DESC:FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
“PROCESS FOR PREPARATION OF RUXOLITINIB”
Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at Plot No. 170-172,
Chandramouli Industrial Estate,
Mohol Bazarpeth, Solapur 413213
The following specification describes the nature of the invention:
2
Field of Invention
The present invention provides a process for the preparation of ruxolitinib or a salt thereof.
Background of Invention
Ruxolitinib which is chemically known as, (R)-3-(4-(7H-pyrrolo [2,3d]pyrimidin-5 4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, is represented by a compound of formula I,
I
Ruxolitinib is marketed as ruxolitinib phosphate and is indicated for the treatment 10 of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thromocythemia myelofibrosis.
Summary of the Invention
In one embodiment, the present invention provides a process for the preparation of 15 ruxolitinib, a compound of formula I or salt thereof,
I
comprising the steps of:
a) reacting a compound of formula III with a compound of formula IV to obtain a 20 compound of formula II;
3
III IV II
wherein R1 is a nitrogen protecting group and R2 is a hydroxyl protecting group;
b) deprotecting the compound of formula II to obtain ruxolitinib, a compound of
5 formula I; and
c) optionally, converting the obtained ruxolitinib to its salt.
In one embodiment, the present invention provides a compound of formula IIIa
IIIa
10 Brief description of drawing
Fig 1 is characteristic XRPD of ruxolitinib as obtained in example 4.
Fig 2 is characteristic DSC of ruxolitinib as obtained in example 4.
Detailed description of the invention
In one embodiment, the present invention provides a process for the preparation of
15 ruxolitinib, a compound of formula I or salt thereof,
I
comprising the steps of:
4
a) reacting a compound of formula III with a compound of formula IV to obtain a compound of formula II;
III IV II
wherein R1 is a nitrogen protecting group and R2 is a hydroxyl protecting group; 5
b) deprotecting the compound of formula II to obtain ruxolitinib, a compound of formula I; and
c) optionally, converting the obtained ruxolitinib to its salt.
In one embodiment, R1 may be selected from the group consisting of H, arylalkyl, acyl, lower alkoxycarbonyl, arylkyloxy carbonyl, lower alkanesulfonyl, 10 arylsulfonyl, tri(lower alkyl)silyl, triphosgene.
In one embodiment, R1 may be selected from the group consisting of benzyl, tosyl, mesyl, tertiary-butyloxy carbonyl and carbobenzyloxy.
In one embodiment, R2 may be selected from the group consisting of SO2R3 wherein R3 is C1-C6 alkyl, haloalkyl. The halo may be selected from chloro, bromo 15 or iodo.
In one embodiment, R2 may be selected from the group consisting phenyl or optionally substituted phenyl; benzyl or optionally substituted benzyl, allyl, trityl; C(O)R4 wherein R4 is H, alkyl or substituted alkyl.
In one embodiment, in step a) R1 is tosyl. 20
In one embodiment, in step a) R2 is SO2CF3.
In one embodiment, in step a) the compound of formula III is reacted with a compound of formula IV in presence of a base and a solvent.
The base may be organic or inorganic base. The inorganic base may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide and 25
5
the like; carbonates such as sodium carbonate, potassium carbonate and the like; bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide and the like. The organic base may be selected from the group consisting of organic base may be selected from but is not limited to morpholine, 5 diethylamine, diisobutylamine, dibenzylamine, dicyclohexylamine, tert-butyl amine, cyclopropyl amine, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine and the like.
In one embodiment, the reaction may be carried out in the presence of a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-10 propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl 15 alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; amides such as dimethyl acetamide, dimethyl formamide; water; or mixtures thereof.
In one embodiment, the reaction may be carried out at a temperature ranging from 20 about 0?C to about reflux temperature of the solvent. In one embodiment, the reaction may be carried out at temperature from about 70?C to about 95?C.
In one embodiment, in step b), the deprotection of compound of formula II, depending on the protecting group may be carried out using either a base or acid.
In one embodiment, the base used for deprotection may be a base as discussed 25 above.
In one embodiment, the acid may be an organic or inorganic acid. The organic acid used may include an acid such as formic acid, acetic acid, citric acid, tartaric acid, bitartaric acid, benzoic acid, lactic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid and the 30 like. The inorganic acid used may include an acid such as hydrochloric acid,
6
hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid,
trifluoroacetic acid, and the like. Preferred acids include trifluoroacetic acid,
hydrochloric acid and hydrobromic acid.
In one embodiment, the deprotection may be carried out in presence or absence of
5 a solvent.
The solvent in step b) is as discussed supra.
In one embodiment, in step c) the ruxolitinib may be optionally converted to a salt.
In one embodiment, the salt is phosphoric acid salt.
In one embodiment, the ruxolitinib is reacted with phosphoric acid in a suitable
10 solvent.
The solvent is as discussed supra.
In one embodiment, ruxolitinib the compound of formula II is reacted with
phosphoric acid at a temperature from about -5?C to about reflux temperature of the
solvent.
15 In one embodiment, the present invention provides a process for the preparation of
the compound of formula III comprising the steps of:
a) converting a compound of formula VIII to a compound of formula IX;
VIII IX
20 b) reducing the compound of formula IX to a compound of formula X; and
X; and
c) O-protecting the compound of formula X to obtain the compound of formula III.
25
III
7
In one embodiment, in step a) of the above process the compound of formula VIII
is reacted with cyano compound in presence of a base and solvent to obtain the
compound of formula IX.
The solvent and base are as discussed supra.
5 In one embodiment, the cyano compound is selected from the group consisting of
acetonitrile, propionitrile or butyronitrile.
In one embodiment, the cyano compound is acetonitrile.
In one embodiment, in step b) the compound of formula IX is reduced to obtain a
compound of formula X in presence of resolving agent and a reducing agent.
10 In one embodiment, in step b) the racemic compound of formula IX is reduced to
obtain a compound of formula X in presence of catalyst and a reducing agent.
The reducing agent borane dimethyl sulfide.
The catalyst is R-CBS [Corey Bakshi Shibata].
In one embodiment, step c) involves reacting the compound of formula X with a
15 hydroxy protecting group in presence of a base and a solvent to obtain the
compound of formula III.
In one embodiment, the protecting group may be selected from the group consisting
of tosyl, mesyl, triflate.
In one embodiment, the present invention provides a process for the preparation of
20 the compound of formula IV comprising the steps of:
a) converting compound of formula VII to a compound of formula VI; wherein, R5
is halo.
VII VI
25 b) reacting a compound of formula VI with a compound of formula V to obtain the
compound of formula IV.
8
VI V IV
In one embodiment, in step a) the compound of formula VII is reacted with an amine
protecting group in presence of a base to obtain a compound of formula VI.
5 In one embodiment halo is selected from chloro, bromo or iodo.
The reaction may be carried out at a temperature of about 0?C to about 35?C.
In one embodiment, in step b) the compound of formula VI reacted with pyrazole
compound of formula V in presence of base, solvent and a catalyst to obtain the
compound of formula IV.
10 In one embodiment, the solvent and the base are as discussed supra.
The catalyst may be an organometallic palladium complex selected from the group
consisting of palladium triphenyl phosphine or Bis (triphenyl phosphine) palladium
dichloride.
In one embodiment, the present invention provides a process for the preparation of
15 compound of formula V comprising treating a compound of formula XI with a
compound of formula XII.
V XI XII
In one embodiment, the above process comprises reacting the compound of formula
20 XI with XII in presence of phase transfer catalyst, alkali metal salt or alkaline earth
metal salt of an acid. The acid may be organic or inorganic acid.
In one embodiment, the reaction of the compound of formula XI with XII is carried
in presence of alkali metal salt of organic acid such as potassium acetate.
In one embodiment, the present invention provides a compound of formula IIIa
9
IIIa.
In one embodiment, the present invention provides a process for the preparation of crystalline ruxolitinib phosphate comprising the steps of:
a) contacting ruxolitinib phosphate with a solvent or mixture of solvents to obtain 5 a reaction mixture;
b) optionally, heating the reaction mixture of step a);
c) cooling the reaction mixture of step a) or step b);
d) isolating crystalline ruxolitinib phosphate.
In one embodiment, “contacting” refers to treating, suspending or slurrying. 10
In one embodiment, in step a) the solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, cyclohexane, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl 15 tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene 20 dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of crystalline ruxolitinib phosphate comprising the steps of:
a) contacting ruxolitinib phosphate with a solvent or mixture of solvents to obtain 25 a reaction mixture;
b) optionally, heating the reaction mixture of step a);
c) adding an antisolvent;
f) cooling the reaction mixture of step a) or step b);
10
g) isolating crystalline ruxolitinib phosphate.
In embodiment, in step a) the solvent is as discussed above.
In one embodiment, in step ‘c)’, the anti-solvent is selected from the group consisting of alcohols, ketones, nitriles, water, and mixtures thereof.
In one embodiment, in step ‘c)’, the anti-solvent is selected from the group 5 consisting of C1-C8 alcohols, C3-C10 ketones, C1-C3 nitriles, water, and mixtures thereof.
In one embodiment, in step ‘c)’, the anti-solvent is selected from the group consisting C1-8 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; C3-C10 ketones such as acetone, methyl 10 isobutyl ketone, ethyl methyl ketone and the like; C1-C3 nitrile solvents such as acetonitrile, propionitrile and the like; water; and mixtures thereof.
In one embodiment, crystalline ruxolitinib phosphate is isolated from a mixture of C1-C6 alcohol and ester.
In one embodiment, crystalline ruxolitinib phosphate is isolated from a mixture of 15 ethanol and ethyl acetate.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
20
11
Examples
Example 1: Preparation of 4-Chloro-7-tosylpyrrolo [2,3-d]-pyrimidine
4-Chloro-7H-pyrrolopyrimidine (10 g) and p-toluene sulfonyl chloride (19.99 g) in acetone (80 mL) was added to sodium hydroxide solution (5.73 g). Reaction mixture was stirred for about 4-6 hours at 25?C. Solid was precipitated and filtered, 5 washed with mixture of acetone and water to obtain 17 g (84.8%) of title compound.
Example 2: Preparation of 7-(4-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-7H-pyrrolo [2,3-d]pyrimidine
To a round bottom flask, added 4-chloro-7-tosyl-pyrrolo [2,3-d]-pyrimidine (10 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.56 g), K2CO3 10 (8.97 g), water (90 mL) and 1-butanol (180 mL) were added at 25-30?C. The resulting reaction mixture was degassed and treated with Pd(PPh3)4 (0.38 g) at 25-30?C. The reaction mixture was heated to reflux for about 8 to 12 hours. After completion, reaction mixture was cooled to 40-45°C, filtered through a celite bed. The layers were separated, and aqueous layer was extracted with ethyl acetate. The 15 organic layer was concentrated under reduced pressure to remove solvents, and the crude product was isolated with tetrahydrofuran to obtain 5 g (45 %) of solid material.
Example 3: Preparation of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile 20
(1S)-2-Cyano-1-cyclopentylethyl trifluoromethanesulfonate (9.58 g), 7-(4-Methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (10 g) were added to dimethyl formamide (50 mL) at 25-30?C to obtain a reaction mixture. Potassium carbonate was added to the reaction mixture and stirred at 90-95°C for five hours. The reaction mixture was concentrated under reduced pressure 25 at 40-45°C and the residue was diluted with ethyl acetate. Organic layer was washed with water and brine and pH was adjusted to 3-5 using concentrate HCl. The aqueous layer was washed with ethyl acetate and pH adjusted to 8-10 with 10% aqueous NaOH solution. Ethyl acetate was added. The layer separated and ethyl acetate layer was concentrated under vacuum to obtained residue. To this 30 dichloromethane was added at 25-30°C to obtain clear solution. Slowly added
12
phosphoric acid to obtain precipitation at 20-30°C. Heated reaction mass at 35-40°C for about 60 min, cooled to 25-30°C, charged ethyl acetate to the reaction mass and stirred for about 60 min. Filtered the slurry, washed solid with ethyl acetate. After vacuum drying obtained ruxolitinib phosphate. Yield: 3.0 g
Example 4: Preparation of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-5 d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile phosphate
10 g of crude (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile phosphate was dissolved in 5 mL of ethanol and 50 ml ethyl acetate by heating to 50°C for 60 minutes. Cooled reaction mass to 25-30°C. Stirred for about 120 minutes at 25-30°C, filtered and dried under vacuum, obtained about 10 8 g (80%) of solid.
Example 5: Preparation of 3-cyclopentyl-3-oxo-propionitrile
In presence of inert atmosphere charged 1,4-dioxane (100 ml), sodium hydride (2.02 g) and acetonitrile (3.46g) and stirred at room temperature for about 30 minutes. (10 g) Methyl cyclopentane carboxylate or ethyl cyclopentanecarboxylate 15 was added slowly to obtain a reaction mixture. The reaction mixture was stirred at 25-30°C for about 30 minutes, then slowly heated to 95-100°C for 5 hours. After completion of reaction, cooled to 0-5°C. Slowly added water at 0-5°C, charged dichloromethane and stirred for about 10 minutes. Separated both the organic layer and aqueous layer. Aqueous phase was acidified with a 1N HCl and extracted with 20 dichloromethane. Combined dichloromethane layers, washed with water. Distilled out dichloromethane layer under vacuum at 40-45°C and degassed for about 30 minutes to obtain desired compound (6.2 g, 64.3%).
Example 6: Preparation of (S)-3-cyclopentyl-3-hydroxypropionitrile
In nitrogen atmosphere charged tetrahydrofuran (100 ml), R-CBS (1.0 M in toluene, 25 7.2 ml) and borane dimethyl sulfide (2.0 M in tetrahydrofuran, 13 ml) were added, and the reaction temperature was cooled to 0°C, solution of 3-cyclopentyl-3-oxo-propionitrile (20 g) in dry tetrahydrofuran (50 ml) was added drop wise. After completion of addition, temperature was raised to 25?C and maintained for about 10-12 hours. Cooled to 0°C and 50 ml of methanol was added slowly. Maintained 30
13
for 30 minutes, 250 ml of toluene was added. Washed with 0.2M H2SO4 and H2O. Organic layer was concentrated to obtain 10.05 g of a yellow oil (yield 45.45 %).
Example 7: Preparation of 2-cyano-1-cyclopentylethyl trifluoromethanesulfonate
3-Cyclopentyl-3-hydroxypropanenitrile (14 g) was added to dichloromethane (140 5 mL) under nitrogen atmosphere and cooled to 0°C. Pyridine (16 ml) was added to the reaction mixture and stirred at 0°C for 30 minutes. Triflic anhydride (34.05 g) was added drop wise over a period of 30 minutes and then stirred at 0°C for 2 hours. Water was added to the reaction mixture, stirred for about 20 minutes at 0-5°C. The layers were separated. Organic layer was washed with water, saturated sodium 10 bicarbonate and brine. Organic layer was concentrated to obtain pale brown liquid. Yield: 10.6 g (39.20%).
Example 8: Preparation of (1S)-2-cyano-1-cyclopentylethyl methane sulfonate
3-Cyclopentyl-3-hydroxypropanenitrile (10 g) was added to dichloromethane (110 mL) under nitrogen and cooled to 0°C. Pyridine (12ml) was added to the reaction 15 mixture and stirred at 0°C for about 30 minutes. Methane sulfonyl chloride (20.05 g) was added drop wise over a period of 30 minutes and was then stirred at 0°C for 2 hours. Water was added to the reaction mixture, stirred for 20 minutes at 0-5°C. Separated organic and aqueous layer. Organic layer was washed with water, saturated sodium bicarbonate and brine. The organic layer was concentrated to 20 obtain pale brown liquid. Yield: 8.6 g (55.12%).
Example 9: Preparation of (1S)-2-cyano-1-cyclopentylethyl 4-methylbenzenesulfonate
3-Cyclopentyl-3-hydroxypropanenitrile (10 g) was added to dichloromethane (100 mL) under nitrogen and cooled to 0°C. Pyridine (20ml) was added to the reaction 25 mixture and stirred at 0°C for 30 minutes. 4-Methylbenzenesulfonyl chloride (14.05 g) was added and then stirred at 0°C for 2 hours. Water was added to the reaction mixture, stirred for about 20 minutes at 0-5°C. Separated organic and aqueous layer. Organic layer was washed with water, saturated sodium bicarbonate and brine. Organic layer was concentrated to obtain brown liquid. Yield: 12.6 g (59.79%). 30
14
Example 10: Preparation of 4-Pyrazoleboronic Acid Pinacol Ester
Under nitrogen atmosphere, 7.35 g of 1-H-4-bromopyrazole, 14.0 g of diboronic acid pinacol ester, 6.0 g of potassium acetate, 2.15 g of tetrabutylammonium bromide, 0.1 g were taken in a 500 ml four-necked flask. Organometallic palladium catalyst complex (Pd(PPh3)2Cl2), and 100 ml of 1,4-dioxane was added reaction 5 mixture, and stirred under reflux with heating for about 12 hours. After completion, reaction mixture was cooled to 25-30oC and filtered under reduced pressure to obtain white product 8.8g, Yield 94.0%.

,CLAIMS:We claim
1] A process for the preparation of ruxolitinib, a compound of formula I or salt thereof,
I 5
comprising the steps of:
a) condensing a compound of formula III with a compound of formula IV to obtain a compound of formula II;
III IV II 10
wherein R1 is a nitrogen protecting group and R2 is a hydroxy protecting group;
b) deprotecting the compound of formula II to obtain ruxolitinib, a compound of formula I; and
c) optionally, converting the obtained ruxolitinib to its salt.
2] The process as defined in ‘A’, wherein in step (a), R1 may be selected from the 15 group consisting of benzyl, tosyl, mesyl, tertiary-butyloxy carbonyl and carbobenzyloxy.
3] The process as defined in ‘A’, wherein in step (a), R2 may be selected from the group consisting of SO2R3 wherein R3 is C1-C6 alkyl, halo alkyl wherein halo is selected from chloro, bromo or iodo. 20
16
4] The process as defined in ‘A’, wherein the compound of formula III is prepared by a process comprising the steps of:
a) converting a compound of formula VIII to a compound of formula IX;
VIII IX 5
b) reducing the compound of formula IX to a compound of formula X; and
X; and
c) O-protecting the compound of formula X to obtain the compound of formula III
10
III.
5] The process as defined in ‘A’ wherein the compound of formula IV is prepared by a process comprising the steps of:
a) converting the compound of formula VII to a compound of formula VI,
15
VII VI
wherein R5 is halo selected from chloro, bromo or iodo;
b) reacting the compound of formula VI with a compound of formula V to obtain the compound of formula IV
20
17
VI V IV
6] The process as defined in ‘E’, wherein in step (b), the compound of formula V is prepared by a process comprising treating a compound of formula XI with a compound of formula XII. 5
V XI XII
7] A compound of formula IIIa:
IIIa. 10
8] The process as defined in “A” wherein R1 is tosyl.
9] The process as defined in “A” wherein R2 is SO2CF3.