DESC:Field of the Invention:
The present application relates to a process for the preparation of 1-methyl-1Himidazole-
2(3H)-thione, which is known as Methimazole represented by the following
structural formula-1.
5
Formula-1
Background of the Invention:
Methimazole is a Sulfur-containing imidazole derivatives, is known as 1-methyl-1H10
imidazole-2(3H)-thione. It is used for the treatment of hyperthyroidism includes Graves
disease, toxic multinodular goiter, and thyrotoxic crisis.
Methimazole was approved in the United States in 1950, It is on the World Health
Organization's List of Essential Medicines, the safest and most effective medicines needed in
a health system, is available as a generic medication in Europe and Asia in 2017, it was the
244th 15 most commonly prescribed medication in the United States.
Its mechanism of action is to inhibit peroxidase in the thyroid, thereby hindering the
oxidation of iodide absorbed into the thyroid and the coupling of tyrosine, and hindering the
synthesis of thyroxine (T4) and triiodothyronine (T3). Animal experiments have observed
that it can inhibit the synthesis of antibodies by B lymphocytes, reduce the level of thyroid
20 stimulating antibodies in the blood circulation, and restore the function of suppressor T cells
to normal.
The J. Am. Chem. Soc., 71, 4000, (1949) reported the reaction of substituted amino
acetals with thiocyanate to prepare 2-mercapto-1-methylimidazole derivatives.
The US patent US2671088 (herein after referred as US’088) reported a process for
25 the preparation of methimazole by reacting 2-bromo-1, 1-diethoxyethane with methyl amine
and alkali thiocyanate such as potasium thiocyante in DMF.
The patent US’088 exemplified a process for the preparation of methimazole which
involves reacting bromoacetaldehyde diacetal with methylamine under pressure and high
3
temperature to give N-methyl aminoacetaldehyde diacetal, which is further reacted with
alkalithiocyanate to give 1-methyl thioimidazole.
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
5 longer time period and the reaction is incomplete, isolation of N-methyl aminoacetaldehyde
diacetal is very critical, which gives very poor yields.
The following is a schematic representation of the process described in the above patent for
the synthesis of methimazole.
10
Based on the prior art processes there are disadvantages for synthesis of
methimazole. Hence, there is a continuous need to develop an improved process for the
synthesis of methimazole, which is useful for commercial manufacturing with high yields
15 and purity.
The present application describes a process for the preparation of the compound of
formula-1.
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of
20 1, 3-Dihydro-1-methyl-2H-imidazole-2-thione the compound of formula-1.
The second aspect of the present invention is to provide crystalline Form of 1, 3-
Dihydro-1-methyl-2H-imidazole-2-thione compound of formula-1.
Brief description of the drawings:
25 Figure 1: Illustrates the PXRD pattern of crystalline Form of the compound of formula-1
according to example-2
Figure 2: Illustrates the IR spectrum of crystalline Form of the compound of formula-1.
Figure 3: Illustrates the DSC thermogram of crystalline Form of the compound of formula-1.
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, diisopropyl 30
5
ethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), Nmethyl
morpholine (NMM), or mixtures thereof.
The first aspect of the present invention is to provide a process for the preparation of
the compound of formula-1,
5
Formula-1
comprising of:
a) Hydrolysing the compound of formula-2
10 Formula-2
in presence of suitable reagents , 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,
wherein step-a) the suitable base is an inorganic base selected from sodium hydroxide,
15 potassium hydroxide, lithium hydroxide and mixture thereof;
Suitable solvents in step-a,b) are selected from ester solvents, chloro solvents, ether solvents,
nitrile solvents, polar solvents, alcohol solvents, dimethyl formamide, dimethyl sulfoxide,
water and mixture thereof;
wherein in step-a and b) the suitable temperature 0-100°C, Preferably 20-95°C.
20 Preferred embodiment of the present invention is to provide a process for the
preparation of the compound of formula-1:
Formula-1
25 comprising of:
a) Hydrolyzing the compound of formula-2
6
Formula-2
in presence of sodium hydroxide and water to provide the compound of formula-1,
b)refluxing the compound obtained in step-5 a) in isopropanol to provide crystalline form of
the compound of formula-1.
The process of the present invention can be represented schematically as follows:
10
The second aspect of the present invention is to provide crystalline Form of 1, 3-
Dihydro-1-methyl-2H-imidazole-2-thione the compound of formula-1.
The crystalline Form of the present invention is characterized by its powder X-Ray
diffraction pattern having 2-theta peaks at about 12.37, 13.26, 16.09, 16.36, 17.10, 17.57,
15 18.22, 18.50, 19.66, 20.58, 22.50, 24.120, 24.58, 24.81, 25.32, 26.62, 27.62, 27.86, 29.18,
30.67, 31.45, 32.15, 32.40, 34.48, 35.50, 37.54, 38.48, 39.47, 40.09, 40.32, 40.90 and 43.74 ±
0.2° 2? and further as depicted in figure-1. The crystalline Form of the present invention is
characterized by its IR spectrum and is further depicted in figure-2.
The other aspect of the present invention is to provide a process for the preparation of
20 crystalline Form of 1, 3-Dihydro-1-methyl-2H-imidazole-2-thione the compound of formula-
1. Comprising of
a) Suspending the compound of formaula-1 in a suitable organic solvent,
b) stirring the solution at a suitable temperature,
c) isolating the compound as pure crystalline form of compound of formula-1.
25
7
Wherein the suitable solvents are selected from ester solvents, chloro solvents, ether solvents,
nitrile solvents, polar solvents, alcohol solvents, dimethyl formamide, dimethyl sulfoxide,
water and mixture thereof; the suitable temperature 0-100°C, Preferably 20-95°C.
5 The other aspect of the present invention is to provide a process for the preparation of
the compound of formula-1 comprising of
Hydrolyzing the compound of formula-3 with suitable reagent, solvent to provide the
compound of formual-1.
Wherein the suitable base is an inorganic base selected from sodium hydroxide, potassium
10 hydroxide, lithium hydroxide and mixture thereof; the suitable solvents are selected from
ester solvents, chloro solvents, ether solvents, nitrile solvents, polar solvents, alcohol
solvents, dimethyl formamide, dimethyl sulfoxide, water and mixture thereof; the suitable
temperature 0-100°C, Preferably 20-95°C.
15
The process for the preparation of methimazole developed by the present inventors
produces highly pure methimazole with good yield. All the related substances and residual
20 solvents are controlled well within the limits as suggested by ICH guidelines and most of the
related substances are controlled in non-detectable levels.
The compound of formula-1 produced by the process of the present invention are
having chemical purity is greater than 99.5%, preferably greater than 99.7%, more preferably
greater than 99.9% by HPLC .
25
8
Methimazole and its polymorph produced by the present invention can be further 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 5 drying of the product.
PXRD analysis of methimazole 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. 10
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
15
Examples:
Example-1: Preparation of the compound of formula-1.
A round bottom flask was charged with compound of formula--2 (100 g) and water (450 mL) and slowly added sodium hydroxide (32.21 g in 50 mL of water) and stirred for 3 hr at 25--35°C. The reaction mixture was distilled off completely under vacuum under below 80°C. 20 Cooled the reaction mixture to 25--35°C, charged with dichloromethane (400 mL) and stirred for 40 min. Filtered the unwanted material and washed with dichloromethane (100 mL). Carbon (10 g) was charged to the filtrate solution and stirred for 30 min and filtered through hyflow bed and washed with dichloromethane (50 mL). The organic layer was distilled off completely, and charged with isopropanol (50 mL) and n--heptane (100 mL) at 25--35°C and 25 stirred for 30 min. Cooled the reaction mixture to 0--5°C, stirred for 45 min. Filtered the obtained solid and washed with a mixture of isoproponol (100 mL), n--heptane (100 mL) and dried to get the title compound.
Yield: 56.4 g.
30
9
Example--2: Preparation of crystalline Form of the compound of formula--1.
A round bottom flask was charged with the compound of formula-1 ( 100 g) and isopropyl alcohol (400 mL), heated to 75-85°C stirred for 45 min. Charged carbon (5 g) to the above solution and stirred for 15 min at same temperature. Filtered the solution through high flow and washed with isopropanol (100 ml) and distilled off completely. Further, the obtained 5 compound was charged with isopropanol (100 mL) and stirred for 50 min at 0-5°C, filtered the precipitated compound and washed with isopropanol (50 mL) and dried to get the title compound.
Yield: 99 g. Purity by HPLC: > 99 %
10
Example-3: Preparation of the compound of formula-1.
A round bottom flask was charged with compound of formula--2 (100 g) and water (450 mL) and slowly added sodium hydroxide (32.21 g in 50 mL of water) and stirred for 3 hr at 25--35°C. The reaction mixture was distilled off completely under vacuum under below 80°C. Cooled the reaction mixture to 25--35°C, charged with dichloromethane and stirred for 40 15 min. Filtered the unwanted material and washed with dichloromethane. Carbon (10 g) was charged to the filtrate solution and stirred for 30 min and filtered through hyflow bed and washed with dichloromethane. The organic layer was distilled off completely, and charged with isopropanol and stirred for 30 min. Cooled the reaction mixture to 0--5°C, stirred for 45 min and filtered the obtained solid and washed with a mixture of isoproponol and dried to get 20 the title compound.
Yield: 55 g. ,CLAIMS:We claim:
1. A process for the preparation of the compound of formula-1,
Formula-1
5 Comprising of:
a) Hydrolyzing the compound of formula-2
Formula-2
in presence of suitable reagents , solvent to provide the compound of formula-1,
10 b) optionally purifying the compound obtained in step-a) in a suitable solvents to provide the
compound of formula-1,
2. A process for preparation of compound of formula-1 according to claim 1 wherein step-a)
the suitable base is an inorganic base selected from sodium hydroxide, potassium hydroxide,
lithium hydroxide and mixture thereof;
15 3. A process for preparation of compound of formula-1 according to claim 1 Suitable
solvents in step-a and b) are selected from ester solvents, chloro solvents, ether solvents,
nitrile solvents, polar solvents, alcohol solvents, dimethyl formamide, dimethyl sulfoxide,
water and mixture thereof; the suitable temperature 0-100°C, Preferably 20-95°C.
4. A process for the preparation of the compound of formula-1:
20
Formula-1
comprising of:
a) Hydrolyzing the compound of formula-2
25
11
Formula-2
in presence of sodium hydroxide in water to provide the compound of formula-1,
b) refluxing the compound obtained in step-a) in isopropanol to provide crystalline form of
5 the compound of formula-1.
5. A process for preparation of crystalline form of compound of formula-1
a) Suspending the compound of formula-1 in a suitable organic solvent,
b) stirring the solution at a suitable temperature,
c) isolating the compound as pure crystalline form of compound of formula-1.
10 6. A process for preparation of compound of formula-1 according to claim 5 suitable solvents
are selected from ester solvents, chloro solvents, ether solvents, nitrile solvents, polar
solvents, alcohol solvents, acetone solvents, dimethyl formamide, dimethyl sulfoxide, water
and mixture thereof; the suitable temperature 0-100°C, Preferably 20-95°C.
7. A process for preparation of crystalline form of compound of formula-1
15 a) Suspending the compound of formula-1 in a isopropanol,
b) stirring the solution at 75-85°C for 1 hr,
c) isolating the pure crystalline form of compound of formula-1.