METHODS AND INTERMEDIATES FOR PREPARING JAK INHIBITORS
Improved processes and intermediates for preparing ruxolitinib, deuterated analogs of ruxolitinib, and other JAK inhibitors are disclosed.
1 . A process for preparing a compound of Formula E:
the process comprising the step of reacting a compound of Formula B:
a compound of Formula C:
C or a mixture thereof
with formamidine or a salt thereof, or with a trialkyl orthoformate and an ammonium source, or with dimethylformamide dimethyl acetal and an ammonium source;
wherein R 1 is selected from H and a protecting group (PG), and wherein each R 3 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl, or the two R 3 s, taken together with the oxygen atoms to which they are attached, form a 5-7-membered heterocyclic ring which may optionally be substituted.
2 . The process of claim 1 , wherein R 1 is H.
3 . The process of claim 1 , wherein R 1 is a protecting group.
4 . The process of claim 3 , wherein R 1 is a protecting group which is benzyl.
5 . The process of any one of claims 1 - 4 , wherein R 3 is methyl.
6 . The process of any one of claims 1 - 4 , wherein R 3 is ethyl.
7 . The process of any one of claims 1 - 6 , wherein the process comprises reacting a compound of Formula B with formamidine or a salt thereof, or with a trialkyl orthoformate, or with dimethylformamide dimethyl acetal.
8 . The process of any one of claims 1 - 6 , wherein the process comprises reacting a compound of Formula C with formamidine or a salt thereof, or with a trialkyl orthoformate, or with dimethylformamide dimethyl acetal.
9 . The process of any one of claims 1 - 8 , wherein the step of reacting is performed in a protic solvent.
10 . The process of claim 9 , wherein the protic solvent is methanol or n-butanol.
11 . The process of any one of claims 1 - 8 , wherein the step of reacting is performed in an aprotic solvent.
12 . The process of claim 11 , wherein the aprotic solvent is toluene.
13 . The process of any one of claims 1 - 12 , wherein the process comprises the step of reacting a compound of Formula B with formamidine or a salt thereof.
14 . The process of claim 13 , wherein the formamidine or salt thereof is formamidine acetate.
15 . The process of any one of claims 1 - 7 and 9 - 12 , wherein the process comprises the step of reacting a compound of Formula B with ammonium acetate and trimethyl orthoformate.
16 . A process for preparing a compound of Formula E:
the process comprising the step of reacting a compound of Formula A:
with formamidine or a salt thereof, or with an ammonium source and a trialkylorthoformate;
wherein R 1 is selected from H and a protecting group (PG), and wherein each R is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl, or the two R 3 s, taken together with the oxygen atoms to which they are attached, form a 5-7-membered heterocyclic ring which may optionally be substituted; and
the ammonium source is ammonia or an ammonium salt; provided that if each R 3 is ethyl, R 1 is not H.
17 . The process of claim 16 , wherein R 1 is H.
18 . The process of claim 16 , wherein R 1 is a protecting group.
19 . The process of claim 18 , wherein R 1 is a protecting group which is benzyl.
20 . The process of any one of claims 16 - 19 , wherein R 3 is methyl.
21 . The process of any one of claims 16 - 19 , wherein R 3 is ethyl.
22 . The process of claim 16 , wherein the ammonium source is an ammonium salt.
23 . The process of claim 22 , wherein the ammonium salt is ammonium acetate.
24 . The process of any one of claims 16 - 23 , wherein the step of reacting is performed in an aprotic solvent.
25 . The process of claim 24 , wherein the aprotic solvent is bis(2-methyoxyethyl)ether.
26 . The process of any one of claims 16 - 23 , wherein the step of reacting is performed in a protic solvent.
27 . The process of claim 26 , wherein the protic solvent is methanol.
28 . The process of any one of claims 16 - 27 , wherein the process comprises the step of reacting a compound of Formula A with formamidine or a salt thereof.
29 . The process of claim 28 , wherein formamidine or salt thereof is formamidine acetate.
30 . The process of any one of claims 16 - 28 , wherein the process comprises the step of reacting a compound of Formula A with ammonium acetate and a trialkylorthoformate.
31 . A process for preparing a compound of Formula 7:
the process comprising the step of reacting a compound of Formula 6a:
with formamidine or a salt thereof, or with trimethyl orthoformate, or with dimethylformamide dimethyl acetal;
wherein R 1 is selected from H or a protecting group (PG).
32 . The process of claim 31 , wherein R 1 is H.
33 . The process of claim 31 , wherein R 1 is a protecting group which is benzyl (Bn).
34 . A process for preparing a compound of Formula 7:
the process comprising the step of reacting a compound of Formula 5:
with formamidine or a salt thereof; or with an ammonium source and trialkyl orthoformate;
or with an ammonium source and dimethylformamide dimethylacetal;
wherein R 1 is selected from H or a protecting group (PG).
35 . The process of claim 34 , wherein R 1 is H.
36 . The process of claim 34 , wherein R 1 is a protecting group which is benzyl (Bn).
37 . A compound represented by the structure:
or a salt thereof
wherein Bn is a benzyl group.
38 . A process for preparing a compound of Formula 5:
the process comprising the step of reacting a compound of Formula 1:
with Compound 4
and a base;
wherein R 1 is selected from H or a protecting group (PG), and wherein R 2 is C 1 -C 4 alkyl.
39 . The process of claim 38 , wherein R 1 is H.
40 . The process of claim 38 , wherein R 1 is a protecting group which is benzyl (Bn).
41 . The process of any one of claims 38 - 40 , wherein R 2 is methyl.
42 . The process of any one of claims 38 - 40 , wherein R 2 is ethyl.
43 . The process of any one of claims 38 - 42 , wherein the base is NaHMDS.
44 . A process for preparing a compound of Formula 6a:
the process comprising the step of reacting a compound of Formula 5:
with an ammonium source;
wherein R 1 is selected from H or a protecting group (PG).
45 . The process of claim 44 , wherein R 1 is H.
46 . The process of claim 44 , wherein R 1 is a protecting group which is benzyl (Bn).
47 . The process of any one of claims 44 - 46 , wherein the ammonium source is selected from ammonium formate, ammonium chloride and ammonium acetate.
48 . A compound represented by the structure:
or a salt thereof
wherein Bn is a benzyl group.
49 . A compound represented by the structure:
or a salt thereof.
50 . A compound represented by the structure:
or a salt thereof.
51 . A compound represented by the structure:
or a salt thereof
wherein Bn is a benzyl group.
52 . A compound represented by the structure:
or a salt thereof.