Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2003-02-04
2003-12-16
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06664390
ABSTRACT:
FIELD OF THE INVENTION
The invention concerns a one-pot reaction for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (I) ;
or of (3-chloro-4-fluorophenyl)-[7-( 3-morpholino-4-yl-propoxy)-6-aminoquinazolin-4-yl]-amine (VII)
BACKGROUND OF THE INVENTION
The Compound of formula I, (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-ylpropoxy)-6-nitroquinazolin-4-yl]-amine (I)
is a key compound for the preparation of N-[4-[(3-chloro-4-fluorophenyl)-amino]-7-[3-( 4-morpholinyl)-propoxy]-quinazolinyl]-propenamide dihydrochloride (II).
Compound II is representative of a new class of highly effective inhibitors of the EGFR (epidermal growth factor receptor) tyrosine kinase. These inhibitors are useful for the treatment of various tumours, as described, for example, in WO 97/38983.
The original synthesis of compound II is described in J. Med. Chem. 1996, 39, 918-928 and WO 97/38983. The synthesis required 12 steps and was unsuitable for commercial development.
The starting material for the previous synthesis was isomerically pure 7-fluoro-6-nitroquinazolin-4(3H)-one (III)
which was reacted with a 55 molar excess of thionyl chloride and catalytic amounts of DMF in the absence of solvent to give 4-chloro-7-fluoro-6-nitroquinazoline (IV)
After distilling off of the excess thionyl chloride, the 4-chloro-7-fluoro-6-nitroquinazoline obtained as crude product was reacted portionwise with a solution of 1 equivalent of 3-chloro-4-fluoroaniline and 2 equivalents of the highly toxic N,N-dimethylaniline in 2-propanol. After stirring for 6 hours at 25° C., the solution was subjected to an aqueous work-up comprising washing by mixing from 1-10 times with one or more aqueous solutions, each time removing the aqueous layer and finally obtaining 4-(3-chloro-5-fluoroanilino )-7-fluoro-6-nitroquinazoline (V)
in about 90% yield as crude product.
To a suspension of 1 equivalent of 4-(3-chloro-4-fluoroanilino)-7-fluoro-6-nitroquinazoline (V) and 1.5 equivalents of 3-(4-morpholino)-propan-1-ol (VI)
in dimethyl sulphoxide (DMSO) was added dropwise a solution of 3 equivalents potassium trimethyl silanoate in DMSO and the reaction mixture was stirred for about 6 hours. After an aqueous working up, (3-chloro-4-fluoro-phenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4yl]-amine (I) was obtained in about 89% yield.
This synthesis step proved to be especially problematic since, in the case of batch enlargement, variable yields were obtained. Reactions of 4-(3-chloro-4-fluoroanilino)-7-fluoro-6-nitroquinazoline (V), 3-(4-morpholino)-propan-1-ol (VI) and solid sodium hydride in THF, analogously to the process described in WO 97/38983,also lead only to unsatisfactory results.
The (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy )-6-nitroquinazolin-4-yl]-amine (I) obtained was subsequently hydrogenated inter alia over Raney nickel in THF as solvent to give (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-aminoquinazolin-4-yl]-amine (VII)
and then further reacted to give (II) or its dihydrochloride trihydrate.
SUMMARY OF THE INVENTION
Process for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy )-6-nitroquinazolin-4-yl]-amine (I)
or of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy )-6-aminoquinazolin-4-yl]-amine (VII)
characterised in that, in a one-pot reaction, in 3 or 4 reaction steps, one first reacts 7-fluoro-6-nitroquinazolin-4(3H)-one (III)
with thionyl chloride to give 4-chloro-7-fluoro-6-nitroquinazoline (IV)
then reacts this with 3-chloro-4-fluoroaniline to give 4-(3-chloro-4-fluoroanilino )-7-fluoro-6-nitroquinazoline (V)
and subsequently with 3-morpholin-4-yl-propan-1-ol (VI)
to give (I) and possibly hydrogenates (I) directly in the reaction solution to give (VII).
REFERENCES:
patent: WO 97/38983 (1997-10-01), None
Barth Hubert
Schneider Simon
Steiner Klaus
Ashbrook Charles W.
Goodman Rosanne
Ramsuer Robert W.
Warner-Lambert Company LLC
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