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Process for preparation of an Immunomodulatory drug.

IP.com Disclosure Number: IPCOM000244598D
Publication Date: 2015-Dec-24
Document File: 6 page(s) / 282K

Publishing Venue

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Abstract

Synthesis of an immunomodulatory drug used in the treatment of rheumatoid arthritis, autoimmune diseases and multiple sclerosis is disclosed. The process utilizes acetyl chloride in the final step with a mild base to give the final product. The physical characteristics like infra red spectra, X-ray diffractogram, DSC and particle size are also disclosed.

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Process for preparation of an Immunomodulatory drug ____________________________________________________________________________________

An immunomodulatory drug of formula (I), chemically known as (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl) phenyl]but-2-enamide, exhibits its therapeutic action by blocking the enzyme dihydroorotate dehydrogenase. It is used in the treatment of rheumatoid arthritis, autoimmune diseases and multiple sclerosis.           

                                                              

                                                           Compound (I)

Described herein is a process as disclosed in Scheme-1 for preparation of Compound of formula (I) along with the characterization details for the intermediate (IV) and the drug substance (I). The associated impurities of Compound (I) were identified and characterized. The structures of these compounds are also provided.

Scheme-1: Synthesis of Compound (I)

Example 1: Preparation of 2-cyano-N-[(4-(trifluoromethyl)phenyl)] acetamide (IV)

Cyanoacetic acid (compound II; 71 gms) was gradually added to the stirred mixture of phosphorus pentachloride (173 gms) and dichloromethane (650 ml) at -5 to -100C. The reaction mixture was heated to 25 to 300C with continued stirring and after completion of reaction as monitored by HPLC, the mixture was cooled to 0 to -100C followed by addition of 4-aminobenzotrifluride solution (100 gms in 600 ml dichloromethane) at the same temperature. The reaction mass was stirred at 25 to 350C, till completion of the reaction, as monitored by HPLC. After completion of reaction, the reaction mixture was concentrated, cooled, followed by gradual addition of water. The mixture was filtered and the obtained solid was treated with ammonium hydroxide solution, followed by water, filtered and dried to give 2-cyano-N-(4-(trifluoromethyl)phenyl) acetamide (IV).

Yield: 121gms (85.5 %)

The intermediate 2-cyano-N-(4-(trifluoromethyl)phenyl) acetamide was characterized by an X-ray powder diffraction data (Table 1) and the diffraction pattern substantially as depicted in Figure 1.

Table 1:  X-ray powder diffraction peak data for crystalline 2-cyano-N-(4-(trifluoromethyl)phenyl) acetamide 

  

Serial No.

2θ (± 0.2deg)

    1

2.3

2

10.8

3

12.8

4

13.6

5

15.8

6

17.4

7

18.8

8

19.5

9

19.8

10

20.0

11

21.7

12

22.8

Serial No.

2θ (± 0.2deg)

25

35.3

26

35.7

27

36.3

28

37.0

29

39.1

30

39.6

31

40.0

32

41.2

33

45.0

34

46.1

35

48.4

36

49.0

Serial No.

2θ (± 0.2deg)

13

23.3

14

24.7

15

25.1

16

25.8

17

27.4

18

27.9

19

28.5

20

29.0

21

29.6

22

30.0

23

31.6

24

32.1

        

      

                                                   

 

Fig. 1: X-ray powder diffraction pattern of crystalline 2-cyano-N-(4-(trifluoromethyl)phenyl) acetamide    

Example 2: Preparation of Com...