Process for the preparation of tofacitinib and intermediates thereof
A process for the preparation of high purity tofacitinib, which reduces formation of N-methyl impurity is provided. Novel intermediates used in the process to prepare tofacitinib is also provided. A process for the preparation of tofacitinib (I), comprising the steps of: adding cyanoacetic acid in molar equivalent 0.2-1.2 to compound of formula (IIS), followed by addition of carbodiimide coupling agent of formula (III), optionally reacting tofacitinib base with citric acid is further provided.
1 . A process for the preparation of tofacitinib of formula (I) and salt thereof
comprising the steps of:
(a) preparing a compound for formula (II-S)
(ia) by reacting a compound of formula (VI) with a compound of formula (VII) in presence of an inorganic base at 80-100° C. to form a compound of formula (V);
(iia) reacting the compound of formula (V) with an alkali metal hydroxide, wherein the reaction is carried out at 30-65° C. in a solvent system to form a compound of formula (IV);
(iiia) hydrogenation of the compound of formula (IV) at a pH 3-5 using a metal catalyst at 25-60° C. to form a compound of formula (II);
(iva) adding cyanoacetic acid to the compound of formula (II) to form the compound of formula (II-S);
(b) adding cyanoacetic acid in a molar equivalent 0.2-1.2 to compound of formula (II-S),
(c) reacting the reaction mixture with carbodiimide of formula (III) at 0-40° C. in the presence of a coupling agent of formula (III) to form the compound of formula (I),
wherein R is selected from cyclohexyl, isopropyl, ethyl, 3-dimethylamino propyl or its hydrohalide or alkylhalide addition salt.
2 . The process as claimed in claim 1 , wherein step (b) is carried out at a room temperature.
3 . The process as claimed in claim 1 , wherein step (b) is carried out in a solvent selected from aprotic solvent, hydrocarbon, ester, ether, halogenated solvent, and ketone.
4 . The process as claimed in claim 1 , wherein carbodiimide of formula (III) is selected from dicyclohexylcarbiodimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, and N,N′-diisopropylcarbodiimide.
5 . The process as claimed in claim 1 , wherein the coupling agent is selected from hydroxybenzotriazole (HOBt), N-hydroxy-5-norbornene-endo-2,3-dicarboxyimide (HONB), N-hydroxysuccinimide (HOSu), hydroxy-7-azabenzotriazole (HOAt), O-(1H-benzotriazol-1-yl)-tetramethyl uroniumhexafluorophosphate, (HBTU), and TBTU.
6 . The process as claimed in claim 1 , wherein tofacitinib formed in step (c) is reacted with citric acid to obtain tofacitinib citrate.
7 . A process for the preparation of compound of formula (II-S)
comprising the steps of:
(ia) reacting a compound of formula (VI) with a compound of formula (VII) in presence of an inorganic base at 80-100° C. to form a compound of formula (V);
(iia) reacting the compound of formula (V) with an alkali metal hydroxide, wherein the reaction is carried out at 30-65° C. in a solvent system to form a compound of formula (IV);
(iiia) hydrogenation of the compound of formula (IV) at a pH 3-5 using a metal catalyst at 25-60° C. to form a compound of formula (II) in a mass;
(iva) adjusting the pH reaction of the mass using an organic base;
(va) extracting the compound of formula (II) using a solvent from the reaction mass;
(via) adding cyanoacetic acid to form the compound of formula (II-S).
8 . The process as claimed in claim 7 , wherein the compound of formula VI is a salt with an acid selected from hydrochloric acid, tartaric acid, ditoluoyl tartaric acid, acetic acid, and sulfuric acid.
9 . The process as claimed in claim 7 , wherein the organic base is an alkali metal carbonate.
10 . The process as claimed in claim 7 , wherein the alkali metal hydroxide is selected lithium hydroxide, sodium hydroxide, and potassium hydroxide.
11 . The process as claimed in claim 7 , wherein the solvent system is a mixture of water and an alcohol selected from methanol, ethanol, and isopropanol.
12 . The process as claimed in claim 11 , wherein the solvent system is a mixture of water and methanol.
13 . The process as claimed in claim 7 , wherein the metal catalyst is selected from the Palladium (0), Pd on carbon, Pd (OH) 2, palladium acetate, platinum oxide, platinum black, and Raney nickel.
14 . The process as claimed in claim 7 , wherein the pH in step (iiia) is adjusted using an acid selected from hydrochloric acid, acetic acid, and sulfuric acid.
15 . The process as claimed in claim 7 , wherein the organic base is selected from ammonia, mono-, di-, and trialkyl amines.
16 . The process as claimed in claim 15 , wherein the organic base is ammonia selected from aqueous ammonia, gaseous ammonia, and liquid ammonia.
17 . The process as claimed in claim 7 , wherein the solvent in step (va) is a water immiscible solvent.
18 . The process as claimed in claim 17 , wherein the solvent is selected from alcohol, hydrocarbon, ester, and ether.
19 . The process as claimed in claim 7 , wherein hydrogen gas is purged in the reaction mixture after the hydrogenation of the compound of formula (IV).
20 . A composition comprising tofacitinib citrate free from N-methyl impurity and dihydro impurity.
21 . The composition of claim 20 wherein the composition comprises less than 0.5% N-methyl impurity.