Processes For Production of Phenolic 4-Biphenylylazetidin-2-Ones

1 . A process for preparing a compound of structure

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, an allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; and

Q is a chiral auxiliary, said chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center,

said process comprising reacting a compound of formula

with a compound of formula

2 . A process according to claim 1 for preparing a compound of structure

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; and

R 6 is phenyl or benzyl;

said process comprising reacting a compound of formula

with a compound of formula

3 . A process according to claim 2 comprising reacting a compound of formula

wherein ProtB′-O— is a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester, with a Lewis acid and a compound of formula

4 . A process according to claim 2 comprising the sequential steps of

a. reacting a compound of formula

with a trialkylhalosilane in the presence of a base, followed by

b. a Lewis acid, followed by

c. a compound of formula

5 . A process according to claim 2 wherein

R 1 and R 2 are chosen from H and halogen; and

ProtA-O— is chosen from methoxymethyl ether, allyl ether, t-butyl ether, benzyl ether, trimethylsilyl ether, t-butyldimethylsilyl ether and t-butyldiphenylsilyl ether;

6 . A process according to claim 4 wherein said Lewis acid is a halide of a Group 3, 4, 13 or 14 metal.

7 . A process according to claim 6 wherein said Lewis acid is titanium tetrachloride.

8 . A process according to claim 4 wherein

R 1 is hydrogen;

R 2 is fluorine;

X is bromine;

ProtA-O— is benzyl ether; and

ProtB-O— is HO—.

9 . A process according to claim 2 comprising

a. reacting a compound of formula

trimethylchlorosilane in the presence of a tertiary amine to provide a silyl-protected benzyl alcohol; and

b. reacting said silyl-protected benzyl alcohol with titanium tetrachloride and an imine of formula

to provide a compound of formula

10 . A process for preparing a compound of structure

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

said process comprising cyclizing a compound of formula

wherein

R 6 is phenyl or benzyl; and

ProtB′-O— is a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester.

11 . A process according to claim 10 comprising reacting a compound of formula

with N,O-bistrimethylsilylacetamide and a source of fluoride ion.

12 . A process according to claim 11 wherein said source of fluoride ion is tetrabutylammonium fluoride.

13 . A process according to claim 11 wherein

R 1 is hydrogen;

R 2 is fluorine;

X is bromine;

ProtA is benzyl; and

ProtB′ is silyl.

14 . A process according to claim 13 wherein

ProtB′ is chosen from t-butyldimethylsilyl and trimethylsilyl.

15 . A process for preparing a phenolic 4-biphenylylylazetidinone of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

said process comprising reacting a 4-phenylazetidin-2-one of formula

wherein

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

with a phenyl component of formula

wherein

R 10 and R 11 are independently selected from H and (C 1 -C 6 ) alkyl, or R 10 and R 11 together form a 5-6 membered ring.

16 . A process for preparing a 4-biphenylylazetidinone of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

said process comprising reacting a 4-phenylazetidin-2-one of formula

wherein

R 10 and R 11 are independently selected from H and (C 1 -C 6 ) alkyl, or R 10 and R 11 together form a 5-6 membered ring;

with a phenyl component of formula

wherein

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl.

17 . A process according to claim 15 wherein said reacting a 4-phenylazetidin-2-one with a phenyl component is carried out with a phosphine, a palladium salt and a base.

18 . A process according to claim 15 comprising reacting a 4-phenylazetidin-2-one of formula

wherein

ProtA′-O— is chosen from methoxymethyl ether, t-butyl ether, silyl ether, and benzyl ether; and

ProtB-O— is chosen from HO— and silyl ether;

with

in the presence of a phosphine, a palladium salt and a base.

19 . A process according to claim 16 comprising reacting a 4-phenylazetidin-2-one of formula

wherein

ProtA′-O— is chosen from methoxymethyl ether, t-butyl ether, silyl ether, and benzyl ether; and

ProtB-O— is chosen from HO— and silyl ether;

with

in the presence of a phosphine, a palladium salt and a base.

19 . (canceled)

21 . A process according to claim 15 wherein R 1 is hydrogen and R 2 is fluorine.

22 . A process for preparing a compound of formula

comprising reacting an azetidinone of formula

with a boronic acid of formula

and deprotecting,

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is —OH or silyl ether.

23 . A process according to claim 22 for preparing

comprising reacting an azetidinone of formula

with a boronic acid of formula

and deprotecting.

24 . A process according to claim 22 wherein said azetidinone is reacted with said boronic acid in the presence of a phosphine, a palladium salt and an alkali metal carbonate; ProtA′ is benzyl and said deprotection is accomplished by catalytic hydrogenolysis.

25 . A process according to claim 22 wherein said azetidinone is obtained by cyclizing a β-aminoacyloxazolinone of formula

wherein

R 6 is phenyl or benzyl.

26 . A process according to claim 25 wherein said β-aminoacyloxazolinone is obtained by reacting a compound of formula

with a compound of formula

27 . A process for preparing an imine of formula

wherein

R 1 is chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl; and

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether,

said process comprising reacting a phenol of formula

with a source of formaldehyde followed by Schiff base formation by reacting with an aniline of formula

followed by protecting with ProtA.

28 . A process according to claim 27 wherein ProtA is benzyl, X is bromine and R 1 is hydrogen.

29 . A compound of formula:

wherein

R 1 is chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl; and

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether, with the proviso that when ProtA- is benzyl, R 1 is H and X is Br, the compound is solid and greater than 95% pure.

30 . A compound according to claim 29 wherein R 1 is H or fluoro;

X is bromine; and

ProtA-O— is a benzyl ether or silyl ether.

31 . A compound of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, an allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; and

Q is a chiral auxiliary attached at nitrogen, said chiral auxiliary chosen from single enantiomers of cyclic and branched nitrogen-containing moieties possessing at least one chiral center.

32 . A compound according to claim 31 of formula

wherein R 6 is phenyl or benzyl.

33 . A compound of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester.

34 . A compound according to claim 33 of formula

35 . A compound of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; and

R 10 and R 11 are independently selected from H and (C 1 -C 6 ) alkyl, or R 10 and R 11 together form a 5-6 membered ring;

36 . A compound according to claim 35 of formula

37 . A compound of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA-O— is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester.

38 . A compound according to claim 37 of formula

39 . A process for preparing a phenolic 4-biphenylylylazetidinone of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

said process comprising

(a) reacting a 4-phenylazetidin-2-one of formula

wherein

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl;

with a phenyl component of formula

wherein

R 10 and R 11 are independently selected from H and (C 1 -C 6 ) alkyl, or R 10 and R 11 together form a 5-6 membered ring; and

ProtA is a protecting group for a phenol chosen from an oxymethyl ether, an allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

(b) cleaving ProtA to a phenol.

40 . A process for preparing a 4-biphenylylazetidinone of formula

wherein

R 1 and R 2 are chosen from H, halogen, —OH, and methoxy;

ProtA′-O— is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

ProtB-O— is HO— or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

said process comprising

(a) reacting a 4-phenylazetidin-2-one of formula

wherein

R 10 and R 11 are independently selected from H and (C 1 -C 6 ) alkyl, or R 10 and R 11 together form a 5-6 membered ring;

with a phenyl component of formula

wherein

X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl; and ProtA is a protecting group for a phenol chosen from an oxymethyl ether, an allyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; and

(b) cleaving ProtA to a phenol.

41 . A process according to claim 16 wherein R 1 is hydrogen and R 2 is fluorine.