US2002019539A1PendingUtilityA1
Process for the preparation of matrix metalloproteinase inhibitors
Priority: Mar 31, 2000Filed: Mar 30, 2001Published: Feb 14, 2002
Est. expiryMar 31, 2020(expired)· nominal 20-yr term from priority
Inventors:Anne E. BaileyDavid R. HillChi-Nung HsiaoRavi KurukulasuriyaSteve WittenbergerTodd McdermottMaureen A. Mclaughlin
C07D 263/24C07D 233/78C07C 239/20C07D 233/38C07D 205/08C07C 217/34C07C 213/00
37
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Claims
Abstract
The instant invention provides a process for the synthesis of matrix metalloproteinase inhibitors.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . 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).
2 . The process of claim 1 further comprising 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.
3 . The process of claim 1 , wherein the compound of formula (3) is (4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
4 . 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.
5 . The process of claim 4 , wherein 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.
6 . 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.
7 . The process of claim 6 , wherein the compound of formula (5-c) is (5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
8 . A process for preparing a compound of formula (15)
wherein
R 5 is Q 1 or
the process comprising:
(a) reacting a compound of formula (5)
and base.
9 . The process of claim 8 , wherein 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.
10 . 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).
11 . The process of claim 10 , wherein 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.
12 . 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)
13 . The process of claim 12 , wherein 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.
14 . 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.
15 . The process of claim 14 , wherein the compound of formula (20-c) is 3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
16 . 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 product of step (a).
17 . The process of claim 16 , wherein the compound of formula (23) is selected from the group consisting of
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide and benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl)-ethyl)formamide.
18 . A process for preparing a compound of formula (23-b)
the process comprising:
(a) reacting a compound of formula (23-a)
the coupling catalyst, and the compound of formula (6)
and
(b) optionally deprotecting the product of step (a).
19 . The process of claim 18 , wherein the compound of formula (23-b) is 4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-propyl)oxy)-4′-(trifluoromethoxy)-1,1′-biphenyl.
20 . A process for preparing a compound of formula (23-b)
the process comprising:
(a) 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 to provide a compound of formula (2);
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3);
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4)
to provide a compound of formula (5-a),
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (d) or step (e), a coupling catalyst, and a compound of formula (6)
to provide a compound of formula (5-b),
(g) reacting the product of step (f) with base to provide a compound of formula (15),
(h) reacting the product of step (g) with a compound of formula R 9 —CHO, to provide a compound of formula (16),
(i) reacting the product of step (h) with a compound of formula (17)
to provide a compound of formula (18)
(j) reacting the product of step (i) and an oxaziridine forming agent to provide a compound of formula (19)
(k) reacting the product of step (j) with H 2 NOR 2 , or a salt thereof, and base to provide a compound of formula (20-b);
(l) N-formylating the product from step (k) to provide a compound of formula (23-b);
and
(m) optionally deprotecting the product of step (l).
21 . A process for the preparation of a compound of formula (23-b)
the process comprising:
(a) 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, to provide a compound of formula (2);
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3);
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4)
to provide a compound of formula (5-a),
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (e) with base to provide a compound of formula (15),
wherein
R 5 is Q 1 ;
(g) reacting the product of step (f) with a compound of formula R 9 —CHO to provide a compound of formula (16),
wherein
R 5 is Q 1 ;
(h) reacting the product of step (g) with a compound of formula (17)
to provide a compound of formula (18)
wherein R 5 is Q 1 ;
(i) reacting the product of step (h) with an oxaziridine forming agent to provide a compound of formula (19)
wherein
R 5 is Q 1 ;
(j) reacting the product of step (i) with H 2 NOR 2 , or a salt thereof, and base to provide a compound of formula (20);
wherein
R 5 is Q 1 ;
(k) reacting the product of step (j) with a coupling catalyst and a compound of formula (6)
to provide a compound of formula (20),
wherein
R 5 is
(l) N-formylating the product from step (k) to provide a compound of formula (23)
wherein
R 5 is
and
(m) optionally deprotecting the product of step (l).
22 . A process for the preparation of a compound of formula (23)
wherein
R 2 is hydrogen;
and
R 5 is
the process comprising:
(a) reacting a compound of formula (7)
a compound of formula (4)
and base to provide a compound of formula (8)
(b) optionally oxidizing the product from step (a);
(c) hydrogenating the product of step (a) or step (b) to provide a compound of formula (9)
(d) reacting the product from step (c) with base to provide a compound of formula (10)
(e) reacting the product from step (d) with H 2 NOR 2 or a salt thereof, wherein R 2 is a a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11)
wherein
R 2 is a hydroxyl protecting group;
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12)
wherein
R 2 is a hydroxyl protecting group;
(g) reacting the product from step (f) with base to provide a compound of formula (13)
(h) activating the product from step (g) with azide to provide a compound of formula (5-c);
wherein
R 2 is a hydroxyl protecting group;
(i) reacting the product from step (h) with base to provide a compound of formula (15)
wherein
R 1 is —OR 2 ;
R 2 is a hydroxyl protecting group;
R 5 is Q 1 ;
and
L 1 is —NH—;
(j) reacting the product from step (i) with a compound of formula (21)
to provide a compound of formula (22)
wherein
R 2 is a hydroxyl protecting group;
(k) reacting the product from step (j) with acid to provide a compound of formula (20-c)
wherein
R 2 is a hydroxyl protecting group;
(l) N-formylating the product from step (k) to provide a compound of formula (23)
wherein
R 2 is a hydroxyl protecting group;
(m) reacting the product from step (l) with a coupling catalyst and a compound of formula (6)
to provide a compound of formula (23)
wherein
R 2 is a hydroxyl protecting group R 5 is
and
(n) deprotecting the product of step (m).Cited by (0)
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