Process for preparing 1-([3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide
The application relates to processes for the preparation of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl) amino]pyrazole-4-carboxamide (I) which include (i) a synthesis for bromo and iodo pyridine intermediates, (ii) a synthesis of a pyrazole ester intermediate which can be obtained in enantiopure form and (iii) the combination of these intermediates into compound (I).
1 . A process for making a compound of Formula (I)
comprising
a. reacting a compound of Formula (VI)
wherein R 1 is C 1 -C 4 alkyl
with a compound of Formula (XII)
in the presence of a catalyst and of a base wherein R is I or Br, to yield a compound of Formula (XIII)
and
b. converting the compound of Formula (XIII) to the compound of Formula (I).
2 . The method of claim 1 , further comprising a. reacting the compound of Formula (XIII) in the presence of a trialkylamine with a lithium salt, to yield a compound of Formula (XIV)
and
b. converting the compound of Formula (XIV) to the compound of Formula (I).
3 . The method of claim 2 , further comprising forming an active intermediate of the compound of Formula (XIV) and then reacting with ammonia or an ammonia equivalent, in the presence of a base to yield the compound of Formula (I).
4 . A process for making a compound of Formula (XII),
wherein R is I,
comprising
a. reacting a compound of Formula (IX)
with iodine and a lithium amide base, to yield a compound of Formula (X)
and
b. converting the compound of Formula (X) to the compound of Formula (XII).
5 . The process of claim 4 , further comprising in step b reacting the compound of Formula (X) in the presence of a lithium amide base to yield a compound of Formula (XII)a
6 . The process of claim 5 , wherein the compound of Formula (X) is not isolated and purified before being carried on to the compound of Formula (XIIa).
7 . A process for making a compound of Formula (XII),
wherein R is Br,
comprising
a. reacting a compound of Formula (VII)
with an iridium catalyst and bis (pinacolato) diboron to yield a compound of Formula (VIII)
and
b. converting the compound of Formula (VIII) to the compound of Formula (XII).
8 . The process of claim 7 , further comprising
a. reacting the compound of Formula (VIII) with a brominating agent to yield a compound of Formula (XI)
and
b. converting the compound of Formula (XI) to the compound of Formula (XII).
9 . The process of claim 8 , further comprising reacting the compound of Formula (XI) with an alkali methoxide, to yield a compound of Formula (XIIb)
10 . A process for making a compound of Formula (VI)
wherein R 1 is C 1 -C 4 alkyl
comprising
a. reacting a compound of Formula (II)
with
i. Hydrogen cyanide or an equivalent thereof and
ii. POCl 3 or SOCl 2
to yield a compound of Formula (III)
and
b. converting the compound of Formula (III) to the compound of Formula (VI).
11 . The process of claim 10 , further comprising
a. reacting the compound of Formula (III) with a compound of Formula (IV) in the presence of a base
wherein R 1 is C 1 -C 4 alkyl
to yield a compound of Formula (V)
wherein R 1 is C 1 -C 4 alkyl; and
b. converting the compound of Formula (V) to the compound of Formula (VI).
12 . The process of claim 11 , further comprising separating the enantiomers of the compound of Formula (V) to give the compound of Formula (VI).
13 . The process of claim 12 , wherein the separation of enantiomers is achieved by chiral chromatography.
14 . A compound of Formula (V)
wherein R 1 is C 1 -C 4 alkyl.
15 . The compound of claim 14 , wherein the compound is the compound of Formula (VI)
wherein R 1 is C 1 -C 4 alkyl.
16 . A compound of Formula (XIII)
wherein R 1 is C 1 -C 4 alkyl.
17 . A compound of Formula (XIV)
18 . The process of claim 1 , wherein in R 1 of the compound of Formula (VI) is ethyl.
19 . The process of claim 10 , wherein in R 1 of the compound of Formula (VI) is ethyl.
20 . The compound of claim 14 , wherein in R 1 is ethyl.
21 . The compound of claim 15 , wherein in R 1 is ethyl.
22 . The compound of claim 16 , wherein in R 1 is ethyl.
23 . The process of claim 8 , wherein the brominating agent is copper (II) bromide or copper (I) bromide associated to an oxidant.
24 . The process of claim 10 , wherein the hydrogen cyanide equivalent is trimethylsilyl cyanide (TMSCN).
25 . The process of claim 11 , wherein the base is potassium phosphate tribasic or potassium acetate.