CLIAMS:1. A crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, compound of formula-II

Formula-II
or its salts thereof, has purity more than 99 % when measured by HPLC.

2. The crystalline solid form of claim 1, characterized by at least one of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a powder X-ray diffraction pattern having peaks at about 13.43, 14.85, 17.15, 18.09, 19.20, 19.76, 20.27 and 22.46  0.2,
iii. a powder X-ray diffraction pattern having additional peaks at about 6.71, 9.80, 10.33, 10.64, 11.02, 16.14, 16.96, 22.11and 28.20  0.2
iv. a Differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2,
v. a Thermogavimetric Analysis (TGA) substantially in accordance with Figure 3

3. A process for the preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof, compound of formula-II,

Formula-II
has the purity more than 99 % when measured HPLC
the process includes the steps of ;
a) reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid or salt thereof compound of formula (III)

Formula-III
with thiazolidine or salt in the presence of coupling agent in a solvent,
b) optionally adding the activating agent in the reaction mixture of step (a)
c) isolating 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl carbonyl]-1,3-thiazolidine from reaction mixture thereof.

4. The process of claim 3, wherein the solvent is selected from the group comprising one or more of dichloromethane, chlorobenzene, chloroform, carbon tetrachloride and mixture thereof.

5. The process of claim 4, wherein solvent is dichloromethane.

6. The process of claim 3, wherein coupling agent is selected from comprises one or more of N,N'-dicyclohexylcarbodiimide (DCC), and N,N'-diisopropyl carbodiimide (DIC).

7. The process of claim 6, wherein coupling agent is N,N'-dicyclohexylcarbodiimide (DCC).

8. The process of claim 3, wherein activating agent is selected from comprises one or more of 4-dimethylaminopyridine (DMAP), N-hydroxysuccinimide (NHS), 2-hydroxypyridine, N-hydroxyphthalimide esters and 1,1'-carbonyldiimidazole (CDI).

9. The process of claim 8, wherein activating agent is 4-dimethylaminopyridine (DMAP).

10. The process according to claim 1, wherein compound of formula-II subsequently converted to Teneligliptin or a pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

The present invention relates to crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, which is used as an intermediate for the preparation of Teneligliptin or its pharmaceutical acceptable salts thereof. A further aspect of the present invention relates to a process for the preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or salt thereof and its conversion to intermediate to Teneligliptin or its pharmaceutical acceptable salts thereof.
Background of the invention

Teneligliptin is chemically known 3-[[(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl] carbonyl] thiazolidine or its pharmaceutical acceptable salt thereof and is structurally represented by formula (I)

Formula I

Teneligliptin is indicated for the treatment of type 2 diabetes mellitus. US Patent No. 7,074,794 (referred to herein as ‘794) and 8,003,790 (referred to herein as ‘790) describe Teneligliptin and its process for the preparation thereof.

The process described in the US Patent '794 involve the preparation of 3-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (referred to herein as “N-Boc-Pyrrolidine Thiazolidine”) as color less oil. The process employs (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (referred to herein as “N-Boc-Pyrrolidine Thiazolidine”) and thiazolidine in dimethylformamide solvent in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl and hydroxybenzotriazole. The reaction mixture stirred for 18 hour. There are drawbacks of the process, includes oily product, which is difficult to isolate and purify, inter alia formation of desired product in low yield and with inferior quality and reaction takes longer reaction time to complete. Hence, the said process is not industrially feasible.

Thus, an object of the present invention is to provide a crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine to overcome aforesaid problem of oily product and to provide simple, cost effective and industrially feasible processes for the preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or salt thereof.

Summary of the Invention

The present invention provides a crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, compound of formula-II

Formula-II
or its salts thereof, has purity more than 99 % when measured by HPLC.

The present invention provides a process for the preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, compound of formula-II,

Formula-II
has purity more than 99 % when measured by HPLC
the process includes the steps of;
a) reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid or salt thereof compound of formula (III) with thiazolidine or salt in the presence of coupling agent in a solvent,
b) optionally, adding the activating agent in the reaction mixture of step (a)
c) isolating compound of formula-II from reaction mixture thereof.

A further aspect of the present invention relates to conversion of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, compound of formula-II to Teneligliptin or its pharmaceutical acceptable salts thereof.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of crystalline solid form 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine prepared according to Example 1.

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of crystalline solid form 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine prepared according to Example 1.

Figure 3 shows an illustrative example of Thermogavimetric analysis curve of crystalline solid form 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine prepared according to Example 1.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The present invention provides a crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, compound of formula-II

Formula-II
or its salts thereof, has purity more than 99 % when measured by HPLC.

In another aspect, the present invention provides a crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2 and differential scanning calorimetry thermogram as shown in Figure 3.

In another aspect, the present invention provides a crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, having an X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K α-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 13.43, 14.85, 17.15, 18.09, 19.20, 19.76, 20.27 and 22.46  0.2.

The XRPD characteristic peaks of the crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine, has purity more than 99 %, further defined from the Table 1,

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
6.71 13.16 5.48
9.80 9.01 22.06
10.00 8.84 12.95
10.33 8.56 16.36
10.64 8.31 35.11
11.02 8.02 22.62
11.18 7.91 13.04
13.43 6.59 60.99
14.85 5.96 86.30
16.14 5.49 26.39
16.96 5.22 27.99
17.15 5.16 49.85
17.92 4.94 31.59
18.09 4.90 40.53
18.86 4.70 11.08
19.20 4.62 79.75
19.54 4.54 30.57
19.76 4.49 45.87
20.27 4.37 100.00
21.18 4.19 13.84
22.11 4.01 17.50
22.46 3.95 43.60
23.34 3.81 13.75
24.03 3.70 11.10
28.20 3.16 11.21

The crystalline solid form of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine obtained as per Example 1 to the present invention was stored at 25°C for a period of 3 months and no conversion in the other polymorphic form was observed.

In one another embodiment, the present invention provides a process for the preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof, compound of formula-II,

Formula-II
the process includes the steps of;
a) reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid or salt thereof compound of formula (III) ,

Formula-III
with thiazolidine or salt in the presence of coupling agent in a solvent,
b) optionally adding the activating agent in the reaction mixture of step (a)
c) isolating 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine from reaction mixture thereof.

The step a) of the present invention involves the reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid or salt thereof with thiazolidine or salt thereof in the presence of a suitable coupling agent in a solvent at the temperature in between range of 0C to 10C, wherein coupling agent is selected from the group comprising one or more N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

The solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.

The step b) of presentation involves the adding the activating agent in the reaction mixture of step (a), wherein the activating agent is selected from the group comprising one or more of 4-dimethylaminopyridine (DMAP), N-hydroxysuccinimide (NHS), 2-hydroxypyridine, N-hydroxyphthalimide esters and 1,1'-carbonyldiimidazole (CDI).

The step c) involves the isolation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof. Isolation involve filtration of reaction mass and subsequently removal of solvent under vacuum, after completion of reaction, followed by addition of 15% to 20% aqueous solution of base and isopropyl ether in 5 time in quantity of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine. Finally, the reaction mixture filtered to get 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof as white solid.

In another aspect, the present invention provides 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof, compound of formula-II has purity more than 99 % when measured by HPLC

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

Scheme-1

The compounds 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine or its salt thereof can be converted into Teneligliptin or its pharmaceutical acceptable salt thereof according to known methods given in US patent number 7,074,794.

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: Preparation of 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl carbonyl]-1,3-thiazolidine

Charge (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (100 gm) and N,N'-dicyclohexylcarbodiimide (100 gm) in dichloromethane (1000 ml), followed by drop wise addition of thiazolidine (42.4 gm) solution in dichloromethane (200ml). The 4-dimethylaminopyridine (2.6 gm) was added into the reaction mixture at temperature range 0C to 10°C. Reaction mixture was stirred at temperature range 0-10 °C for the period of 3 hours. After completion of reaction, the reaction mass was filtered and the filtrate was distilled out, and residue obtained was treated with 15 % aqueous solution of sodium hydroxide (500 ml) and isopropyl ether (500 ml). The reaction mixture was stirred for 2 hour at temperature range 25C to 35C, then it was filtered to get titled compound as white solid
Yield: 100g (77%)
HPLC Purity: 99 %