein step-1 in which dimethylamine (40%) is condensed with acrylonitrile, where in water is removed by addition of caustic soda flakes to get 3-dimethylamino propionitrile (adduct) and wherein step-2, the 3-dimethylamino propionitrile (adduct) from step-1 is condensed with 3,4,5-trimethoxybenzaldehyde in presence of PEG-600 and potassium methoxide to get 3-(dimethyl)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (adduct ester), wherein the said adduct ester is mixed with aniline and hydrolysed with sulfuric acid to get 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) and in step-3; wherein sodium methoxide in presence of methanol is reacted with guanidine nitrate to get guanidine in the solution; and where in the guanidine solution is reacted with 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) from step-2 to get 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine or trimethoprim.

Full Text

FORM 2 THE PATENT ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION ( See section 10 ; rule 13 ) Title of invention: A PROCESS FOR THE PRODUCTION OF TRIMETHOPRIM 2,4-diamino-5-ethoxy-(3,4,5- trimethoxybenzyl) pynimidine Applicant 1: SHALIL SHROFF Plot no. 645/646, Oberoi Chember II, 5lh Floor. New link road, Andh"eri west, Mumbai 400 053, Maharashtra state, INDIA Indian National Applicant 2:. JAIN PRAKASH Plot no. 645/646, Oberoi Chember II, 5,h Floor, New link road, Andheri west, Mumbai 400 053, Maharashtra state, INDIA Indian National The following specification describes the nature of this invention : FIELD OF INVENTION: This invention relates to a process for the preparation of Trimethoprim or 2,"4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine corresponding to the structural formula : PRIOR ART Trimethoprim namely: 2,4-diamino-5-(3,4,5- trimethoxybenzyl) pyrimidine is useful as antibacterial agents, particularly for tropical applications and is highly active against various germs, such as Proteus vulgaris and in combination with a sulphonamide represents a valuable medicament. European patent No. 0067593 describes a process for the preparation of Trimethoprim in the following three steps. Step-I Dimethyl amine is reacted with acrylonitrile in presence of catalyst hydrochloric acid and hydroquinone to get crude adduct after filtering and washing with water. The crude adduct is re-crystallized from ethyl alcohol-water mixture, filtered, and dried. The use of hydrochloric acid as catalyst, the washing of adduct with water for complete removal of HC1 poses problem. Besides, the crude adduct requires re-crystallization by alcohol-water mixture and there exists the chance of decomposition of adduct during drying. Step-2 3, 4, 5-Trimethoxy benzaldehyde is condensed with adduct (from step-1) and dissolved in Dimethyl sulphoxide and tert-butanol and hydrolysed with potassium tertiary butoxide. The butanol released is evaporated and the anilino compound is precipitated, filtered, washed and dried. The condensation reaction rate is slow due to the use of solvent dimethyl sulphoxide (DMSO)", and takes longer time to complete the reaction. The dimethyl sulphoxide (DMSO) solvent also poses the problem of efficient recovery. Step-3 Guanidine hydrochloride in ethanol is reacted with sodium methoxide to get guanidine and is further reacted with anilino compound (from step-2) to precipitate Trimethoprim, filtered and dried with overall yield of 83% (theory). The cyclisation rate in presence of Dimethyl amine is slow and requires longer time to complete. The reagent guanidine hydrochloride is not commercially easily available and is costly. OBJECTS OF INVENTION: An object of the present invention is to provide a process for the preparation of Trimethoprim which gives good yields and is economical.. Another object of the invention is to provide a process for the preparation of Trimethoprim which reduces the reaction time. Another object of the invention is to provide a process for the preparation of Trimethoprim which eliminates hazardous reagent and is safe to carry out. DESCRIPTION OF THE INVENTION According to the invention there is provided a process for the preparation of Trimethoprim comprising of the following three steps. Step-1 Dimethyl amine (40% solution) is condensed with acrylonitrile and water is removed by addition of caustic soda flakes to dry the 3-dimethylamino propionitrile (Adduct) formed. According to the invention, recrystallization with alcohol-water is eliminated and this improves the reaction to carry out in shorter time According to the invention, the adduct is dried with caustic soda flakes and removing water as an aqueous layer. This eliminates the degradation of adduct by drying at high temperature thereby improving the quality of the adduct. According to the invention, the catalyst is not required for condensation reaction. The use of catalyst HC1 and hydroquinone is eliminated, thereby reducing the handling and corrosion problem. Step-2 The 3-dimethylamino propionitrile (Adduct from step-1) is condensed with 3,4,5-trimethoxy benzaldehyde in the presence of PEG-600 and potassium methoxide to get the 3-(dimethylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (Adduct ester), mixed with Aniline and hydrolysed in presence of sulfuric acid to get 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound). According to the invention the use of PEG-600 helps in more porous structure for K+ ion capturing, resulting in faster reaction; is cheaper and eliminating the costlier use of dimethyl sulphoxide (DMSO).. According to the invention, the use of aniline to replace dimethylamine in acidic medium improves the rate of reaction. Step-3 Sodium methoxide is reacted with Guanidine nitrate in the presence of methanol to get guanidine in solution form and is further reacted with 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (Anilino compound) from step 2 to form 2.4-diamino-5-(3 A5-trimemoxybenzyl) pyrimidine (Trimethoprim)." According to the invention, the use of guanidine nitrate instead of guanidine hydrochloride improves the easy availability at a lesser cost to make the process economical. The following experimental examples are illustrative of the invention but not limitative of the scope there of. EXAMPLE 1. Step-1 Chemical reaction : 106 gm (2.0 moles) of acrylonitrile is added slowly over a period of 10.0 hrs into 2247.4 gm (2.2 moles) of dimethylamine (40% in water) at temperature between 8-l"2°C and maintained at 10°C for further 2.0 hrs. The reaction is carried out till acrylonitrile is less than 0.5% by G.C. The reaction mixture is then treated with 180 gm (4.5 moles) of caustic soda flakes with cooling to ambient temperature and allowed to settle. The organic layer contain 196.0 gm (2.0 moles) 3-dimethylanimo propionitrile (Adduct) is collected and aqueous layer is discarded. Step-2 147 gm (0.24 mole) PEG-600 is mixed with 152 gm (1.55 mole) of 3- dimethylamino propionitrile (adduct), 196 gm (1.0 mole) 3,4,5- trimethoxybenzaldehyde and 50 ml (0.054 mole) Potassium-methoxide solution in methanol, then heated to 80-90°C over a period of 6.0 hrs. The reaction is carried out till 3, 4,5-trimethoxybenzaldehyde is less than 0.5% by TLC, and the 3- (dimethylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile is cooled to room temperature. The 3-(dimethylamino)-2-(3,4.5-tTimethoxybenzy!) prop-2-enenilrile is mixed with 98 gm (1.04 mole) of aniline and hydrolysed with 15-160 gm 50% dilute sulfuric acid till pH-2.5-3.0 and heated to 80-90°C for 2.0 hrs. The mass is diluted with D.M water, cooled, filtered and the cake is washed several times with water till to pH-7.0 (neutral). Cake is dried under reduced pressure to get 294 gm dry 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (Anilino compound) 90.7% of theoretical: 183.2 ml (0.86 mole) sodium methoxide solution in methanol is reacted with 100 gm (0.82 mole) guanidine nitrate at 30-40°C over a period of 2.0 hrs. The mixture is filtered and washed with methanol. The filtrate containing Guanidine solution is collected. The guanidine solution in methanol is reacted with 162 gm (0.5 mole) of 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) and refluxed at 68-75°C over a period of 20-24 hrs. The reaction is carried out till anilino compound is less than 0.5%by TLC. The reaction mass is cooled, filtered and the cake is washed with 150,ml .chilled methanol to remove aniline. The cake mainly trimethoprim is washed with DM water till pH-7.0. Crude trimethoprim dissolved in 1000 ml DM water and 63.4 ml acetic acid to get clear solution at 80-90°C, and then added 4.Ogm activated carbon is added, filtered. Mother liquor is treated with ammonia solution "at 75-80°C till 1 pH-9.0 is achieved. Followed by cooling to ambient temperature, filtered and drying under reduced pressure to get pure 129 gm 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine or trimethoprim (yield 89.0% theoretical). EXAMPLE -2 Step-1 106 gm (2.0 moles) of acrylonitrile is added slowly over a period of 10.0 hrs into 2247.4 gm (2.2 moles) of dimethylamine (40% in water) at temperature between 10-15°C and maintained at 10°C for further 2.0 hrs. The reaction is carried out till acrylonitrile is less than 0.5% by G.C. The reaction mixture is then treated with 180 gm (4.5 moles) of caustic soda flakes with cooling to ambient temperature .and allowed to settle. The organic layer contain 196.0 gm (2.0 mole) 3-dimethylanimo propionitrile (adduct) is collected and aqueous layer is discarded. Step-2 147 gm (0.24 mole) PEG-600 is mixed with 152 gm (1.55 mole) of 3- dimethylamino propionitrile (adduct), 196 gm (1.0 mole) 3.4.5- trimethoxybenzaldehyde and 50 ml (0.054 mole) potassium-methoxide solution in methanol, then heated to 80-90°C over a period of 6.0 hrs. The reaction is carried out till 3, 4,5-trimethoxybenzaldehyde is less than 0.5% by TLC, and the 3- (dimethylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile is cooled to room temperature. The 3-(dimethylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitriIe is mixed with 98 gm (1.04 mole) of Aniline and hydrolysed 15-160 gm 50% dilute sulfuric acid till pH-2.5-3.0 and heated to 80-90°C for 2.0 hrs. The mass is diluted with D.M water, cooled, filtered and the cake is washed several times with water till pH-7.0 (neutral). Cake is dried under reduced pressure to get 294 gm dry 3-(phenylamino)-2-(3,4,5-trimethoxybenzyI) prop-2-enenitrile (anilino compound) 90.7% of theoretical. Step-3 183.2 ml (0.86 mole) sodium methoxide solution in methanol is reacted with 100 gm (0.82mole) Guanidine Nitrate at 35-45°C over a period of 2.0 hrs. The mixture is filtered and washed with methanol. The filtrate containing Guanidine solution is collected. The guanidine solution in methanol is reacted with 162 gm (0.5 mole) of 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) and refluxed at 68-75 °C over a period of 20-24 hrs. The reaction is carried out till anilino compound is less than 0.5% by TLC. The reaction mass is cooled, filtered and the cake is washed with 150 ml chilled methanol to remove aniline. The cake mainly trimethoprim is washed with DM water till pH-7.0. Crude trimethoprim dissolved in 1000 ml DM water and 63.4 ml acetic acid to get clear solution at 80-90°C and then added 4.0 gm activated carbon is added, filtered. Mother liquor is treated with ammonia solution at 75-80°C till pH-9.0 is achieved. Followed by A process for the preparation of 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim) comprising of 3 steps wherein step-1 in which dimethylamine (40%) is condensed with acrylonitrile, where in water is removed by addition of caustic soda flakes to get 3-dimethylamino propionitrile (adduct) and wherein step-2, the 3-dimethylamino propionitrile (adduct) from step-1 is condensed with 3,4,5-trimethoxybenzaldehyde in presence of PEG-600 and potassium methoxide to get 3-(dimethyl)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (adduct ester), wherein the said adduct ester is mixed with aniline and hydrolysed with sulfuric acid to get 3-(phenylamino)-2-(3,4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) and in step-3: wherein sodium methoxide in presence of methanol is reacted with guanidine nitrate to get guanidine in the solution ; and where in the guanidine solution is : reacted with 3-(phenylamino)-2-(3.4,5-trimethoxybenzyl) prop-2-enenitrile (anilino compound) from step-2 to get 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine or trimethoprim. A process as claimed in claim 1, wherein step-1. 2.0 mole of acrylonitrile is condensed with 2.2 mole of DMA to get 2.0 mole of 3-dimethylamino propionitrile (adduct) compound. A process as claimed in claim -2, where in the condensation process is carried out preferably between 8-15°C. A process as claimed in claim-1, wherein in step-2, 1.55 mole of 3- dimethylamino propionitrile (adduct) is condensed with 1.0 mole of 3,4,5- trimethoxybenzaldehyde in presence of 0.24 mole of PEG-600 and 0.054 mole of potassium methoxide to get 3-(dimethyl)-2-(3,4,5- trimethoxybenzyl) prop-2-enenitrile. A process as claimed in claim (1), wherein in step-2. 3-(dimethyi)-2-(3,4.5-trimethoxybenzyl) prop-2-enenitriIe (adduct ester) is mixed with 1.04 mole of aniline and hydrolysed by 0.5 mole of sulfuric acid to get 0.907 mole of 3-(phenylamino)-2-(3,4.5-trimethoxybenzyl) prop-2-enenitrile (anilino compound). 6. A process as claimed in claim (4) wherein the reaction temperature is kept preferably between 80-90°C. 7. A process as claimed in claim (5) wherein the pH is kept, preferably between 2.5-3.0. 8. A process as claimed in claim (1) wherein step - 3, sodium methoxide is reacted with guanidine nitrate reaction temperature is kept preferably between 30-45°C. 9. A process as claimed in claim (1) wherein the yield of trimethoprim is 89% (theory).

Documents:

86-mum-2005-cancelled page(28-12-2005).pdf

86-mum-2005-claims(granted)-(28-12-2005).doc

86-mum-2005-claims(granted)-(28-12-2005).pdf

86-mum-2005-correspondence(28-12-2005).pdf

86-mum-2005-correspondence(ipo)-(30-10-2006).pdf

86-mum-2005-form 1(28-01-2005).pdf

86-mum-2005-form 18(09-03-2005).pdf

86-mum-2005-form 2(granted)-(28-12-2005).doc

86-mum-2005-form 2(granted)-(28-12-2005).pdf

86-mum-2005-form 2(provisional)-(28-12-2005).pdf

86-mum-2005-form 3(28-01-2005).pdf

86-mum-2005-form 9(09-03-2005).pdf