FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A PROCESS FOR THE PREPARATION OF INTERMEDIATES OF ACOTIAMIDE
HYDROCHLORIDE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

FIELD OF THE INVENTION:
The present invention relates to intermediates 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I and ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino] thiazole-4-carboxylate compound represented by structural formula XXI and their use in the preparation of acotiamide hydrochloride trihydrate of structural formula II.

BACKGROUND OF THE INVENTION:
Acotiamide hydrochloride trihydrate is indicated for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia and it acts as an acetylcholinesterase inhibitor. The chemical designation is 2-[N-(4,5-Dimethoxy-2-hydroxybenzoyl)amino]-4-[(2-diisopropylaminoethyl) aminocarbonyl]-l, 3-thiazole hydrochloride trihydrate. It is known from U.S. Patent No 5,981,557 and is represented by compound of structural formula II.


Acotiamide hydrochloride is sold in Japan market under the trade name "ACOFIDE" indicated for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia.
U.S. Patent No. 5,981,557 describes a process for the preparation of compound of structural formula VII, wherein acotiamide is included generically as shown below in scheme no. 1 and 2.


Where in X represents an eliminating group such as p-nitrophenoxy group, a halogen atom or a hydroxy group and D represents a hydroxy or a lower alkoxy group or salt thereof which is useful as an intermediate for the preparation of the invention compound (I).R1, R2 and R3 are the same or different and each independently represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkyl carbonyloxy group, a halogen atom, a nitro group, an amino group, a mono- or di-(lower alkyl)amino group, a mono- or di-(lower alkyl)carbonylamino group, a formylamino group, a mono- or di-(lower alkyl)aminoalkylamino group, or R1 and R2 may be coupled together to form a methylenedioxy group; R4 represents a hydrogen atom or a lower alkyl group; R5 represents a hydrogen atom, a halogen atom or a lower alkyl group; A represents a group represented by the following formula:N-R6R7, wherein R6 and R7 are the same or different and each independently represents a hydrogen atom, a lower alkyl group, a lower alkoxy group etc; B—(CH^m —A may form a piperidinyl, branched alkylamino or phenylamino group which may be substituted by a mono- or di-(lower alkyl)amino group, or a piperazinyl, piperidinyl amino or piperidinyl alkyl amino group which may be substituted by a lower alkyl group, or a salt thereof.


Where in X, R1, R2, R3, R4, R5, A, B, D and m have the same meanings as defined above.
U.S Patent No. 6,197,970 describes a process for the preparation of compound of structural formula XIII, where in acotiamide is included generically as shown below in scheme no. 3.

Where in R2, R3, and R4 are the same or different and each independently represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkyl sulfonyl group, a halogen atom, a nitro group, a cyano group, a mono- or di-lower alkyl amino group, or a mono-or di-lower alkyl carbonyl amino group, or R2 and R3 may join to each other to form a methylenedioxy group; R5 represents a hydrogen atom, a lower alkyl group, a lower alkyl sulfonyl group, a halogen atom, a nitro group, a cyano group, a mono- or di-lower alkyl amino group, or a mono- or di-lower alkyl carbonyl amino group; and R6 represents a hydroxyl group, a lower alkyl group, or a lower alkoxy group. R1 represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted tetrahydropyranyl group; and R2, R3, R4, R5, and R1, have

the same meanings as described above; with a secondary amine or a tertiary amine. R7 and R% are the same or different and each independently represents a hydrogen atom or a lower alkyl group; and m represents an integer of 1-4, A represents a hydroxy group or a lower alkoxy group.
U.S Patent No. 8,841,461 describes a process for the preparation of acotiamide hydrochloride trihydrate represented by compound of structural formula II as shown below in scheme no. 4.


SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide 2-isopropoxy-4,5-dimethoxy benzoic acid compound represented by structural formula I and its use in the preparation of acotiamide hydrochloride trihydrate compound represented by structural formula II.

Another aspect of the present invention is to provide ethyl 2-[(2-isopropoxy-4, 5-dimethoxybenzoyl)amino] thiazole-4-carboxylate compound represented by structural formula XXI and its use in the preparation of acotiamide hydrochloride trihydrate compound represented by structural formula II.

Another aspect of the present invention is to provide a process of preparing 2-isopropoxy-4, 5-dimethoxybenzoic acid compound represented by structural formula I.
Another aspect of the present invention is to provide a process of preparing ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI.

Another aspect of the present invention is to provide a process of preparing 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I, comprising reacting 2-hydroxy-4,5-dirhethoxybenzoic acid compound represented by structural formula XV with an isopropyl-halide in the presence of alkali metal halide.

Another aspect of present invention is to provide a process of preparing ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI comprising condensing 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I with ethyl 2-aminothiazole-5-carboxylate compound represented by structural formula XXII in the presence of base.


Another aspect of present invention is to provide a process for the preparation of Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII comprising treating ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylatecompound represented by structural formula XXI with alew is acid in the presence of an organic solvent.

DETAILED DESCRIPTION OF INVENTION:
2-hydroxy-4,5-dimethoxy benzoic acid compound represented by structural formula XV can be prepared by the processes known in the art such as those described in U.S patent number 9,096,511,which is incorporated herein by reference only.
The reaction of 2-hydroxy-4,5-dimethoxy benzoic acid compound represented by structural formula XV with isopropyl halide can be carried out in the presence of an alkali metal halide.
The examples of isopropyl-halide are isopropyl bromide, isopropyl chloride or isopropyl iodide.
The examples of alkali metal halide may include but not limited tolithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, cesium chloride, cesium bromide, or cesium iodide.
The reaction of 2-hydroxy-4,5-dimethoxy benzoic acid compound represented by structural formula XV with isopropyl halide can be carried Out in the presence of an organic solvent.
The organic solvent may be polar organic solvent.

The example of polar organic solvent may include but not limited to mono-methyl formamide, dimethyl formamide, diethyl formamide, dimethyl acetamide,dimethylsulphoxide, N-methyl pyrrolidone or mixture(s) thereof.
The reaction of 2-hydroxy-4,5-dimefhoxybenzoic acid compound represented by structural formula XV with isopropyl halide can be carried out in the presence of an organic or an inorganic base.
The examples of inorganic base may include but not limited to alkali metal or alkaline earth metal such as sodium'hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and phosphates such as disodium monohydrogen phosphate, dipotassium monohydrogen phosphate, trisodium phosphate, tripotassium phosphate and the like.
The examples of organic base may include but not limited to triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium bis(trimethylsilylamide), potassium tert-butoxide, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-Diazabicyclo[4.3.0]non-5-ene(DBN).
The reaction of 2-hydroxy-4,5-dimethoxybenzoic acid compound represented by structural formula XV with isopropyl halide can be carried out at a temperature in the range of 40°C to 160°C
The 2-isopropoxy-4,5-dimefhoxybenzoic acid compound represented by structural formula I can be isolated by extracting the reaction mixture with toluene, which after usual workup (base-acid treatment) filtration, washing, drying under oven at elevated temperature gives the title compound.


The 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I may be converted into acotiamide hydrochloride trihydrate compound represented by structural formula II by process scheme illustrated below in scheme no. 5:


The compound of the XXII may be prepared by methods such as those described in Chinese patent number 10213422, which is incorporated herein by reference only.
The condensation of 2-isopropoxy-4,5-dimethoxy benzoic acid compound represented by ;
structural formula I with ethyl 2-aminothiazole-5-carboxylate compound represented by structural formula XXII may be carried out in an organic solvent in the presence of base.

The condensation of 2-isoprbpoxy-4,5-dimethoxy benzoic acid compound represented by structural formula I with ethyl 2-aminothiazole-5-carboxylate compound represented by structural formula XXII may be carried out in the presence of chlorinating agents.
The organic solvent may include halogenated hydrocarbon solvents.
The examples of halogenated hydrocarbon solvents may include but not limited to methylene dichloride, ethylene dichloride, carbon tetrachloride or chloroform.
The example of base may include but not limited to triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium bis(trimethylsilylamide), potassium tert-butoxide, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-Diazabicyclo[4.3.0]non-5-ene(DBN).
The examples of chlorinating agents may include but not limited to thionyl chloride (SOCI2) or phosphorus pentachloride (PCI5), but also commonly with sulfuryl chloride (SO2CI2) and phosphorus trichloride (PCI3).
The condensation of 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I with ethyl 2-aminothiazole-5-carboxylate compound represented by structural formula XXII may be carried out at a temperature in the range of 10°C to 80°C.
The ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI may be isolated by treating the reaction mixture with an aqueous sodium bicarbonate solution followed by complete distillation of dichloromethane and then resulting suspension was cooled, filtered, washed with water and recrystallized in an alcohol solvent.
The examples of an alcohol solvent may include but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol.
The Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII can be prepared by treating ethyl 2-[(2-isopropoxy-4,5-

dimethoxybenzoyl)amino]thiazole-4-carboxylatecompound represented by structural formula XXI with an lewis acid in the presence of an organic solvent.
Examples of lewis acid may include but not limited to aluminium chloride, ferric chloride, antimony trichloride, antimony pentachloride or stannic chloride.
The examples of organic solvent may include but not limited to dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, dimethyl formamide or the combination(s) thereof.
The Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII may be isolated by the steps of quenching, distillation, filtration, washing, recrystallization or the combination thereof.
The quenching of reaction mixture can be carried out with cold IN HC1 solution.
The recrystallization of Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII may be carried out in an alcohol solvent.
The examples of alcohol solvent may include but not limited to methanol, ethanol, n-propanol, isopropanol, butanol or isobutanol.
The Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII can further be converted into acotiamide hydrochloride trihydrate compound represented by structural formula II by methods described in prior art such as those described in U.S patent number 8,841,461,which is incorporated herein by reference only.

EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of 2-isopropoxy-4, 5-dimethoxybenzoic acid compound represented by structural formula I
The solution of 2-hydroxy-4,5-dimethoxybenzoic acid compound represented by structural formula XV(14 g) in DMSO (100 mL) were added potassium carbonate (50g), potassium iodide (1.4g) and isopropyl bromide (26.5 mL) at 25°C. The resulting reaction mixture was then heated to 60°C and agitated for 6 hours. The resulted reaction mixture was then cooled and quenched with water (280 mL) and toluene (140 mL). The organic layer was separated and remaining aqueous layer was again extracted with toluene (70 mL). Both toluene layers were combined, dried over anhydrous sodium sulphate and concentrated to get oily residue. The oily residue was added potable water (210 mL) and sodium hydroxide (14 g) at 25°C and then resulting reaction mixture was then heated to reflux temperature for 3 hours and then cooled to 25°C. The pH of the reaction mixture was adjusted to 2-3 by adding concentrated hydrochloric acid. The resulting solid was filtered, washed with water, sucked dry and dried in oven at 50°C for 4 hours to get crude compound. The resulting crude compound was recrystallized in isopropyl alcohol (2 mL) to get title compound.
Yield: 11.8 g
Purity: 99.8% (By HPLC).
Example 2: Preparation of ethyl 2-[(2-isopropoxy-4, 5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI
To the stirred solution of 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I (50 g) in methylene chloride (250 mL) was added ethyl 2-amino-l, 3-thiazole-4-carboxylate compound represented by formula-XXII (50g), thionyl chloride (150 mL) and dimethyl amino pyridine (DMAP) (0.3 g) at 25°C. The resulting reaction mixture was heated to reflux temperature and further stirred for 3 hours. The resulting reaction mixture was

concentrated under reduced pressure and then reaction mixture was neutralised by aqueous solution of sodium bicarbonate. The traces of methylene dichloride was removed completely at 40-45 °C under reduced pressure and then resulting reaction mixture was cooled to 0°C and agitated for 1 hour. The resulting solid was filtered and washed with water to get crude title compound. The crude compound was treated with methanol (250 mL) at 50°C for 30 minutes and then resulting suspension was cooled to 25°C, filtered and dried at 45°C under reduced pressure for 2 hours.
Yield: 65 g
Purity: 99.9% (By HPLC).
Example 3: Preparation of Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazoIe-4-carboxylate compound represented by structural formula XXIII
To the stirred solution of ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI (100 g) in a mixture of methylene dichloride (2000 mL) and dimethyl formamide (100 mL) was added A1C13(240 g) at 28-32°C in 30 minutes. The resulting reaction mixture was heated to 33-38°C and agitated for 30 minutes. The resulting reaction mixture was quenched into precooled IN HC1 solution in another flask at 0-10°C and then methylene dichloride was distilled out at 40-45°C. The resulting solid was filtered, washed with water (100 mL) to get crude compound. The crude compound was treated with methanol (80 mL) at 50°C and then resulting suspension was cooled to 25°C, filtered and dried at 45°C under reduced pressure for 2 hours.
Yield: 70 g.
Purity: 99.9% (By HPLC)

WE CLAIM:
1. A 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I and its use in the preparation of acotiamide hydrochloride trihydrate compound represented by structural formula II.

2. A ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI and its use in the preparation of acotiamide hydrochloride trihydrate compound represented by structural formula II.


3. A process for the preparation of 2-isopropoxy-4,5-dimethoxybenzoic acid compound represented by structural formula I comprising reacting 2-hydroxy-4,5-dimethoxybenzoic acid compound represented by structural formula XV with an isopropyl-halide in the presence of alkali metal halide.


4. The process according to claim no 3, wherein isopropyl-halide is selected from the group comprising of isopropyl bromide, isopropyl chloride or isopropyl iodide.
5.The process according to claim no 3, where in alkali metal halide is selected from the group comprising of lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, cesium chloride, cesium bromide, or cesium iodide.
6. A process for the preparation of ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI comprising condensing 2-isopropoxy-4,5-dimethoxy benzoic acid compound represented by structural formula I with ethyl 2-aminothiazole-5-carboxylate compound represented by structural formula XXII in the presence of base.

7.The process according to claim no 6, wherein base is selected from the group comprising of
triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium
diisopropylamide, potassium bis(trimethylsilylamide), potassium tert-butoxide, 4-
dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene(DBU) or 1,5-
diazabicyclo[4.3.0]non-5-ene(DBN).

8. A process for the preparation Ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXIII comprising treating ethyl 2-[(2-isopropoxy-4,5-dimethoxybenzoyl)amino]thiazole-4-carboxylate compound represented by structural formula XXI with an lewis acid in the presence of an organic solvent.

9. The process according to claim no 8, wherein lewis acid is selected from the group
comprising of aluminium chloride, ferric chloride, antimony trichloride, antimony pentachloride
or stannic chloride.
10. The process according to claim no 8, wherein organic solvent is selected from the group
comprising of dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, dimethyl
formamide or the combination(s) thereof.