Processes for Production of 4-(Biphenylyl)Azetidin-2-One Phosphonic Acids
The present invention relates to processes for the production of 4-(biphenylyl)azetidin-2-one phosphonic acid 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 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; and
ProtA-O— is benzyl ether.
9 . A process according to claim 2 comprising
a. reacting a compound of formula
with 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
and when ProtB-O is OH, cleaving ProtB′-O—,
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-(biphenylyl)ylazetidinone 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
ProtD-O— is HO— or a protecting group for a phosphonic acid chosen from an alkyl ester, a phenyl ester and a benzyl 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-(biphenylyl)azetidinone 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
ProtD-O— is HO— or a protecting group for a phosphonic acid chosen from an alkyl ester, a phenyl ester and a benzyl 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.
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
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
ProtD-O— is —OH, —OCH 3 or —OCH 2 CH 3 .
23 . A process according to claim 22 for preparing
comprising reacting an azetidinone of formula
wherein ProtA′ is benzyl or t-butyldimethylsilyl, with a dioxaborole of formula
and deprotecting.
24 . A process according to claim 22 wherein said azetidinone is reacted with said dioxaborole in the presence of a phosphine, a palladium salt and an alkali metal carbonate;
ProtA′ is benzyl and said deprotection is accomplished by hydrogenolysis with hydrogen gas and palladium on carbon; and
ProtD is H.
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;
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
ProtD-O— is HO— or a protecting group for a phosphonic acid chosen from an alkyl ester, a phenyl ester and a benzyl ester.
38 . A compound according to claim 37 chosen from
and salts and solvates thereof.
39 . (3′-(Benzyloxy)-4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)phosphonic acid dicyclohexylammonium salt according to claim 38 .
40 . A process for preparing [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonic acid
comprising
(1) reacting 4-bromo-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene with trimethylphosphine in the presence of a catalytic amount of a radical initiator followed by reduction to provide dimethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate;
(2) hydrolyzing dimethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate by treatment with bromotrimethylsilane followed by water; and
(3) isolating [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonic acid.
41 . A process according to claim 40 wherein said radical initiator is 1,1′-azobis(cyclohexanecarbonitrile) and said reduction is accomplished by treatment with tributyltin hydride or tris(trimethylsilyl) silane.
42 . The compound of claim 34 , as a crystalline solid of greater than 99% diastereomeric purity, melting above 113° C.
43 . The compound of claim 34 characterized in that the compound is obtained by a process of crystallization from isopropyl alcohol/water.
44 . A process according to claim 16 wherein R 1 is hydrogen and R 2 is fluorine.