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US 2011/0257391 A1Published application
Process for production of quinazoline derivative
AssigneeShionogi & Co., Ltd.
InventorsMotoyuki Hagihara, Shoji Shinomoto
Life of this patent
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Abstract
A process for preparing a compound (III) is provided, in which the compound (III) is prepared from a methoxycarbonyl derivative through a methoxyamide derivative. These two reaction steps are continuously carried out and substantially the same as one step. The compound (III) is useful as a synthetic intermediate for preparing a dual tyrosine kinase inhibitor and can be conveniently prepared in high yield according to the present invention.
Claims16
A process for preparing a compound represented by the formula (III):
- wherein R2 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by the formula:
- -Y-Ry wherein -Y- is —O—, —S—, —SO2—, or alkylene which may be intervened with —O—, —S— or —N(Rz)—;
- and Ry is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- Rz is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl;
- R3 and R4 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino;
- a salt, or a solvate thereof;
- characterized in that
- Reaction A, in which a compound represented by the formula (I):
- wherein R1 is a group represented by the formula:
- —O—Rx or —S—Rx wherein Rx is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl or a group represented by the formula (II):
- wherein L1 is substituted or unsubstituted C2-C3 alkylene;
- R2 , R3 and R4 are as defined above,
- is reacted with a compound represented by the formula:
- (RbO—)N(—Ra)H
- wherein Ra and Rb are each independently substituted or unsubstituted C1-C3 alkyl;
- or a salt thereof,
- and one or more metallic reagent(s) selected from the group consisting of Grignard reagent, sodium hydride, alkyllithium, alkenyllithium, alkynyllithium, phenyllithium, and lithium amide;
- and reaction B, in which the product of reaction A is reacted with 1-propynyl metal acetylide;
- are carried out substantially as one step by continuously conducting these two reactions.
16 more elements
A crystalline form of monohydrate of the compound represented by the formula (IV):
Dependencies are inferred from the claim text.