1. A process for the preparation of Ruxolitinib phosphate of formula (1),
which comprises:
5 a) reacting 4-chloro-7H-pyrrolo[2,3-d] pyrimidine of formula (12)
with (2-(chloro methoxy) ethyl) trimethyl silane of formula (11)
in the presence of a base to provide 4-chloro-7-((2-(trimethyl silyl) ethoxy)
10 methyl)-7H-pyrrolo [2,3-d] pyrimidine of formula (10);
b) reacting the compound of formula (10) with the compound of formula (9)
in the presence of catalyst and a base to provide 4-(1H-pyrazol-4-yl)-7-((2-
15 (trimethylsilyl) ethoxy) methy1)-7H-pyrrolo[2,3-d] pyrimidine of formula
(8);
24
c) reacting compound of formula (8) with (E)-3-cyclopentylacrylonitrile of
formula (7)
5 in the presence of a base to provide 3-cyclopentyl-3-(4-(7-((2-(trimethyl
silyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)- l H-pyrazol- l -y1)
propane nitrile of formula (6);
d) deprotecting 3-cyclopentyl-3-(4-(7-((2-(trimethyl silyl) ethoxy) methyl)-7H10 pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl) propane nitrile of formula
(6) with boron trifluoride diethyl etherate to provide 3-cyclopentyl-3-(4-(7-
(hydroxymethyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)
propane nitrile of formula (5);
15 e) treating the compound of formula (5) with an organic base in water to
provide 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-
cyclopentylpropanenitrile of formula (4);
25
f) treating the compound of formula (4) with phosphoric acid and a solvent
(IPA) to provide 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-
3-cyclopentylpropanenitrile phosphate of formula (3);
5
g) reacting the compound formula (3) with a base followed by resolution to
provide (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-
cyclopentylpropanenitrile (2S,3S)-2,3-bis(benzoyloxy)succinate of formula
(2);
10
h) treating the compound of formula (2) with aqueous sodium carbonate
solution to provide Ruxolitinib (1a), further treating with phosphoric acid to
obtain Ruxolitinib phosphate of formula (1); and
i) optionally, purifying Ruxolitinib phosphate using suitable solvents.
15 2. The process as claimed in claim 1, wherein in step a) the base is selected
from sodium methoxide, sodium ethoxide, sodium tertiary butoxide,
potassium methoxide, potassium ethoxide, potassium tert-butoxide and/or
mixtures thereof.
26
3. The process as claimed in claim 1, wherein in step b) the catalyst is selected
from Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf),
PdCl2(dppf).CH2Cl2, PdCl2(dppp), Cyclopentadienyl allyl palladium,
allylpalladium(II) chloride dimer (Pd(allyl)Cl)2,(2-Butenyl) chloro
5 palladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-
phenylallyl)chloride dimer, di-μ-chlorobis[2-(amino-N)[1,1’-biphenyl]-2-
yl-C]dipalladium(II), di-μ-chloro bis[2-(dimethylamino)15 methyl]phenylC,N]dipalladium(II), dichloro[9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene]palladium (Pd(Xantphos)Cl2).
10 4. The process as claimed in claim 1, wherein in step b) the base is selected
from sodium acetate, sodium diacetate, potassium acetate, calcium acetate,
magnesium acetate, ammonium acetate and/or mixtures thereof.
5. The process as claimed in claim 1, wherein in step c) the base is selected
from sodium carbonate, potassium carbonate, lithium carbonate and/or
15 mixtures thereof.
6. The process as claimed in claim 1, where in step e) the organic base is
selected from ethylenediamine, monomethylamine or triethylamine.
7. The process as claimed in claim 1, wherein in step g) the resolving agent is
selected from mandelic acid, 2-chloromandelic acid, camphor sulfonic acid,
20 tartaric acid, lactic acid, malic acid, acetyl mandelic acid, 3-bromocamphor8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic
acid, «dibenzoyl tartaric acid, (+)-di-p-toluoyl tartaric acid, (-)-di-p-toluoyl
tartaric acid, (-)-DBTA and (+)-DBTA.
8. The process as claimed in claim 1, wherein in step g) the base is selected
25 from sodium carbonate, potassium carbonate, lithium carbonate and/or
mixtures thereof.
9. The process as claimed in claim 1, wherein the solvent used in each step is
selected from polar aprotic solvents, alcohol solvents, hydrocarbon
solvents, nitrile solvents, and polar solvents such as water.