CLIAMS:1. A process for the preparation of intermediate of Linagliptin of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises condensation of 8-bromo xanthine compound of Formula A:

Formula A

or its pharmaceutically acceptable salt with 3-(R)-Boc aminopiperidine of Formula B:

Formula B

or its pharmaceutically acceptable salt using an organic base in the presence of a solvent.

2. The process of claim 1, wherein the 3-(R)-Boc aminopiperidine or its salt is 1 to 1.5 molar equivalents for the equivalent of 8-bromo xanthine of Formula A or its salt.

3. The process of claim 1, wherein the base is 1 to 4 molar equivalents per the equivalent of the compound of Formula A or its salt.

4. The process of claim 1, wherein the organic base is selected from he group of Triethyl amine (Et3N), trimethyl amine (Me3N), pyridine, tributylamine and diisopropyl ethyl amine (DIPEA).

5. The process of claim 1, wherein the solvent is dimethyl acetamide, dimethyl formamide or dimethyl sulfoxide.

6. The process of claim 1, wherein the condensation reaction is performed at elevated temperature, for example, at 100 °C.

7. The process of claim 1, wherein the Boc-Linagliptin or its salt is used as key intermediate to prepare Linagliptin or its pharmaceutically acceptable salt.

8. The process of claim 1, wherein the Boc-Linagliptin or its salt has the purity of about 95% by HPLC.
,TagSPECI:FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION: A Process For Preparing Intermediate of Linagliptin
2. APPLICANT (S) (a) NAME: WOCKHARDT RESEARCH CENTRE (b) NATIONALITY: INDIAN (c) ADDRESS: D-4, M.I.D.C INDUSTRIAL AREA, CHIKALTHANA, AURANGABAD- 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides a process for preparing intermediate of Linagliptin, Boc-Linagliptin, by using an organic base.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION

The present invention provides a process for preparing intermediate of Linagliptin which involves condensation of 8-Bromo Xanthine compound with 3-(R)-Boc aminopiperidine using an organic base.

Linagliptin is chemically known 1H-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]- and is structurally represented by formula (I):

Formula I

Linagliptin is approved for the treatment of Diabetes and is available in the market as Tradjenta® with the strength 5 mg of Tablet for oral administration.

U.S. Patent No. 7,407,955 describes Linagliptin and process for the preparation thereof. Further, Matthias et al., in Journal of Medicinal Chemistry 2007 50(26) Pages 6450-6453, discloses a process for the preparation of Linagliptin from Boc protected Linagliptin.

The process disclosed in the US ‘955 and Matthias article for Boc protected Linagliptin involves condensation of 8-bromo xanthine compound with 3-(R)-Boc aminopiperidine in presence potassium carbonate. The process of prior art is represented in the following scheme:

The inventors of the present invention surprisingly found that the positive improvement, for example, yield and purity, due to the use of organic base than the inorganic base for condensation reaction to provide Boc protected Linagliptin.

The present invention provides a process for preparing intermediate of Linagliptin of Formula II or pharmaceutically acceptable salt thereof:

Formula II
and its conversion to Linagliptin or pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for the preparation of intermediate of Linagliptin of Formula II or its pharmaceutically acceptable salt, which comprises condensation of 8-bromo xanthine compound of Formula A

Formula A

or its pharmaceutically acceptable salt with 3-(R)-Boc aminopiperidine of Formula B

Formula B
or its pharmaceutically acceptable salt using an organic base in presence of a solvent.

In another aspect, the present invention provides a process for the preparation of intermediate of Linagliptin of Formula II or its pharmaceutically acceptable salt, which comprises condensation of 8-bromo xanthine compound of Formula A or its pharmaceutically acceptable salt with 3-(R)-Boc aminopiperidine of Formula B or its pharmaceutically acceptable salt using an organic base such as N,N-Diisopropylethylamine.

In another aspect, the present invention provides a process for the preparation of Linagliptin or pharmaceutically acceptable salt thereof, which comprises:

a) condensation of 8-bromo xanthine compound of Formula A or its pharmaceutically acceptable salt with 3-(R)-Boc aminopiperidine of Formula B or its pharmaceutically acceptable salt using an organic base such as N,N-Diisopropylethylamine in the presence of dimethyl acetamide to provide Boc protected Linagliptin; and

b) deprotection of Boc-Linagliptin of step a) using triflouroacetic acid in presence of dichloromethane to provide Linagliptin.

The starting material, 3-(R)-Boc aminopiperidine or its salt may be used 1 to 1.5 molar equivalents for the equivalent of 8-bromo xanthine compound of Formula A or its salt for preparing Boc-Linagliptin.

The base used for the condensation reaction may be 1 to 4 molar equivalents per the equivalent of the compound of Formula A or its salt.

The suitable organic base used for the condensation of bromo xanthine compound of Formula A or its pharmaceutically acceptable salt with 3-(R)-Boc aminopiperidine of Formula B or its pharmaceutically acceptable salt is selected from Triethyl amine (Et3N), trimethyl amine (Me3N), pyridine, tributylamine, diisopropyl ethyl amine (DIPEA) in presence of a suitable solvent.

The solvent for the condensation reaction of the present invention includes but are not limited to dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide and the like. Other solvents may include alcohol such as methanol, ethanol, isopropanol and n-butanol; hydrocarbon such as n-hexane, n-heptane, cyclohexane and toluene; and their combination with dimethyl acetamide.

The condensation reaction may be conducted at elevated temperature of about 45 to about reflux temperature. The reaction may be maintained till to the completion of starting materials at elevated temperature, for example, to about 2 hours or more.

After completion of the reaction, the reaction mixture may be quenched with quenching agent, for example, water or acid, and then subjected for solid isolation by using suitable techniques, for example, slurry for a certain period of time, cooling, recrystallization and the like.

The process of the present invention is depicted in the following scheme:

The salt or pharmaceutically acceptable salt compounds of the present invention may include but are not limited to hydrochloride, hydrobromide, methane sulfonate, p-toluene sulfonate, trifluoroacetate, tartrate salt and the like.

The obtained Boc-Linagliptin or its salt is used for the conversion to Linagliptin by the treatment of acid, for example, triflouroacetic acid, in presence of chlorinated solvent, for example, dichloromethane.

The resultant Boc-Linagliptin or its salt obtained from the present invention has purity greater than about 95% determined by HPLC method. The yield of the Boc-Linagliptin or its salt may be greater than about 92%

The present invention is further illustrated by the following example, which does not 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 application.

EXAMPLES:

Example-1:

Bromo xanthine (5 gm) and Boc-Amino piperidine (3.4 gm) were added into dimethyl acetamide (50 mL) at room temperature. Diisopropylethyl amine (5.6 gm) was added to the reaction mixture and then heated to 100-110 °C and maintain for 12 hours. After completion of reaction, reaction mixture was quenched with water (50 mL) and stirred at RT for 30 minutes. The precipitated material was filtered, washed with water (20 mL) and dried under vacuum at 65-70 °C to get Boc-Linagliptin (5.75 gm, 92% yield) with HPLC purity > 96.76 % (0.19 % of bromopurine (starting material) observed).