PROCESSES FOR PREPARING AN S1P-RECEPTOR MODULATOR
This application relates to processes for preparing an S1P-receptor modulator, which is useful in the treatment of diseases or disorders associated with activity of S1P, including CNS disorders.
1 . A process for preparing Compound 1 having the formula:
or a salt thereof, comprising reacting Compound 2, having the formula:
with Compound 3, having the formula:
in the presence of RA1, wherein RA1 is a reducing agent, to provide Compound 1, or a salt thereof.
2 . The process of claim 1 , wherein RA1 is a hydride reducing agent.
3 . The process of claim 1 , wherein RA1 is sodium cyanoborohydride.
4 . The process of claim 1 , wherein the reacting of Compound 2 with Compound 3 is performed in the presence of S1, wherein S1 is a protic solvent.
5 . The process of claim 4 , wherein S1 is methanol.
6 . The process of claim 1 , wherein the reacting of Compound 2 with Compound 3 comprises using about 1 to about 2 molar equivalents of Compound 3 relative to Compound 2.
7 . The process of claim 1 , wherein the reacting of Compound 2 with Compound 3 comprises using about 1 to about 3 molar equivalents of RA1 relative to Compound 2.
8 . The process of claim 1 , wherein the reacting of Compound 2 with Compound 3 is performed at room temperature.
9 . The process of claim 1 , further comprising precipitating Compound 1 from a solution comprising Compound 1 and Sla, wherein Sla is an aprotic solvent.
10 . The process of claim 9 , wherein Sla is DMSO.
11 . The process of claim 1 , further comprising precipitating Compound 1 from a solution comprising Compound 1 and S1b, wherein S1b is a mixture of a protic solvent and A1, wherein A1 is an acid.
12 . The process of claim 11 , wherein S1b is a mixture of water and A1.
13 . The process of claim 11 , wherein A1 is acetic acid.
14 . The process of claim 1 , wherein Compound 2 is prepared by a process comprising reacting Compound 4, having the formula:
with A2, wherein A2 is an acid.
15 . The process of claim 14 , wherein A2 is an organic acid.
16 . The process of claim 14 , wherein A2 is trifluoroacetic acid.
17 . The process of claim 14 , wherein the reacting of Compound 4 with A2 is performed in the presence of S2, wherein S2 is a halogenated solvent.
18 . The process of claim 17 , wherein S2 is methylene chloride.
19 . The process of claim 14 , wherein the reacting of Compound 4 with A2 comprises using about 1 to about 20 molar equivalents of A2 relative to Compound 4.
20 . The process of claim 14 , wherein the reacting of Compound 4 with Compound A2 is performed at room temperature.
21 . The process of claim 14 , wherein Compound 4 is prepared by a process comprising reacting Compound 5, having the formula:
with a compound of Formula II:
wherein X is Br, Cl, or I, in the presence of B1, wherein B1 is a base.
22 . The process of claim 21 , wherein X is Br or Cl.
23 . The process of claim 21 , wherein X is Br.
24 . The process of claim 21 , wherein B1 is a carbonate base.
25 . The process of claim 21 , wherein B1 is potassium carbonate.
26 . The process of claim 21 , wherein the reacting of Compound 5 with the compound of Formula II in the presence of B1 is performed in the presence of S3, wherein S3 is a polar aprotic solvent.
27 . The process of claim 26 , wherein S3 is acetonitrile.
28 . The process claim 21 , wherein the reacting of Compound 5 with the compound of Formula II in the presence of B1 comprises using about 1 to about 5 molar equivalents of the compound of Formula II relative to Compound 5.
29 . The process of claim 21 , wherein the reacting of Compound 5 with the compound of Formula II in the presence of B1 comprises using about 1 to about 5 molar equivalents of B1 relative to Compound 5.
30 . The process of claim 21 , wherein the reacting of Compound 5 with the compound of Formula II in the presence of B1 is performed at a temperature between about 45° C. and about 55° C.
31 . The process of claim 21 , wherein Compound 5 is prepared by a process comprising reacting Compound 6 having the formula:
with B4, wherein B4 is a base.
32 . The process of claim 31 , wherein B4 is sodium hydroxide.
33 . The process of claim 31 , wherein the reacting of Compound 6 with B4 can be performed in the presence of S4, wherein S4 is a polar solvent.
34 . The process of claim 33 , wherein S4 is water.
35 . The process of claim 31 , wherein Compound 6 is prepared by a process comprising reacting Compound 7 having the formula:
with P1, wherein P1 is a phosphorous reagent.
36 . The process of claim 35 , wherein P1 is triphenylphosphine or phosphorous tribromide.
37 . The process of claim 35 , wherein the reacting of Compound 7 with P1 can be performed in the presence of S5, wherein S5 is a polar aprotic solvent.
38 . The process of claim 37 , wherein S5 is acetonitrile or THF.
39 . The process of claim 35 , wherein the reacting of Compound 7 with P1 is further performed in the presence of a mixture of pyridine and hexachloroethane.
40 . The process of claim 35 , wherein Compound 7 is prepared by a process comprising reacting Compound 8 having the formula:
wherein R is C 1-2 alkyl;
with A3, wherein A3 is an acid.
41 . The process of claim 40 , wherein A3 is HCl.
42 . The process of claim 40 , wherein the reacting of Compound 8 with A3 can be performed in the presence of S6, wherein S6 is a polar aprotic solvent.
43 . The process of claim 42 , wherein S6 is ethyl acetate.
44 . The process of claim 40 , wherein R is ethyl.
45 . The process of claim 40 , wherein R is methyl.
46 . The process of claim 40 , wherein Compound 8 is prepared by a process comprising reacting Compound 9 having the formula:
with Compound 12 having the formula:
wherein R is C 1-2 alkyl, in the presence of B3, wherein B3 is a base.
47 . The process of claim 46 , wherein B3 is triethylamine.
48 . The process of claim 46 , wherein the reacting of Compound 9 with Compound 12 can be performed in the presence of S7, wherein S7 is a polar aprotic solvent.
49 . The process of claim 48 , wherein S7 is ethyl acetate.
50 . The process of claim 46 , wherein Compound 12 is prepared by a process comprising reacting Compound 13 having the formula:
with sodium C 1-2 alkoxide.
51 . The process of claim 50 , wherein the sodium C 1-2 alkoxide is sodium methoxide.
52 . The process of claim 50 , wherein the sodium C 1-2 alkoxide is sodium ethoxide.
53 . The process of claim 51 , wherein the reacting of Compound 13 with sodium methoxide is performed in the presence of S10, wherein S10 is methanol.
54 . The process of claim 52 , wherein the reacting of Compound 13 with sodium ethoxide is performed in the presence of S10, wherein S10 is ethanol.
55 . Compound 1, or a salt thereof, prepared by the process of claim 1 .
56 . A compound of Formula Ia:
or a salt thereof, wherein R 1 is H, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted by 1-5 halo, or optionally substituted by a C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl group.
57 . The compound of claim 56 wherein R 1 is C 1-6 alkyl.
58 . A compound, having the following formula:
or a salt thereof.
59 . A compound, having the following formula:
or a salt thereof.
60 . A compound of Formula Ib:
or a salt thereof, wherein R 1 is H, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted by 1-5 halo, or optionally substituted by a C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl group.
61 . The compound of claim 60 wherein R 1 is C 1-6 alkyl.
62 . A compound, having the following formula:
or a salt thereof.