FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
ONE POT PROCESS OF PREPARING 2-(CHLOROMETHYL)-4-METHYL-QUINAZOLINE-LINAGLIPTIN INTERMEDIATE
2. APPLICANT:
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS:Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East),
Mumbai, Maharashtra India Pin Code: 400055,
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
Present invention relates to one pot process of preparing 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) which is an intermediate of linagliptin compound represented by structural formula (II).

BACKGROUND OF THE INVENTION:
Linagliptin is chemically defined as 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione and is known from the US patent number 7,407,955 and is represented by structural formula (II).

Linagliptin is approved in US as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and is marketed by brand name Tradjenta. Linagliptin is also approved in the US in combination with Metformin hydrochloride which is marketed by the brand name Jentadueto and linagliptin is also approved in the US in combination with Empagliflozin which is marketed by the brand name Glyxambi.
U.S.Patent No. 7,407,955 discloses process for preparation of 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) wherein 2-chloromethyl-4-methyl-quinazoline-3-oxide compound represented by structural formula (III) is reduced using phosphorus trichloride in chloroform.


It further describes conversion of 2-(Chloromethyl)-4-methyl-quinazoline compound of structural formula (I) in to Linagliptin compound of structural formula (II) as depicted below:

U.S.Patent No. 7,820,815 describes the process wherein solution of 2-aminoacetophenone compound represented by structural formula (IV) in 1,4-dioxane is purged with hydrogen chloride gas followed by addition of chloroacetonitrile at -10°C to obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I), The process is difficult to scale-up and is not suitable for commercial production.


Chinese Patent No. 104892609B discloses reaction of 2-aminoacetophenone compound represented by structural formula (IV)with hydroxylamine HC1 in ethanol and in the presence of 10% NaOH solution to provide (E)-l-(2-Aminophenyl)ethan-l-one oxime compound represented by structural formula (V) which is further treated with chloroacetyl chloride in acetic acid to provide compound represented by structural formula (III) which is converted to linagliptin N-oxide compound represented by structural formula (VI) and which is finally converted to linagliptin compound represented by structural formula (II).

The process of Chinese Patent No. 104892609B does not provide preparation of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I); however it provides preparation of 2-chloromethyl-4-methyl-quinazoline-3-oxide compound represented by structural formula (III). The process of Chinese Patent No. 104892609B involves lengthy work-up for isolation of intermediate compounds which decreases productivity and increases cost of production.

The process for preparation of 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) known in the prior art are disadvantageous as they involve multiple steps and each step have lengthy work-up for isolation of the intermediate which makes process tedious, decreases productivity, increases cost of production and hence economically less viable. Further, prior art processes involves use of hazardous reagents with critical reaction parameter like very low reaction temperature and are not suitable for commercial production.
In view of the above the inventors of present invention have designed an efficient, economical and eco-friendly process for the preparation of 2-(Chloromethyl)-4-methyl-quinazoline compound of structural formula (I) which is intermediate of Linagliptin compound of structural formula (II).
OBJECT OF THE INVENTION:
An object of present invention is to provide one pot process of preparing 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) which is an intermediate of linagliptin compound represented by structural formula (II).

Another object of the present invention is to provide a simple, cost efficient and environment friendly process for preparation of Linagliptin compound represented by structural formula
(II).


SUMMARY OF THE INVENTION:
An aspect of present invention is to provide an efficient, economical, less hazardous and eco-friendly process for the preparation of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I).
Another aspect of present invention is to provide onepot process of preparing 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) comprising:
i. reacting 2-aminoacetophenone compound represented by structural formula (IV) with hydroxylamine hydrochloride in the presence of base to obtain compound represented by structural formula (V) which is used for next step without isolation;

ii. reacting compound represented by structural formula (V) from step (i) with chloroacetyl chloride to obtain compound represented by structural formula (III) which is used for next step without isolation;

iii. reacting compound represented by structural formula (III) from step (ii) with a metal reagentto obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I);


iv. optionally converting compound of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) in to linagliptin compound represented by structural formula (II).
Another aspect of present invention is to provide one pot process of preparing of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) comprising:
i. reacting 2-aminoacetophenone compound represented by structural formula (IV) with hydroxylamine hydrochloride in solvent in the presence of base to obtain compound represented by structural formula (V) which is used for next step without isolation;

ii. reacting compound represented by structural formula (V) from step (i) with chloroacetyl chloride in presence of acid and chlorinated solvent to obtain compound represented by structural formula (III) which is used for next step without isolation;

iii, reacting compound represented by structural formula (III) from step (ii) with a metal reagent selected from iron, zinc, palladium on carbon or phosphorous trichloride to obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I).


iv. optionally converting compound of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) in to linagliptin compound represented by structural formula (II).
Yet another aspect of present invention is to provide a process for the preparation of 2-(Chloromethyl)-4-methyl-quinazoline compound represented -by structural formula (I) comprising:
i. reacting 2-aminoacetophenone compound represented by structural formula (IV) with hydroxylamine hydrochloride in polar protic solvent selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid or mixture(s) thereof,in the presence of base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, Dimethylaminopyridine (DMAP) or pyridine to obtain compound represented by structural formula (V) which is used for next step without isolation;

ii. reacting compound represented by structural formula (V) from step (i) with chloroacetyl chloride in presence ofacetic acid and chlorinated solvent to obtain compound represented by structural formula (III) which is used for next step without isolation;

iii. reacting compound represented by structural formula (III) from step (ii) with iron or phosphorous trichloride to obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I).


iv. optionally converting compound of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) in to linagliptin compound represented by structural formula (II).
DETAIL DESCRIPTION OF THE INVENTION:
2-Aminoacetophenone compound represented by structural formula (IV) is available commercially.
According to an aspect of the invention 2-Aminoacetophenone compound represented by structural formula (IV) is reacted with hydroxylamine hydrochloride in solvent and in the presence of base at a temperature in the range of 20°C to 80°C for the period of 1 hour to 5 hours to obtain compound represented by structural formula (V).
The solvent is polar protic solvent selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid or mixture(s) thereof.
The base is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, Dimethylaminopyridine (DMAP) or pyridine.
The compound represented by structural formula (V) is used for next step without isolation and reacted in-situ with chloroacetyl chloride in presence of acid and chlorinated solvent at a temperature in the range of 20°C to 80°C for the period of 1 hour to 12 hours to obtain compound represented by structural formula (III).
The chlorinated solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform or mixture(s) thereof.

The acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid or mixture(s) thereof.
The compound represented by structural formula (III) is used for next step without isolation and is reacted in-situ with a metal reagentat a temperature in the range of 0°C to 80°C for the period of 1 hour to 8 hours to obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I).
The metal reagentis selected from but not limited to iron, zinc, palladium on carbon (Pd/C), phosphorous trichlorideetc.
The compound represented by structural formula (I) is isolated by means of filtration, recrystallization in water, alcohol solvent selected from the group consisting of methanol, ethanol, propanol, ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and methyl tertiary butyl ether or mixture thereof and drying in oven at 60°C.
2-(Chloromethyl)-4-methyl-quinazoline compound of structural formula (I) can be converted to Linagliptin compound of structural formula (II) by method disclosed in U.S. Patent No. 7,407,955 or by any other process known in the art.
EXAMPLES:
In the following examples, 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: 2-(ChIoromethyl)-4-methyl-quinazoline:
To a solution of 2-Aminoacetophenone (10 g) in mixture of water (42 mL) and methanol (7.5 mL) was added Sodium hydroxide (23.6 g) and hydroxylamine HC1 (15-5 g)at a temperature in the range of 20°C to 30°C. The resulting reaction mixture was heated and stirred at a temperature in the range of 50°C to 55°C for a period of 3 hours. After completion of reaction, water (30 mL) was added to the reaction mixture and pH 6.0 to 7.0 was maintained

with Acetic acid. Dichloromethane (80 mL) was added in reaction mixture and stirred for a period of 15 minutes. The organic layer was separated out and washed with water. The organic layer was dried over sodium sulphate and then Acetic acid (20 mL) and Chloroacetyl chloride (11.6 mL)was added to organic layer. The resulting reaction mixture was stirred at a temperature in the range of 50°C to 55°C for a period of 8 hours. After completion of reaction, iron powder (8.25 g) was added in reaction mixture at a temperature in the range of 50°C to 55°C. The reaction mixture was stirred at a temperature in the range of 50°C to 55°C for a period of 1 hour. After completion of reaction, reaction mixture was filtered and washed with dichloromethane to obtain filtrate. The resulting filtrate was added Water (50 mL) and pH 6.5 to 7.5 was adjusted with sodium carbonate solution. Then organic layer was separated and dried over sodium sulphate. The resulting organic layer was charcoalized and filtered through supercell bed and bed was washed with dichloromethane (20 mL). The organic layer was distilled out and resulting residuewas crystallized in methyl tertiary butyl ether to obtain solid. The resulting solid was filtered, washed with methyl tertiary butyl ether and dried in oven at 60°C.
Yield=12.9g(90%). HPLC Purity= 99.24 %.
Example 2: 2-(Chloromethyl)-4-methyl-quinazoline:
To a solution of 2-Aminoacetophenone 5 g in mixture of water (21 mL) and methanol (3.5 mL) was addedsodium hydroxide (11.8 g) and hydroxylamine HC1 (9 g) at a temperature in the range of 20°C to 30°C. The resulting reaction mixture was heated and stirred at a temperature in the range of 50°C to 55°C for a period of 3 hours. After completion of reaction, water (20 mL) was added to the reaction mixture and pH 6.0 to 7.0 was maintained with Acetic acid. Dichloromethane (50 mL) was added in reaction mixture and stirred for 15 minutes. The organic layer was separated out and washed with water. The organic layer was dried over sodium sulphate and then Acetic acid (12 mL) and chloroacetyl chloride (6 mL)was added to organic layer. The reaction mixture was stirred ata temperature in the range of50°C to 55°C for a period of 8 hours. After completion of reaction, Water (30 mL) was added in reaction mixture and pH 6.5 to 7.5 was adjusted with sodium carbonate solution. The organic layer was separated and dried over sodium sulphate. Phosphorous trichloride (2.9 g) was added in organic layer ata temperature in the range of 5°C to 15°C and stirred for a

period of 4 hours. After completion of reaction, water (50 mL) was added in reaction mixture and the organic layer was separated and washed with water and dried over sodium sulphate. The resulting organic layer was charcoalized and filtered through supercell bed and bed was washed with dichloromethane (20 mL) to obtain filtrate. The resulting filtrate was distilled out and resulting residue was crystallized in methanol-water to obtain solid. The resulting solid was filtered, washed with methanol-water and dried in oven at 60°C.
Yield= 6.4 g (90 %). HPLC Purity= 99.10%.

We claim:
1. one pot process of preparing 2-(chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) comprising:
i) reacting 2-aminoacetophenone compound represented by structural formula
(IV) with hydroxylamine hydrochloride in the presence of base to obtain , compound represented by structural formula (V) which is used for next step without isolation;

ii) reacting compound represented by structural formula (V) from step (i) with chloroacetyl chloride to obtain compound represented by structural formula (III) which is used for next step without isolation;

iii) reacting compound represented by structural formula (III) from step (ii) with a metal reagent to obtain 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I);

iv) optionally converting compound of 2-(Chloromethyl)-4-methyl-quinazoline compound represented by structural formula (I) in to linagliptin compound represented by structural formula (II).

2. The process as claimed in claim 1 (i) wherein base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, Dimethylaminopyridine (DMAP) and pyridine.
3. The process as claimed in claim 1 (i) is carried out in solvent selected from group consisting of water, methanol, ethanol, isopropanol, acetic acid or mixture(s) thereof.
4. The process as claimed in claim 1 (i) wherein 2-Aminoacetophenone compound represented by structural formula (IV) is reacted with hydroxylamine hydrochloride at a temperature in the range of 20°C to 80°C.
5. The process as claimed in claim 1 (ii) wherein compound represented by structural formula (V) from step (i) is reacted in-situ with chloroacetyl chloride in presence of acid and chlorinated solvent to obtain compound represented by structural formula
(III).
6. The process as claimed in claim 5 wherein acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid or mixture(s) thereof.
7. The process as claimed in claim 5 wherein chlorinated solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform or mixture(s) thereof.
8. The process as claimed in claim 5 wherein compound represented by structural formula (V) from step (i) is reacted in-situ with chloroacetyl chloride at a temperature in the range of 20°C to 80°C.
9. The process as claimed in claim 1 (iii) wherein metal reagent is selected from iron, zinc, palladium on carbon and phosphorous trichloride.
10. The process as claimed in claim 1 (iii) wherein compound represented by structural formula (III) is reacted in-situ with a metal reagent at a temperature in the range of 0°C to 80°C.