Abstract: The present invention related to novel crystalline forms of methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo [2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4] hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate compound of formula (I) and their process for the preparation thereof.
1. Crystalline form-M of methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-
2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-1H-
benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-
methyl-1-oxobutan-2-yl] carbamate of formula (I) characterized by:
i) Powder X-ray diffractogram peaks at about 3.1, 6.3, 7.6, 8.5, 9.0, 10.2, 12.2, 12.7,
13.5, 14.1, 15.4, 16.5, 17.3, 17.6, 18.3, 19.4, 20.3, 21.0, 22.9, 23.2, 25.8, 26.4, 27.5,
29.3 ± 0.2 degrees of two-theta;
ii) powder X-ray diffraction pattern as shown in figure-1.
2. A process for the preparation of crystalline form-M of methyl [(2S)-1-{(6S)-6-[5-(9,9-
difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-
azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-
5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate of formula (I),
comprising of:
a) Suspending methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) adding suitable anti-solvent to the reaction mixture at a suitable temperature,
d) stirring the reaction mixture,
e) cooling the reaction mixture to a suitable temperature,
f) isolating crystalline form-M of compound of formula (I).
3. A process for the preparation of crystalline form-M of methyl [(2S)-1-{(6S)-6-[5-(9,9-
difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-
azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-
5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate of formula (I),
comprising of:
a) Suspending methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate in dimethylformamide,
b) heating the reaction mixture to 55-60ºC,
c) adding methyl tert-butyl ether to the reaction mixture at 55-60ºC,
d) stirring the reaction mixture,
e) cooling the reaction mixture to 25-30ºC,
f) isolating crystalline form-M of compound of formula (I).
4. The process according to claim 3, wherein in step-a), the suitable solvent is selected from polar aprotic solvents, alcohol solvents having C1-C5 carbon atoms, chloro solvents, hydrocarbon solvents, ester solvents or mixtures thereof; in step-b), the suitable temperature ranging from 30°C to the reflux temperature of the suitable solvent; in step-c), the suitable anti-solvent is selected from ether solvents, hydrocarbon solvents; in step-e), the suitable temperature is ranging from -25°C to 30°C.
5. Crystalline Form-S of methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benz--imidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate of formula (I) is characterized by:
i) powder X-ray diffractogram peaks at about 7.4, 8.5, 9.2, 9.5, 11.2, 12.1, 12.6, 13.2,
17.7, 18.5, 19.9, 20.4, 20.7, 22.3, 22.6, 23.1, 24.3, 26.2 ± 0.2 degrees of two theta
values;
ii) powder X-ray diffractogram pattern as shown in figure-2.
6. A process for the preparation of crystalline Form-S of methyl [(2S)-1-{(6S)-6-[5-(9,9-
difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-
azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-
5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate of formula (I),
comprising the steps of:
a) Suspending methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-1H-
benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid to provide crystalline Form-S of compound of formula (I).
7. A process for the preparation of crystalline form-S of methyl [(2S)-1-{(6S)-6-[5-(9,9-
difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-
azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-
5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate of formula (I),
comprising the steps of:
a) Suspending methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate in n-heptane,
b) heating the reaction mixture to 60-65ºC,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 25-30ºC,
e) filtering the precipitated solid to provide crystalline Form-S of compound of formula (I).
8. Amorphous form of methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzim
-idazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-
oxobutan-2-yl] carbamate of formula (I) which is characterized by:
i) Its powder X-ray diffractogram pattern as illustrated in figure-3, ii) its DSC pattern as illustrated in figure-4,
9. A process for the preparation of amorphous form of methyl [(2S)-1-{(6S)-6-[5-(9,9-
difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-
azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-
5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate, comprising the steps of:
a) Suspending methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl] carbamate in a mixture of acetone and water,
b) heating the reaction mixture to 60-65ºC,
c) stirring the reaction mixture,
d) cooling the reaction mixture to a 25-30º,
e) filtering and drying the obtained compound to provide amorphous form of compound of formula (I).
10. The process according to claim 6) and claim 9), in step-a) the suitable solvent is selected from polar solvents, ketone solvents, water or mixtures thereof; in step-b), the suitable temperature used is ranging from 30°C to the reflux temperature of the suitable solvent; in step-d), the suitable temperature is ranging from -25°C to 30°C.
| # | Name | Date |
|---|---|---|
| 1 | 201641015652-Other Patent Document-050516.pdf | 2016-06-01 |
| 2 | 201641015652-Form 2(Title Page)-050516.pdf | 2016-06-01 |
| 3 | 201641015652-Form 1-050516.pdf | 2016-06-01 |
| 4 | OTHERS [03-05-2017(online)].pdf | 2017-05-03 |
| 5 | Drawing [03-05-2017(online)].pdf | 2017-05-03 |
| 6 | Description(Complete) [03-05-2017(online)].pdf_92.pdf | 2017-05-03 |
| 7 | Description(Complete) [03-05-2017(online)].pdf | 2017-05-03 |
| 8 | Assignment [03-05-2017(online)].pdf | 2017-05-03 |
| 9 | Correspondence by Applicant_ Form 5,Complete Specification_08-05-2017.pdf | 2017-05-08 |