9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof
OSTERMEIER MARKUS,PFRENGLE WALDEMAR,HUCHLER GUENTHER,SIEGER PETER
申请号：
NZ61391712
公开号：
NZ613917A
申请日:
2012.01.27
申请国别(地区):
NZ
年份:
2015
代理人:
摘要：
Disclosed is crystalline 9-[4-(3-chloro-2-fluorophenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate of formula (I) optionally in the form of the tautomers thereof, wherein reflections in the X-ray powder diagram occur at dhkl values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Å, and has corresponding values 2theta of 12.43, 15.33, 18.92, 20.37, 21.38, 23.06 and 24.67. Also disclosed is a process for the stereoselective preparation of the crystalline compound of formula (I) starting from 1,4-cyclohexanedione-mono-ethyleneketal. Also disclosed is a process for the chlorination of tert-butyl (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate or tert-butyl (trans)-9-(4-oxo-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate with a reactant selected from among N-chlorosuccinimide/triphenylphosphane oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide, to form tert-butyl (trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate. Further disclosed are intermediates such as tert-butyl (trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate and (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride.
