Process for making M1 receptor positive allosteric modulators

1. A process for the preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein R 1 is C 1-6 alkyl, or C 6-10 aryl

comprising introducing an alcohol protecting group (APG) onto a compound of Formula 8

to make a compound of Formula 9:

coupling the compound of Formula 9 with a compound of Formula 10

in the presence of a first palladium catalyst complex to make a compound of Formula 11, wherein X is a metal-containing moiety and Y is a leaving group,

alkylating the compound of structural Formula 11 using a alkylating reagent to provide a compound of Formula 12:

by way of step (1) or step (2) wherein:

step (1) comprises adding the alkylating reagent to the reaction mixture comprising the compound of Formula 11 without further isolation to make a compound of Formula 12, or step (2) comprises isolating the compound of Formula 11 and reacting it with the alkylating reagent in the presence of a first palladium catalyst complex to provide a compound of Formula 12, and deprotecting the alcohol protecting group in the compound of Formula 12 and isolating a compound of Formula I.

2. The process of claim 1 wherein the alcohol protecting group is selected from the group consisting of tert-butyldimethylsilyl, trimethylsilyl, acetyl, and tetrahydropyranyl.

3. The process of claim 1 wherein the first palladium catalyst complex is selected from the group consisting of PCy3-G2-palladacycle (Chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II)), (Pd(tBu 3 P) 2 , Pd2dba3, Pd 2 dba 3 -CHCl 3 , Pd(OAc) 2 , Pd(dba) 2 , Pd(TFA) 2 , Pd(MeCN) 2 Cl 2 , Pd(allyl)Cl dimer, Pd(cinnamyl)Cl dimer (Bis[cinnamyl palladium(II) chloride]), Pd(aminobiphenyl)Cl dimer ((2′-amino-[1,1′-biphenyl]-2-yl)palladium(II) chloride dimer), and Pd(aminobiphenyl)OMs dimer ((2′-amino-[1,1′-biphenyl]-2-yl)palladium(II) methanesulfonate).

4. The process of claim 3 wherein the first palladium catalyst complex is selected from the group consisting of Pd(tBu 3 P) 2 , Pd 2 dba 3 and Pd 2 dba 3 -CHCl 3 .

5. The process of claim 1 wherein the leaving group is selected from the group consisting of halogen, OSO 2 R^, OMs (mesylate), OTs (tosylate), OBs (besylate), OSO 2 CF 3 (OTf), OSO 2 CF 2 CF 2 CF 2 CF 3 , OP(O)(OR i ) 4 , OC(O)R i , OC(O)OR i and OC(O)NR i R ii , wherein R^ is selected from the group consisting of C 1-6 alkyl, C 1-4 fluoroalkyl, and C 6-10 aryl, R i and R ii are independently selected from H, C 1-6 alkyl, and C 1-4 fluoroalkyl; and the metal-containing moiety is selected from the group consisting of Li, MgCl, MgBr, MgI, ZnCl, ZnBr, ZnI, SnMe 3 , Sn(n-Bu) 3 , B(OH) 2 , B(OR) 2 , B(pinacol), B(N-methyliminoacetate), and BF 3 K.

6. The process of claim 5 wherein the leaving group is selected from the group consisting of chloro, bromo, fluoro, and iodo and the metal-containing moiety is selected from the group consisting of ZnCl, ZnBr, and ZnI.

7. The process of claim 1 wherein the alkylating reagent is selected from the group consisting of MeZnCl, Me 2 Zn, MeB(OH) 2 , MeMgCl/ZnCl 2 , MeLi/ZnCl 2 , and SnMe 4 .

8. The process of claim 7 wherein the alkylating reagent is MeZnCl.

9. The process of claim 1 wherein alkylation is performed using step (1).

10. The process of claim 1 wherein alkylation is performed using step (2).

11. The process of claim 1 wherein the alcohol protecting group is tert-butyldimethylsilyl or trimethylsilyl, the first palladium catalyst complex is Pd(tBu 3 P) 2 , the leaving group is selected from the group consisting of chloro, bromo, and fluoro, the metal-containing moiety is selected from the group consisting of ZnCl, and the alkylating reagent is MeZnCl.

12. A process for the preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein R 1 is C 1-6 alkyl, comprising:

contacting a compound of formula 8:

with a borylating agent in the presence of a second palladium catalyst complex, optionally a second ligand, and an inorganic base make a compound of Formula 9A:

wherein Z is selected from the group consisting of B(pinacol), B(OH) 2 , BF 3 K, and B(N-methyliminoacetate),

coupling compound of Formula 9A with a compound of Formula 10A:

wherein W is OCOR W and R W is C 1-6 alkyl, or C 1-4 haloalkyl,

in the presence of a third palladium catalyst complex, optional third ligand and an inorganic base to produce a compound of Formula I.

13. The process of claim 12 wherein the second and third palladium catalyst complex is selected from the group consisting of PCy3-G2-palladacycle (Chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II)), (Pd(tBu 3 P) 2 , Pd 2 dba 3 -CHCl 3 , Pd(OAc) 2 , Pd(dba) 2 , Pd(TFA) 2 , Pd(MeCN) 2 Cl 2 , Pd(allyl)Cl dimer, Pd(cinnamyl)Cl dimer (Bis[cinnamyl palladium(II) chloride]), Pd(aminobiphenyl)Cl dimer ((2′-amino-[1,1′-biphenyl]-2-yl)palladium(II) chloride dimer), and Pd(aminobiphenyl)OMs dimer ((2′-amino-[1,1′-biphenyl]-2-yl)palladium(II) methanesulfonate).

14. The process of claim 12 wherein the borylating agent is a compound of Formula B or B′:

15. The process of claim 12 wherein Z is B(pinacol).

16. The process of claim 12 wherein Z is B(OH) 2 .

17. The process of claim 12 wherein 9A solution contains a mixture of 9A with B(pinacol) and 9A with B(OH) 2 .

18. The process of claim 12 wherein the second palladium catalyst complex is PCy3-G2-palladacycle.

19. The process of claim 12 wherein the inorganic base is selected from the group consisting of KOAc, K 2 CO 3 , K 3 PO 4 , KF, Cs 2 CO 3 , KOH, NaOH, LiOH, DIPEA, KHCO 3 , and NaHCO 3 .

20. The process of claim 12 wherein in the coupling of 9A and 10A step the third palladium catalyst complex is Pd(OAc) 2 , a third ligand is present which is RuPhos, and an inorganic base is present which is K 2 CO 3 .

21. A process for the preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl, comprising deprotecting a compound of Formula 12:

and isolating a compound of Formula I, wherein APG is alcohol protecting group.