Claims:We claim:
1. A process for the preparation of the compound of formula-1
5 Formula-1
comprising of:
a) reacting the compound of formula-2,
Formula-2
10 with sulfur, ethylchloroformate, suitable base and solvent to provide the compound of
formula-1,
b) optionally purifying the compound obtained in step-a) using suitable solvent to provide
the compound of formula-1.
2. The process according to claim 1, wherein step-a) the suitable base is organic base is
15 selected from dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine,
diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl
morpholine (NMM); suitable solvent in Step-a) are selected from ester solvents, chloro
solvents, ether solvents, nitrile solvents, polar solvents, dimethylformamide,
dimethylsulfoxide or any mixture thereof; preferable solvent tetrahydrofuran;
20 wherein step-b) suitable solvents are selected from ester solvents, chloro solvents, ether
solvents, nitrile solvents, polar solvents, alcohol solvents, dimethylformamide,
dimethylsulfoxide or any mixture thereof; preferable solvent isopropanol;
3. The process according to claim 1 where in step-a) the suitable temperature is 0-40 °C; in
step-b) the suitable temperature is 0-100°C, Preferably 20-95°C.
25 4. A process for the preparation of the crystalline Form-1 of compound of formula-1 and
characterized by any of the following:
i) X-ray diffractogram having peaks at about 10.13, 12.48, 14.15, 18.25, 19.06, 20.27,
23.40, 25.20, 26.67, 27.11, 28.55, 28.85 and 30.76 ± 0.2° 2è or
10
ii) its powder X-Ray diffraction pattern substantially in accordance with that shown in figure-1; or
iii) its differential scanning calorimetric (DSC) thermogram shown in figure-3,
the process comprising:
a) stirring the compound of formula-1 in a suitable solvent, 5
b) stirring the reaction mixture at suitable temperature,
c) filtering the obtained solid in step-b) to provide the crystalline form-1 of compound of formula-1.
5. The process according to claim 5 wherein in step-a) the suitable solvent is selected from ester solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar 10 solvents, alcohol solvent, dimethylformamide, dimethylsulfoxide or any mixture thereof; preferable solvent isopropanol; in step-a & b) suitable temperature is 0-100°C, Preferably 20-95°C.
6. Use of crystalline Form-1 of ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate compound of formula-1 obtained according to any of preceding claims in the 15 preparation of pharmaceutical composition.
7. The pharmaceutical composition comprising 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole -1-carboxylate compound of formula-1 obtained according to any of preceding claims and a pharmaceutically acceptable carrier. , Description:Field of the Invention:
The present application relates to a process for the preparation of Ethyl 3-methyl-2-
thioxo-2,3-dihydro-1H-imidazole-1-carboxylate, which is known as Carbimazole represented
5 by the following structural formula-1.
Formula-1
10 Background of the Invention:
Carbimazole is a Sulfur-containing imidazole derivatives, is known as Ethyl 3-
methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate. It is used for the treatment of
hyperthyroidism.
Carbimazole is a prodrug of methimazole, which is responsible for antithyroid
15 activity of carbimazole. Methimazole is know as 1-methyl-1H-imidazole-2(3H)-thione is
approved drug for the treatment of antithyroid.
The patent US2815349 (herein after referred as US’349) first disclosed antithyroid
compunds such as ethyl-3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate and
20 preparation thereof.
The patent US’349 exemplified a process for the preparation of carbimazole which
involves reacting bromoacetaldehyde diacetal with methylamine under pressure and high
temperature to give N-methyl aminoacetaldehyde diacetal, which is further reacted with
alkalithiocyanate to give 1-methyl thioimidazole. The obtained 1-methyl thioimidazole is
25 reacted with ethylchloroformate in presence of pyridine to obtain carbimazole.
According to above said process, the reaction of bromoacetadehyde diacetal with
methyl amine involves a very high temperature and pressure in the reaction vessel. It requires
longer time period and the reaction is incomplete, which gives very poor yields
3
The following is a schematic representation of the process described in the above patent for
the synthesis of carbimazole.
5
Based on the prior art processes there are disadvantages for synthesis of carbimazole,
Hence, there is a continuous need to develop a improved process for synthesis of
carbimazole, which is useful for commercial manufacturing with high yields and purity.
The present application describes a process for the preparation of the compound of
10 formula-1 .
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of
the compound of formula-1.
The second aspect of the present invention is to provide crystalline Form of Ethyl 3-
15 methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate compound of formula-1,
designated as crystalline form-1.
The third aspect of the present invention is to provide process for the preparation of
crystalline Form-1 of carbimazole.
20 Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form-1 of compound of formula-1
according to example-2
Figure 2: Illustrates the IR spectrum of crystalline Form-1 of compound of formula-1.
Figure 3: Illustrates the DSC thermogram of crystalline Form-1 of compound of formula-1.
25 Figure 4: Illustrates the PXRD pattern of crystalline Form-1 of compound of formula-1
according to example -3
4
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet-ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” 5 such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as 10 dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as 15 methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof. 20
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal 25 alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, 30
5
diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The first aspect of the present invention is to provide a process for the preparation of
5 compound of formula-1,
Formula-1
10 comprising of:
a) Reacting the compound of formula-2
Formula-2
15
with sulfur, ethylchloroformate, in presence of suitable base and solvent to provide the
compound of formula-1,
b) optionally purifying the compound obtained in step-a) in a suitable solvents to provide
the compound of formula-1,
20 wherein step-a) the suitable base is an organic base selected from dimethylamine,
diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine,
pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM);
Suitable solvents in step-a) are selected from ester solvents, chloro solvents, ether solvents,
nitrile solvents, polar solvents, dimethylformamide, dimethylsulfoxide or any mixture
25 thereof; preferable solvent tetrahydrofuran;
wherein step-b) suitable solvents are selected from ester solvents, chloro solvents, ether
solvents, nitrile solvents, polar solvents, alcohol solvents, dimethylformamide,
dimethylsulfoxide or any mixture thereof; preferable solvent isopropanol;
6
wherein step-a) the suitable temperature 0-40°C and ; wherein step-b) the suitable
temperature is 0-100°C, Preferably 20-95°C.
Preferred embodiment of the present invention is to provide a process for the
preparation of the compound of formula-1 :
5
Formula-1
comprising of:
a) Reacting the compound of formula-2,
10
Formula-2
with sulfur, ethylchloroformate and triethylamine in tetrahydrofuran to provide the
compound of formula-1,
b) Purifying the compound obtained in step-a) using isopropanol to provide the compound
15 of formula-1.
The process of the present invention can be represented schematically as follows:
20
The second aspect of the present invention is to provide crystalline Form of ethyl 3-
methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate compound of formula-1, The
crystalline Form-1 of the present invention is characterized by its powder X-Ray diffraction
pattern having peaks at about 10.13, 12.48, 14.15, 18.25, 19.06, 20.27, 23.40, 25.20, 26.67,
25 27.11, 28.55, 28.85 and 30.76 ± 0.2° 2? and further it is depicted in figure-1. The crystalline
7
Form-1 of the present invention is characterized by its IR spectrum and is further depicted in figure-2.
The third aspect of the present invention is to provide process for the preparation of
crystalline Form-1 of compound of formula-1 5
a) stirring the compound of formula-1 in a suitable solvent,
b) stirring the reaction mixture at suitable temperature,
c) filtering the obtained solid in step-b) to provide the crystalline form-1 of compound of formula-1.
wherein step-a) the suitable solvent is selected from ester solvents, chloro solvents, ether 10 solvents, polar aprotic solvents, nitrile solvents, polar solvents, alcohol solvent, dimethylformamide, dimethylsulfoxide or any mixture thereof; preferable solvent isopropanol; wherein step-a & b ) the suitable temperature is 0-100°C, preferably 20-95°C.
Carbimazole and its polymorph produced by the present invention can be further 15 micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. 20
PXRD analysis of carbimazole was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
The process described in the present invention was demonstrated in examples 25 illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
30
8
Examples:
Example-1: Preparation of the compound of formula-1.
A round bottom flask was charged with tetrahydrofuran (1200 ml) and compound of formula-2 (200 gm), stirred for 30 mints. Cooled the reaction mixture to 0-10°C, added ethyl chloroformate (273.6 gm) and stirring was continued for 90 mints at same temperature. 5 Triethylamine (246.4 gm) was added to the reaction mixture at 0-10°C stirred for 3 hrs, followed by addition of Sulfur (78 gm) and stirred at 25-35°C for 22 hrs. Cooled the reaction mixture to 0-10°C and stirred for 1hr, the obtained solid was filtered and washed with tetrahydrofuran (200 ml). The obtained wet compound was charged with water (1000 ml), stirred for 60 mints at 25-35°C and filtered. The obtained compound washed with water (200 10 ml) and dried to get the title compound.
Yield: 289.79 gm.
Example-2: Preparation of crystalline Form-1 of the compound of formula-1.
A round bottom flask was charged with the compound of formula-1 ( 200 gm) and isopropyl 15 alcohol (2000 ml), heated to 75-85°C stirred for 45 min. Charged carbon (20 gm) to the above solution and stirred for 15 mints. The solution was filtered through high flow and washed with isopropanol (200 ml). The filtrate solution was cooled to 10-20°C and stirred for 60 mints. The obtained solid was filtered, washed with with isopropanol (100 ml) and dried to get the title compound. 20
Yield: 176.36 gm
Example-3: Preparation of crystalline Form-1 of the compound of formula-1.
A round bottom flask was charged with the compound of formula-1 ( 50 gm) and methanol (600 ml), heated to 50-60°C stirred for 30 min. Charged carbon (4 gm) to the above solution 25 and stirred for 25 mints. The solution was filtered through high flow and washed with methanol (60 ml). Cooled the filtrate solution to 10-20°C and stirred for 60 mints. Filtered the obtain solid , washed with methanol (40 ml) and dried to get the title compound.
Yield: 38.53 gm