DESC:FIELD OF THE INVENTION

The present invention relates to a process for preparation of 2-Bromo-2’,5’ Dimethoxyacetophenone of formula I as an intermediates of Midodrine hydrochloride. The present invention further relates to a process for the preparation of 2-Bromo-2’,5’ Dimethoxyacetophenone of formula I by acetylation reactions 1,4-Dimethoxy Benzene in presences of Acetyl Chloride and further brominating 2,5-Dimethoxy Acetophenone to 2-Bromo-2’,5’ Dimethoxyacetophenone of formula I

BACKGROUND OF THE INVENTION

Midodrine is classified as an antihypotensive drug. It was first described and claimed in the U.S. Pat. No. 3,340,298 The method of preparation taught in U.S. Pat. No. '298 is based on a conventional amidation reaction in which the aminoethanol derivatives of formula 3 are reacted with protected aminoacids or aminoacid derivatives of formula 4 in the presence of N,N'-dicydohexylcarbodiimide (DCC) to form an amide bond. The obtained intermediates of formula are then deprotected by hydrogenation under pressure in acetic acid to yield after treatment with hydrochloric acid, Midodrine Hydrochloride in very low overall yields of 30-40%.

Midodrine hydrochloride is an excellent drug with reliable efficacy and safe use for the treatment of orthostatic hypotension and urinary incontinence.
Its biggest feature is that it can raise standing blood pressure and improve the symptoms of hypotension without any side effects of exciting the heart.
Midodrine hydrochloride has a good effect on stress urinary incontinence, and because it does not enter the brain or nervous system from the bloodstream, its side effects are lower than other urinary incontinence treatment drugs.

The chemical name of Midodrine Hydrochloride is 2-amino-N-[2-(2.5-dimethoxybenzene)-2-hydroxyethyl]acetamide hydrochloride.

Among them, 2-Bromo-2’5’-Dimethoxy Acetophenone is an important intermediate for preparing Midodrine Hydrochloride.

One is to prepare 2-amino-1(2.5-dimethoxybenzene)-ethanol by nitrification and reduction of 2.5-dimethoxybenzaldehyde as a raw material (reference: Azchphorm 1975: 308 339-346).

This method not only uses very toxic sodium cyanide, but also uses expensive lithium aluminum hydride with harsh reaction conditions and a large amount of flammable and explosive ether. The obtained product needs to be separated and purified by column chromatography, which cannot be adapted. Large-scale industrial production.

Thus, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure 2-Bromo-2’5’-Dimethoxy Acetophenone in high yields. The preparation method of the present invention has the advantages of moderate reaction condition, strong exclusivity for generating byproduct, high yield, low cost of raw materials, etc. The present invention is a new method for large-scale industrial production.

SUMMARY OF THE INVENTION
Accordingly, in one aspect, present invention provides an improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I

Comprises:
a) Alkylation reaction of 1,4-Hydroqinone compound of formula-II with Dimethyl Sulfate in presence base and solvent of to obtain 1,4-Dimethoxy Benzene compound of formula III;

b) Acetylation reactions of 1,4-Dimethoxy Benzene compound of formula III with Acetyl Chloride in presences of Aluminum chloride and solvent to obtain 2,5-Dimethoxy Acetophenone compound of formula IV;

c) Brominating the 2,5-Dimethoxy Acetophenone compound of formula IV with brominating agent and solvent to obtain 2 -Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I;

In another aspect, 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I is used for the preparation of Midodrine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms below have the meanings indicated.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

In the first embodiment the present invention provides an improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I

comprises:
a) Alkylation reaction of 1,4-Hydroqinone compound of formula-II with Dimethyl Sulfate in presence base and solvent of to obtain 1,4-Dimethoxy Benzene compound of formula III;

b) Acetylation reactions of 1,4-Dimethoxy Benzene compound of formula III with Acetyl Chloride in presences of Aluminum chloride and solvent to obtain 2,5-Dimethoxy Acetophenone compound of formula IV;

c) Brominating the 2,5-Dimethoxy Acetophenone compound of formula IV with brominating agent and solvent to obtain 2 -Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I;

According to the embodiment of the present invention, there is provided a process for the preparation of 1,4-Dimethoxy Benzene compound of formula III by Alkylation reaction of 1,4-Hydroqinone compound of formula-II with Dimethyl Sulfate in presence base and solvent of to obtain 1,4-Dimethoxy Benzene compound of formula III;

The reaction is preferably conducted in solvent or a mixture of solvents selected from the group consisting of acetonitrile, benzonitrile, ethyl acetate, alcohols such as methanol, ethanol, and isopropanol, carboxylic acids, and ketones such as methyl ethyl ketone, dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

The reaction is preferably conducted in presences of base selected from the group consisting sodium hydroxide, Potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.

According to the embodiment of the present invention, there is provided a process for the preparation of Acetylation reactions of 1,4-Dimethoxy Benzene compound of formula III with Acetyl Chloride in presences of Aluminum chloride and solvent to obtain 2,5-Dimethoxy Acetophenone compound of formula IV;

The reaction is preferably conducted in solvent or a mixture of solvents selected from the group consisting of acetonitrile, benzonitrile, ethyl acetate, alcohols such as methanol, ethanol, and isopropanol, carboxylic acids, and ketones such as methyl ethyl ketone, dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

According to the embodiment of the present invention, there is provided a process for the preparation of Brominating the 2,5-Dimethoxy Acetophenone compound of formula IV with brominating agent and solvent to obtain 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I;

The solvents used in step of the bromination are polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane or mixtures thereof. These solvents are liquid at room temperature and preferably have a boiling point of 35°C to 130°C, more preferably 50°C to 100°C and in particular of 75°C to 85°C.

Brominating agents are selected from but not limited to phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide; Br2; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N-bromosuccinimide (NBS) or mixtures thereof.

In the process of the present invention the bromination agent is added to a solution of 2,5-Dimethoxy Acetophenone compound of formula IV in a solvent and chilled to 0°C to 25°C. During the addition of the bromination agent the mixture is preferably kept at a temperature within the range of 0°C to 25°C. After the addition of the bromination agent is completed the reaction mixture is preferably stirred for an additional time period of few minutes to 5 to 50 hours maintaining temperature between 0°C to 25°C. The crude product 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I is purified by recrystallization in presences of organic solvent such as methanol, ethanol, propanol, butanol, diethylether, di-isopropylether, methyl tert-butyl ether or mixture thereof.

The resulting mixture is concentrated and the product obtained is dried to obtain highly pure 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I having purity greater than 99.2% preferably greater than 99.9%.

The above process can be represented stepwise as shown below:

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
EXAMPLE 1: Preparation of 1, 4-Dimethoxy Benzene

110.11 gm, 1.0 mole 1, 4-Hydroqinone was added to 440 ml Toluene and 220 ml Water. The reaction mass was heated at 55 to 60°C. In the reaction mass drop wise addition of 200 gm ,5.0 mole Sodium Hydroxide solution +200 ML Water solution and 504 gm ,4.0 mole Dimethyl Sulfate for 2- hrs at 55 to 60° C, after addition the reaction mass was maintained for 4-hrs at reflux temperature. The reaction mass was allowed to cool at 55 to 60°C. Then 440 ml Water was charged. The reaction mass was maintained for 1-hrs at 55 to 60°C. Layer was separated and extracted with 220 ml Toluene, layer in aqueous layer was separated. To the reaction mass add 10 gm, 0.025 mole Sodium Hydroxide + 220 ml Water in organic layer, Organic layer was separated. Organic layer was distilled out completely to give 1,4-Dimethoxy Benzene. Dry (wt ;-127 gm)
Yield : -92.27%, (yield : -92%, purity by GC :- 99.50 %

EXAMPLE 2: Process of Preparation of 2,5-Dimethoxy Acetophenone

After taking 138.16 g, 1.0 mole 1,4-Dimethoxy Benzene was added to 552 ml Dichloromethane. Chilled to 10 to 15° C. charged 160.65 gm,1.20 mole Aluminum chloride .Stirred for 30 min at 10 to 15° C. Drop wise addition of 96.40 gm,1.23 mole Acetyl Chloride for 3- hrs at 10 to 15° C. Stirred for 1-hrs at 10 to 15° C. Dumping reaction mass in 276 g ice and 276 g water. Stirred for 1-hrs at 20 to 30° C. Layer separation. Organic layer was distilled out completely to give 2,5-Dimethoxy Acetophenone. Crude (wt :165.7 gm) Yield : 91-%, purity by GC:- 98.10 %

EXAMPLE 3: Process of Preparation of 2 -Bromo- 2’,5,-Dimethoxy Acetophenone

Take 180.20 g, 1.0 mole 2,5-Dimethoxy Acetophenone with 810 ml Methanol. The reaction mass was chilled to 0 to 10°C and a clear solution is obtain. 161.09g, 1.01 mole Bromine was added drop for 3- hrs at 0 to 10°C and stirred for 3- hrs at 0 to 10° C . The reaction mass was filtered, chilled and washed with 25 ml methanol twice. The reaction mass was dried at 40 to 50° C to give 2-Bromo- 2’,5,-Dimethoxy Acetophenone (Wt : 208 gm) Yield: 80%, purity by GC:- 98.50 %

EXAMPLE 4: Process of Purification of 2 -Bromo- 2’,5,-Dimethoxy Acetophenone

2-bromo- 2’,5,-dimethoxy acetophenone Tech(208 gm) was added to 832 ml Methanol. Heating was carried out to reflux. After obtaining clear solution it was allowed to cool at room temperature. The reaction mass was chilled at 5 to 10°C. The reaction mass was filtered and chilled and further washed with 25mlmethanol twice. It was dried at 40 to 50°C to give pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone (Wt: 191.36 gm)
Yield: 92%, purity by GC: - 99.10 %
,CLAIMS:CLAIMS
We Claim,
1. An improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I

Comprises:
d) Alkylation reaction of 1,4-Hydroqinone compound of formula-II with Dimethyl Sulfate in presence base and solvent of to obtain 1,4-Dimethoxy Benzene compound of formula III;

e) Acetylation reactions of 1,4-Dimethoxy Benzene compound of formula III with Acetyl Chloride in presences of Aluminum chloride and solvent to obtain 2,5-Dimethoxy Acetophenone compound of formula IV;

f) Brominating the 2,5-Dimethoxy Acetophenone compound of formula IV with brominating agent and solvent to obtain 2 -Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I;

2. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, solvent is selected from the group consisting of acetonitrile, benzonitrile, ethyl acetate, methanol, ethanol, and isopropanol, carboxylic acids, methyl ethyl ketone, dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, or dioxane or mixtures thereof.

3. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, base is selected from the group consisting sodium hydroxide, Potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.

4. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, Brominating agents are selected from but not limited to phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide; Br2; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N-bromosuccinimide (NBS) or mixtures thereof.

5. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, process for the preparation of 1,4-Dimethoxy Benzene compound of formula III by Alkylation reaction of 1,4-Hydroqinone compound of formula-II with Dimethyl Sulfate in presence base and solvent of to obtain 1,4-Dimethoxy Benzene compound of formula III;

6. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 5 wherein, solvent is selected form dimethylsulfoxide, tetrahydrofuran, dimethylformamide, toluene, methanol, water or mixtures thereof.

7. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 5 wherein, base is selected from the group consisting sodium hydroxide, Potassium hydroxide.

8. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, process for the preparation of Acetylation reactions of 1,4-Dimethoxy Benzene compound of formula III with Acetyl Chloride in presences of Aluminum chloride and solvent to obtain 2,5-Dimethoxy Acetophenone compound of formula IV;

9. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 8 wherein, solvent is selected form chloroform, dichloromethane, carbon tetrachloride toluene, methanol, water or mixtures thereof.

10. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, process for the preparation of Brominating the 2,5-Dimethoxy Acetophenone compound of formula IV with brominating agent and solvent to obtain 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I;

11. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 10 wherein, the solvents used the bromination are selected form acetone, DMF, acetonitrile, DMSO, sulfolane, methanol, ethanol, propanol, butanol, methylene chloride, chloroform, monochlorobenzene, ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane or mixtures thereof.

12. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 10 wherein, solvents are liquid at room temperature and preferably have a boiling point of 35°C to 130°C, more preferably 50°C to 100°C and in particular of 75°C to 85°C.

13. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 10 wherein, Brominating agents are selected from but not limited to phenyltrimethyl ammoniumtribromide; dibromodimethylhydantoin (DBDMH); potassium bromide; Sodium bromide; Br2; hydrobromic acid; N-bromophthalimide; N-bromoacetamide, N-bromosuccinimide (NBS) or mixtures thereof.

14. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 10 wherein, bromination agent is added to a solution of 2,5-Dimethoxy Acetophenone compound of formula IV in a solvent and chilled to 0°C to 25°C

15. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, crude product 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I is purified by recrystallization in presences of organic solvent such as methanol, ethanol, propanol, butanol, diethylether, di-isopropylether, methyl tert-butyl ether or mixture thereof.

16. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, highly pure 2-Bromo- 2’,5,-Dimethoxy Acetophenone compound of formula I having purity greater than 99.2% preferably greater than 99.9%.

17. The improved process for the preparation of highly pure 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I as claimed in claim 1 wherein, 2 -Bromo- 2’,5,-Dimethoxy Acetophenone of formula I is used for the preparation of Midodrine hydrochloride.

Dated this 17th Day of Jan, 2022