Processes and intermediates for making a JAK inhibitor

1. A process, comprising:

reacting a compound of Formula III:

with a compound of Formula IV:

under Suzuki coupling conditions to form a compound of Formula II:

wherein:

Z is H or a protecting group;

P 1 is a protecting group;

X 1 is halo; and

R 1 and R 2 are each independently H or C 1-6 alkyl; or

R 1 and R 2 , together with the two oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, 3, or 4 C 1-4 alkyl groups.

2. The process according to claim 1 , wherein P 1 is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), 2-tetrahydropyranyl (THP), 1,1-diethoxymethyl, (trimethylsilyl)ethoxymethyl (SEM), N-pivaloyloxymethyl (POM) or tert-butoxycarbonyl.

3. The process according to claim 1 , wherein the compound of Formula III has Formula IIIa:

4. The process according to claim 1 , wherein the compound of Formula IV has Formula IVa:

5. The process according to claim 1 , wherein the Suzuki coupling conditions comprise heating a reaction mixture comprising the compound of Formula III, the compound of Formula IV, a Suzuki coupling catalyst, a base and a solvent component.

6. The process according to claim 5 , wherein the Suzuki coupling catalyst is Pd(dppf) 2 Cl 2 , [1,1 ’-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II), tetrakis(triphenylphosphine)palladium(0), or tetrakis(tri(o-tolyl)phosphine)palladium(0).

7. The process according to claim 5 , wherein the Suzuki coupling catalyst is [1,1’-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II).

8. The process according to claim 5 , wherein the base is sodium carbonate, potassium carbonate, or cesium fluoride.

9. The process according to claim 5 , wherein the base is cesium fluoride.

10. The process according to claim 1 , further comprising deprotecting the compound of Formula II to form a compound of Formula V:

or salt thereof.

11. The process according to claim 1 , wherein the process comprises reacting a compound of Formula IIIa:

with a compound of Formula IVa:

under Suzuki coupling conditions to form a compound of Formula IIa:

wherein the Suzuki coupling conditions comprise heating a reaction mixture comprising the compound of Formula IIIa, the compound of Formula IVa, [1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II), cesium fluoride, and a solvent component, wherein the solvent component comprises water and tert-butanol.

12. The process according to claim 11 , further comprising deprotecting the compound of Formula IIa to form a compound of Formula V:

or salt thereof, wherein the deprotecting comprises reacting the compound of Formula IIa with hydrochloric acid in a second solvent component.

13. The process according to claim 12 , further comprising reacting the compound of Formula V, or salt thereof, with a compound of Formula VI:

in the presence of a reducing agent to form a compound of Formula I:

or a salt thereof.

14. The process according to claim 13 , wherein the compound of Formula V, or salt thereof, is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-y1)acetonitirile dihydrochloride salt.

15. The process according to claim 13 , wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

16. The process according to claim 13 , wherein the reducing agent is sodium triacetoxyborohydride.

17. The process according to claim 13 , further comprising reacting the compound of Formula I with adipic acid to form the adipate salt of the compound of Formula I.