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
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 Al3818 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.
1. A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine of AL3818 exhibiting at least one of following characters:
a melting point at 208° C.-210° C.;
a DSC Melting Range (Endo): 207-220° C. with Peak Temp=216° C., pattern shown in FIG. 1 ;
a TGA thermogram that doesn't exhibit significant weight loss until at 205-215° C., pattern shown in FIG. 2 .
2. A crystalline form of 1-((4-(4-Fluoro-1-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 10 characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows:
Angle
d value
13.344
6.62986
15.858
5.58405
16.799
5.27326
17.640
5.02377
18.770
4.72373
20.650
4.29771
21.633
4.10463
23.087
3.84934
25.128
3.54112
26.607
3.34755.
3. A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 26 characteristic peaks with all intensity % expressed in d values and angles as follows:
d
Intensity
NO.
Angle
value
(%)
1
10.892
8.11623
2.1
2
11.589
7.62991
6.1
3
12.195
7.25174
5.9
4
13.344
6.62986
36.2
5
15.858
5.58405
31.5
6
16.799
5.27326
77.9
7
17.640
5.02377
18.8
8
18.770
4.72373
11.9
9
19.987
4.43884
7.2
10
20.650
4.29771
42.0
11
21.633
4.10463
15.3
12
23.087
3.84934
100.0
13
24.356
3.65157
3.5
14
25.128
3.54112
14.6
15
25.669
3.46768
3.8
16
26.607
3.34755
18.0
17
26.607
3.34755
3.1
18
29.050
3.07132
5.7
19
29.797
2.99602
1.5
20
30.681
2.91167
4.3
21
31.853
2.80718
1.2
22
33.524
2.67095
2.8
23
34.789
2.57667
2.6
24
35.873
2.50131
2.2
25
37.391
2.40313
3.9
26
38.637
2.32846
1.4.
4. A pharmaceutical composition that comprises as an active ingredient a compound as defined in claim 1 of the compound and a pharmaceutically acceptable carrier.
5. A method of treating an optometric disease, said method comprising administering a compound as defined in claim 1 .
6. A method of treating as claimed in claim 5 , wherein an optometric disease is AMD and the combing anti-VEGF antibody is ranibizumab, or the VEGF trap is aflibercep.
7. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising a compound as defined in claim 1 and pharmaceutically acceptable excipients to a subject in need thereof.
8. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 1 with an anti-VEGF antibody or VEGF trap to a subject in need thereof.
9. A process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yl-oxy)methyl)cyclopropanamine (AL3818) according to claim 1 where AL3818 can be prepared according to Process A1 when R is H by deprotecting intermediate (Z-1) with HCOONH4 (ammonium formate) and Pd/C in an alcoholic solvent at 25° C.-80° C. for 0.1-4 hours (Z-1) can be prepared by reacting intermediate (X1) with (Y1-1) at the presence of KI or NaI with K 2 CO 3 in acetone or DMF at a temperature of 60° C.−160° C. for 2-24 hours.