Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-13
2002-08-27
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06441189
ABSTRACT:
TECHNICAL FIELD
This invention relates to a process for the preparation of matrix metalloproteinase inhibitors and to intermediates useful in the process.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases are a class of extracellular enzymes such as collagenase, stromelysin, and gelatinase which are believed to be involved in tissue destruction which accompanies a number of diseases including arthritis and cancer. There is, therefore, a continuing need for compounds which are inhibitors of matrix matalloproteinase.
The instant invention discloses a synthesis of metalloproteinase inhibitors from ((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate (Sibi, M. P., Rutherford, D., Sharma, R.
J Chem. Soc. Perkin Trans.
1994, 13, 1, 1675). Although an efficient synthesis of this compound has been reported, racemization occurs during the sequence, causing a reduction in the enantiomeric excess of the final product. This invention discloses a method for the preparation of ((4S)-2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate which significantly reduces racemization.
SUMMARY OF THE INVENTION
In one embodiment of the instant invention is disclosed a process for preparing a compound of formula (3)
wherein
R
1
is selected from the group consisting of hydrogen, an amino protecting group, and —OR
2
;
R
2
is hydrogen or a hydroxy protecting group;
L
1
is —O— or —N(R
3
)—, wherein R
3
is hydrogen or an amino protecting group; and
X is O or S, the process comprising:
(a) reacting a compound of formula (2)
wherein
R
4
is a carboxyl protecting group, with a reducing agent to provide a first reaction mixture; and
(b) adjusting the pH of the first reaction mixture to about 2 to about 6; and
(c) isolating the compound of formula (3).
In a preferred embodiment the compound of formula (3) is (4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
Another embodiment of the instant invention comprises reacting a compound of formula (1)
a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-a)
or a compound of formula (5-b)
wherein
Q
1
is selected from the group consisting of halide, methanesulfonate, and trifluoromethanesulfonate;
Y is nitrogen or C(H);
R
6
is selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, aminosulfonyl, aminosulfonylalkyl, aryl, arylalkyl, cyano, cyanoalkyl, halo, haloalkyl, (heterocycle)oxy, (heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy, phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluorothioalkoxy, perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl, sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl; and
L
2
is —O— or —S—, the process comprising:
(a) activating the hydroxyl of the compound of formula (3)
(b) reacting the product of step (a), a compound of formula (4)
and base to provide the compound of formula (5-a)
(c) optionally oxidizing the product of step (b); and
(d) optionally reacting the product of step (b) or step (c) and a compound of formula (6)
wherein
Q
2
is selected from the group consisting of trialkylstannanes, boronic acid, boronic esters, magnesium halides, zinc halides, and silyl(alkyl)cyclobutanes, and a coupling catalyst.
In a preferred embodiment the compound of formula (5-a) is
(4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one and the compound of formula (5-b) is
(4R)-4-(((4′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)oxy)methyl)-1,3-oxazolidin-2-one.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-c)
the process comprising:
(a) reacting a compound of formula (7)
wherein
R
4
is alkyl, a compound of formula (4)
and base to provide a compound of formula (8)
(b) optionally reacting the product from step (a) and an oxidant;
(c) reacting the product of step (a) or step (b), hydrogen, and a hydrogenation catalyst to provide a compound of formula (9)
(d) reacting the product from step (c) and base to provide a compound of formula (10)
(e) reacting the product from step (d) and a compound of formula H
2
NOR
2
, or a salt thereof, wherein
R
2
is a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11)
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12)
(g) reacting the product from step (f) and base to provide a compound of formula (13)
and
(h) reacting the product from step (g) and azide under dehydrating conditions.
In a preferred embodiment the compound of formula (5-c) is
(5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (15)
the process comprising:
(a) reacting a compound of formula (5)
and base.
In a preferred embodiment the compound of formula (15) is selected from the group consisting of
(2S)-2-amino-3-((4′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)oxy)-1-propanol,
(2S)-2-amino-3-(4-bromophenoxy)-1-propanol, and
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20),
or a salt thereof, wherein
R
7
and R
8
, together with the atoms to which they are attached, form a heterocycle selected from the group consisting of 5,5-dimethyl-1,3-oxazolidine-2,4-dionyl; 1-methyl-2,4-imidazolidinedionyl; 1,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl; 5,5-dimethyl-2,4-imidazolidinedionyl; 1,2-dimethyl-1,2,4-triazolidine-3,5-dionyl; 4,4-dimethyl-2,6-piperidinedione; 8-azaspiro(4.5)decane-7,9-dionyl; 3a,6-dihydro-1H-benzo(de)isoquinoline-1,3(2H)-dionyl; 2,4(1H,3H)-quinazolinedionyl; 1-methyl-2,4(1H,3H)-pyrimidinedionyl; and 1,1-dioxo-1,2-benzisothiazol-3(2H)-onyl, the process comprising:
(a) reacting a compound of formula (15-a)
and a compound of formula R
9
—CHO, wherein
R
9
is optionally substituted aryl, to provide a compound of formula (16)
(b) reacting the product of step (a) and a compound of formula (17) under Mitsunobu conditions
to provide a compound of formula (18)
(c) reacting the product of step (b) and an oxaziridine forming agent to provide a compound of formula (19)
(d) reacting the product of step (c) and a compound of formula H
2
NOR
2
, or a salt thereof, and base; and
(e) optionally deprotecting the product of step (d).
In a preferred embodiment the compound of formula (20) is selected from the group consisting of
3-((2S)-2-(hydroxyamino)-3-((4′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione and
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-b)
or a salt thereof, the process comprising:
(a) reacting the compound of formula (20-a)
the coupling catalyst, and the compound of formula (6)
In a preferred embodiment the compound of formula (20-b) is
3-((2S)-2-(hydroxyamino)-3-((4′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-c)
or a salt thereof, the process comprising:
(a) reacting a compound of formula (15-b)
and a compound of formula (21)
to provide a compound of formula (22)
and
(b) reacting the product from step (a) and acid.
In a preferred embodiment the compound of formula (20-c) is
3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
Another embodiment of the instant invention comprises a process for preparing a compound of formula (23)
the process comprising:
(a) N-formylating the compound of formula (20); and
(b) optionally deprotecting the produ
Bailey Anne E.
Hill David R.
Hsiao Chi-nung W.
Kurukulasuriya Ravi
McDermott Todd
Abbott Laboratories
McKane Joseph K.
Saeed Kamal
Steele Gregory W.
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