METHOD FOR STEREOSELECTIVE SYNTHESIS OF BICYCLIC HETEROCYCLES

摘要

Stereoselective preparation of (cis)- and trans-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one, comprises e.g. (a) converting 1,4-cyclohexanedione-mono-ethylene ketal to 1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one (1a), (b) converting (1a) to 1,4-diaza-spiro[5.5]undecane-5,9-dione-hydrochloride (2a), (v) reacting (2a) with a protecting group reagent to nitrogen protected compounds (19a), and (x) converting (19a) to nitrogen protected compounds (18a). Stereoselective preparation of (cis)- and trans-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one, optionally in the form of their tautomers, and their acid addition salts, comprises: either (a) converting 1,4-cyclohexanedione-mono-ethylene ketal to 1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one (1a), (b) converting (1a) to give 1,4-diaza-spiro[5.5]undecane-5,9-dione-hydrochloride (2a), (v) reacting (2a) with a protecting group reagent to nitrogen protected diaza-spiro[5.5]undecane-dione compounds of formula (19a), (x) converting (19a) to nitrogen protected 9-hydroxy-1,4-diaza-spiro[5.5]undecan-one compounds of formula (18a), (r) reacting (18a) with nitrogen protected 6-hydroxy-7-methoxy-3H-quinazolin-4-one compounds of formula (23a) to give nitrogen protected 7-methoxy-6-(5-oxo-1,4-diaza-spiro[5.5]undec-9-yloxy) -3H-quinazolin-4-one compounds of formula (21a), (s) splitting the protecting group of (21a) to give (cis)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one (22a), and (t) chlorinating (22a) and subsequently reacting with 3-chloro-2-fluoroaniline to give cis product; or the steps (a), (b), (z) converting (2a) to give nitrogen protected 9-hydroxy-1,4-diaza-spiro[5.5]undecan-5-one compounds of formula (16a), (h) converting (16a) to nitrogen protected 9-hydroxy-1,4-diaza-spiro[5.5]undecan-5-one compounds of formula (6a), (p) reacting (6a) with (23a) to give nitrogen protected 7-methoxy-6-(5-oxo-1,4-diaza-spiro[5.5]undec-9-yloxy)-3H-quinazolin-4-one compounds of formula (7a), (q+m) splitting the protecting group of (7a) to give (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one (12a), and (n+o) chlorinating (12a) and subsequently reacting with 3-chloro-2-fluoroaniline to give trans product. Sg1 : protecting group comprising optionally substituted benzyl, benzyloxycarbonyl or optionally substituted acetyl; and Sg2 : protecting group comprising optionally substituted benzyl. Independent claims are included for: (1) the (cis)- and trans-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one, and its salt with inorganic or organic acids and bases; (2) the compounds (18a); (3) the compound (22a), and its salt with inorganic or organic acids and bases; (4) (trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one (13a), and its salt with inorganic or organic acids and bases; (5) nitrogen protected 1,4-diaza-spiro[5.5]undecane-5,9-dione compounds of formula (4a), and its salt with inorganic or organic acids and bases; (6) nitrogen protected 9-hydroxy-1,4-diaza-spiro[5.5]undecan-5-one compounds of formula (5a), and its salt with inorganic or organic acids and bases; and (7) the compounds (6a), (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-1,4-diaza-spiro[5.5]undecan-5-one (12a) and their salts with inorganic or organic acids and bases. Sg3 : a protecting group comprising butyloxycarbonyl or alkoxycarbonyl. [Image] [Image] [Image] ACTIVITY : Cytostatic; Respiratory-Gen. MECHANISM OF ACTION : Tyrosine kinase-mediated signal transduction inhibitor.