Process For Production Of 4-Biphenylyazetidin-2-Ones
The present invention relates to processes for the production of 4-biphenylylazetidin-2-one derivatives of formula
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 2 wherein said compound of formula
is reacted with said compound
of formula
in the presence of a Lewis acid, 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; and
ProtA-O— is benzyl ether.
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 12 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 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;
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 5 is a sugar or protected sugar;
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;
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 5 is a sugar or protected sugar;
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.
20 . (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 XII:
comprising reacting XV
wherein X′ is Br or Cl, with bis(pinacolato)diboron in the presence of a palladium catalyst, a trivalent phosphine and a base to produce XII.
23 . A process according to claim 22 wherein X′ is Cl, said palladium catalyst is bis(dibenzylideneacetone) palladium [(dba) 2 Pd]; said phosphine is tricyclohexyl phosphine; said base is potassium acetate; and the reaction is carried out in diglyme at 150-175° C.
24 . A process for preparing a compound of formula XIII
wherein X′ is Br or Cl, comprising reacting a silylated sugar lactone of formula
wherein ProtD 1a , ProtD 1b , ProtD 1c and ProtD 1d are trialkylsilyl groups, with a Grignard reagent followed by methanolysis.
25 . A process according to claim 24 wherein said Grignard reagent is 4-chlorophenylmagnesium bromide and methanolysis is accomplished with methanesulfonic acid in methanol.
26 . A process for preparing a compound of formula XII:
comprising:
(1) treating a protected sugar lactone of formula
wherein ProtD 1a , ProtD 1b , ProtD 1c and ProtD 1d are trialkylsilyl groups, with a Grignard reagent
followed by methanol and an acid to provide a compound of formula XIII:
wherein X′ is Br or Cl;
(2) treating XIII with an excess of an acetylating reagent chosen from acetic anhydride in the presence of a base, acetyl chloride in the presence of a base, pentafluorophenyl acetate in the presence of a base and acetylimidazole in the presence of a platinum catalyst to provide XIV:
(3) reducing XIV with a silane and a Lewis acid to provide XV:
(4) reacting XV with bis(pinacolato)diboron in the presence of a palladium catalyst to produce XII.
27 . A process according to claim 26 for preparing a compound of formula C4-acetyl:
comprising:
(1) treating a protected sugar lactone of formula CC0
wherein ProtD 1a , ProtD 1b , ProtD 1c and ProtD 1d are trimethylsilyl or t-butylimethylsilyl groups with a Grignard reagent of formula
followed by methanol and an acid to provide a compound of formula CC3:
(2) treating CC3 with an excess of acetic anhydride in the presence of a base to provide CC4:
(3) reducing CC4 with triethylsilane and a Lewis acid to provide CC5:
(4) reacting CC5 with bis(pinacolato)diboron in the presence of a palladium catalyst, a trivalent phosphine ligand and a base to produce C4-acetyl:
28 . A process for preparing a compound of formula
comprising reacting an azetidinone of formula
with a dioxaborole 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;
ProtB-O— is —OH or silyl ether; and
ProtC-O— is a protecting group for a sugar alcohol chosen from a benzyl ether, a silyl ether and an ester.
29 . A process according to claim 28 for preparing
comprising reacting an azetidinone of formula
with a dioxaborole of formula
and deprotecting.
30 . A process according to claim 28 wherein said azetidinone is reacted with said dioxaborole in the presence of a phosphine, a palladium salt and an alkali metal carbonate;
ProtC is acetyl and said deprotection is accomplished by hydrolysis with aqueous base; and
ProtA′ is benzyl and said deprotection is accomplished by catalytic hydrogenolysis.
31 . A process according to claim 28 wherein said azetidinone is reacted with said dioxaborole in the presence of a phosphine, a palladium salt and an alkali metal carbonate;
ProtC is acetyl and said deprotection is accomplished by methanolysis in the presence of fluoride ion; and
ProtA′ is benzyl and said deprotection is accomplished by catalytic hydrogenolysis.
32 . A process according to claim 28 wherein said azetidinone is obtained by cyclizing a β-aminoacyloxazolinone of formula
wherein
R 6 is phenyl or benzyl.
33 . A process according to claim 32 wherein said β-aminoacyloxazolinone is obtained by
reacting a compound of formula
with a compound of formula
34 . 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.
35 . A process according to claim 34 wherein ProtA is benzyl, X is bromine and R 1 is hydrogen.
36 . A process for producing a compound of formula E2 from a compound of formula E1
comprising treating a 0.5M solution of said compound of formula E1 in methanol with four equivalents of potassium fluoride at 35° C. to 75° C.
37 . 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.
38 . A compound according to claim 37 wherein R 1 is H or fluoro; X is bromine; and
ProtA-O— is a benzyl ether or silyl ether.
39 . A compound of formula
wherein
X is chosen from iodine, bromine, chlorine, toluenesulfonyl, methanesulfonyl and trifluoromethanesulfonyl; and
ProtD a , ProtD b , ProtD c and ProtD d are hydrogen or protecting groups for a sugar chosen independently from benzyl, silyl, acyl, ketal, acetal, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, allyl, 2-methylallyl and t-butyl.
40 . A compound according to claim 39 wherein X is chlorine and ProtD a , ProtD b , ProtD c and ProtD d are trialkylsilyl protecting groups.
41 . A compound according to claim 39 wherein X is chlorine and ProtD a , ProtD b , ProtD c and ProtD d are acetyl.
42 . A compound 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
ProtD a , ProtD b , ProtD c and ProtD d are hydrogen or protecting groups for a sugar chosen independently from benzyl, silyl, acyl, ketal and acetal.
43 . A compound according to claim 42 of formula
wherein
ProtD a , ProtD b , ProtD c and ProtD d are H, benzyl, silyl or acyl.
44 . A compound according to claim 39 wherein ProtD a , ProtD b , ProtD c and ProtD d are all acetyl, trimethylsilyl or t-butyldimethylsilyl.
45 . 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.
46 . A compound according to claim 45 of formula
wherein R 6 is phenyl or benzyl.
47 . 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.
48 . A compound according to claim 47 of formula
49 . 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;
50 . A compound according to claim 49 of formula
51 . 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;
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 5 is a protected sugar.
52 . A compound according to claim 51 of formula
wherein
ProtD e is hydrogen or acetyl.
53 . A compound according to claim 52 of formula
54 . A compound of formula
wherein one of R 7a and R 7b is H and the other is OH or taken together R 7a and R 7b are ═O.
55 . A compound of formula
56 . A process according to claim 16 wherein said reacting a 4-phenylazetidin-2-one with a phenyl component is carried out with a phosphine, a palladium salt and a base.
57 . A compound according claim 42 wherein ProtD a , ProtD b , ProtD c and ProtD d are all acetyl, trimethylsilyl or t-butyldimethylsilyl.
58 . A process according to claim 16 wherein R 1 is hydrogen and R 2 is fluorine.