US2003216440A1PendingUtilityA1
Process for preparing arylacetylaminothiazoles
Priority: Dec 15, 1999Filed: Apr 4, 2003Published: Nov 20, 2003
Est. expiryDec 15, 2019(expired)· nominal 20-yr term from priority
A61P 9/00A61P 37/00A61P 25/28A61P 35/00A61P 31/12A61P 29/00A61P 31/04A61K 31/427A61P 19/02A61P 17/14C07D 231/12A61K 31/454C07D 417/14C07D 249/08C07D 233/56C07D 417/12
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Claims
Abstract
The present invention relates to new, efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 12 and R 13 are each independently hydrogen, alkyl, aryl or heteroaryl; R 3 , R 7 , R 10 and R 11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and X is CH or N, which are novel, potent inhibitors of cyclin dependent kinases (cdks). The present invention also concerns a new process for the preparation of formylarylacetates and formylarylacetic acids.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for the preparation of a compound having the formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 12 and R 13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R 3 , R 7 , R 10 and R 11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N;
which comprises the steps of:
(a) reacting an arylacetate or an arylacetic acid having the formula II
10 wherein:
R 1 , R 2 , R 3 and X are as described hereinabove;
R is hydrogen, alkyl, aryl or heteroaryl; and
W is halogen or sulfonate;
with an olefin having the formula III
10 wherein:
Y is CHO, C(O)R, COOR, CONRR 1 , CN, NO 2 , SO 2 OR or SO 2 NRR 1 ;
Z is hydrogen, CHO, C(O)R, COOR, CONRR 1 , CN, NO 2 , SO 2 OR or SO 2 NRR 1 ; and
R, R 1 and R 4 are as described hereinabove;
in the presence of a palladium catalyst in a suitable solvent or solvent mixture to form a vinyl-substituted arylacetate or vinyl-substituted arylacetic acid;
(b) reacting the vinyl-substituted arylacetate or vinyl-substituted arylacetic acid with an oxidizing reagent in a suitable solvent or solvent mixture to form a formylarylacetate or formylarylacetic acid compound;
(c) reacting the formylarylacetate or formylarylacetic acid compound with a 5-(oxazolylalkylthio)-2-aminothiazole compound having the formula VI
10 wherein:
R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as described hereinabove; in the presence of a coupling reagent in a suitable solvent or solvent mixture to form an amide; and
(d) reacting the amide with an amine in the presence of a reducing reagent in a suitable solvent or solvent mixture to form the compound of formula I.
2 . The process as recited in claim 1 , wherein the arylacetate or the arylacetic acid in step (a) is a haloarylacetate or a haloarylacetic acid.
3 . The process as recited in claim 2 , wherein the haloarylacetic acid is a bromoarylacetic acid.
4 . The process as recited in claim 3 , wherein the bromoarylacetic acid is 4-bromophenylacetic acid.
5 . The process as recited in claim 1 , wherein the olefin in step (a) is an alkyl acrylate.
6 . The process as recited in claim 1 , wherein the palladium catalyst in step (a) is palladium acetate, palladium diacetate or palladium halide.
7 . The process as recited in claim 6 , wherein the palladium catalyst is palladium diacetate.
8 . The process as recited in claim 1 , wherein the solvent in step (a) is a hydrocarbon, an ether, an amide, a ketone or a mixture thereof.
9 . The process as recited in claim 8 , wherein the solvent is the amide and the amide is dimethylformamide.
10 . The process as recited in claim 1 , wherein step (a) forms a vinylarylacetate or a vinylarylacetic acid.
11 . The process as recited in claim 1 , wherein the oxidizing reagent in step (b) is O 3 , KMnO 4 or NaIO 4 /OsO 4 .
12 . The process as recited in claim 11 , wherein the oxidizing reagent is NaIO 4 /OsO 4 .
13 . The process as recited in claim 1 , wherein the solvent in step (b) is a hydrocarbon, an ether, an ester, an amide, a mixture thereof or an aqueous mixture thereof.
14 . The process as recited in claim 13 , wherein the solvent is the aqueous mixture of an ether and water.
15 . The process as recited in claim 1 , wherein the 5-(2-oxazolylalkylthio)-2-aminothiazole compound in step (c) is a 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound.
16 . The process as recited in claim 15 , wherein the 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound is 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole.
17 . The process as recited in claim 1 , wherein the coupling reagent in step (c) is a carbodiimide, a haloformate or a thionyl halide.
18 . The process as recited in claim 17 , wherein the coupling reagent is the thionyl halide.
19 . The process as recited in claim 1 , wherein the solvent in step (c) is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester or a mixture thereof.
20 . The process as recited in claim 19 , wherein the solvent is the halogenated hydrocarbon and the halogenated hydrocarbon is dichloromethane.
21 . The process as recited in claim 1 , wherein the amine in step (d) is a primary amine or a secondary amine.
22 . The process as recited in claim 21 , wherein the amine is the primary amine and the primary amine is a primary aliphatic amine.
23 . The process as recited in claim 1 , wherein the reducing reagent in step (d) is NaBH 4 , NaBH(OAc) 3 or Et 3 SiH/TFA.
24 . The process as recited in claim 23 , wherein the reducing reagent is NaBH(OAc) 3 .
25 . The process as recited in claim 1 , wherein the solvent in step (d) is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester or a mixture thereof.
26 . The process as recited in claim 25 , wherein the solvent is the ether and the ether is tetrahydrofuran.
27 . A process for the preparation of a compound having the formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 12 and R 13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R 3 , R 7 , R 10 and R 11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N;
which comprises the steps of:
(a) reacting an alkylarylacetate or alkylarylacetic acid compound having the formula VIII
10 wherein:
R 1 , R 2 , R 3 , R 4 , R 5 and X are as described hereinabove;
R is hydrogen, alkyl, aryl or heteroaryl; and
W is halogen or sulfonate;
with a 5-(2-oxazolylalkylthio)-2-aminothiazole compound having the formula VI
10 wherein:
R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as described hereinabove; in the presence of a coupling reagent and in a suitable solvent or solvent mixture to form an amide; and
(b) reacting the amide with an amine in a suitable solvent or solvent mixture to form the compound of formula I.
28 . The process as recited in claim 27 , wherein the alkylarylacetate or alkylarylacetic acid in step (a) is a haloalkylarylacetate or a haloalkylarylacetic acid.
29 . The process as recited in claim 28 , wherein the haloalkylarylacetic acid is a bromoalkylarylacetic acid.
30 . The process as recited in claim 29 , wherein the bromoalkylarylacetic acid is bromomethylphenylacetic acid.
31 . The process as recited in claim 27 , wherein the 5-(2-oxazolylalkylthio)-2-aminothiazole compound in step (a) is a 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound.
32 . The process as recited in claim 31 , wherein the 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compound is 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole.
33 . The process as recited in claim 27 , wherein the coupling reagent in step (b) is a carbodiimide, a haloformate or a thionyl halide.
34 . The process as recited in claim 33 , wherein the coupling reagent is the carbodiimide and the carbodiimide is an alkylcarbodiimide.
35 . The process as recited in claim 27 , wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester or a mixture thereof.
36 . The process as recited in claim 35 , wherein the solvent is the halogenated hydrocarbon and the halogenated hydrocarbon is dichloromethane.
37 . The process as recited in claim 27 , wherein the amine in step (b) is a primary amine or a secondary amine.
38 . The process as recited in claim 37 , wherein the amine is the primary amine and the primary amine is a primary aliphatic amine.
39 . The process as recited in claim 27 , wherein the solvent in step (b) is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide or a mixture thereof.
40 . The process as recited in claim 39 , wherein the solvent is an amide and the amide is dimethylformamide.
41 . A process for the preparation of a compound having the formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 12 and R 13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R 3 , R 7 , R 10 and R 11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N;
which comprises the steps of:
(a) reacting an aldehyde having the formula VII
10 wherein:
R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are as described hereinabove; with an organometallic reagent in a suitable solvent or solvent mixture to form an alcohol derivative;
(b) reacting the alcohol derivative with a halide; and
(c) reacting the halide compound with an excess of a primary amine or a secondary amine in a suitable solvent, or solvent mixture to form the compound of formula I.
42 . The process as recited in claim 41 , wherein the organometallic reagent in step (a) is methylmagnesium bromide.
43 . The process as recited in claim 41 , wherein the solvent in step (a) is ether.
44 . The process as recited in claim 41 , wherein the halide in step (b) is thionyl chloride.
45 . The process as recited in claim 41 , wherein the solvent in step (c) is ethanol.
46 . A process for the preparation of a formylarylacetate or formylarylacetic acid which comprises the following steps:
(a) reacting a haloarylacetate or haloarylacetic acid having formula II 10 wherein:
R is hydrogen, alkyl, aryl or heteroaryl;
R 1 and R 2 are each independently hydrogen, alkyl, aryl or heteroaryl;
R 3 is hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
W is halogen or sulfonate; and
X is CH or N;
with an olefin having the formula III
10 wherein:
R 4 is hydrogen, alkyl, aryl or heteroaryl;
Y is CHO, C(O)R, COOR, CONRR 1 , CN, NO 2 , SO 2 OR or SO 2 NRR 1 ;
Z is hydrogen, CHO, C(O)R, COOR, CONRR 1 , CN, NO 2 , SO 2 OR or SO 2 NRR 1 ; and
R and R 1 are as described hereinabove;
in the presence of a palladium catalyst in a suitable solvent or solvent mixture to form a vinyl-substituted arylacetate or vinyl-substituted arylacetic acid; and
(b) reacting the vinyl-substituted arylacetate or vinyl-substituted arylacetic acid with an oxidizing reagent in a suitable solvent or solvent mixture to form the formylarylacetate or formylarylacetic acid compound.
47 . The process as recited in claim 46 , wherein the olefin in step (a) is alkyl acrylate.
48 . The process as recited in claim 47 , wherein the alkyl acrylate is ethyl acrylate.
49 . The process as recited in claim 46 , wherein the oxidizing reagent in step (b) is O 3 , KMnO 4 or NaIO 4 /OsO 4 .
50 . The process as recited in claim 49 , wherein the oxidizing reagent is NaIO 4 /OsO 4 .Join the waitlist — get patent alerts
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