Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts
AssigneeAdvenchen Pharmaceuticals, LLC
InventorsGuoqing Paul Chen, Changren Yan
Life of this patent
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Abstract
The present invention relates a new process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818). A stable crystalline form of A13818 has been prepared. Salts and their crystalline forms of AL3818 have been also prepared. Anti-cancer and optometric activities of AL3818 and its salts have been further tested. New process has been outlined in Scheme I.
Claims24
A process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)methyl)cyclopropanamine (AL3818) by condensing intermediate (X1) with (Y1) in a solvent at the presence of KI or NaI, or intermediate (X2) with (Y2) to form intermediate (Z) which is deprotected to give the final compound (AL3818) in Scheme I.
- Wherein
- R is selected from H and C1-C6alkoxy;
- R is further selected from H and —OMe.
A salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)-methyl)-cyclopropanamine, wherein the salt is selected from:
- a bishydrochloride acid salt, a bishydrochloridehydrate acid salt, a bismaleic acid salt and a succinic acid salt.
A crystalline form of the succinic acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)methyl)cyclopropanamine according claim 11 wherein the crystalline form exhibits a XRPD having 7 of the following characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows:
- NO.
- Angle
- d value
- Intensity (%)
- 1
- 5.765
- 15.31849
- 12.9
- 2
- 8.038
- 10.98994
- 7.4
- 3
- 11.639
- 7.59700
- 27.7
- 4
- 12.950 6
- 6.83065
- 100
- 5
- 16.141 5
- 5.48683
- 18.0
- 6
- 17.483 5
- 5.06846
- 18.7
- 7
- 18.385
- 4.82175
- 17.8
- 8
- 19.394
- 4.57325
- 1.1
- 9
- 20.756
- 4.27609
- 13.4
- 10
- 22.034
- 4.03092
- 2.8
- 11
- 23.167
- 3.83630
- 1.8
- 12
- 24.085
- 3.69200
- 16.9
- 13
- 24.485
- 3.63268
- 14.6
- 14
- 25.737
- 3.45874
- 13.7
- 15
- 28.621
- 3.11637
- 6.4
- 16
- 29.255
- 3.05025
- 22.1
- 17
- 31.357
- 2.85048
- 0.9
- 18
- 31.967
- 2.79743
- 2.1
- 19
- 35.630
- 2.51780
- 2.4
A pharmaceutical composition comprising:
- a bishydrochloride acid, bishydrochloridehydrate acid, bismaleic acid or succinic acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine;
- and
- a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.