反应详情

A mixture of 5 parts of cis-5-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide, 3.2 parts of 2-methylthio-4-pyrimidinol and 79 parts of acetonitrile was stirred over weekend at reflux temperature. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and ammonia (aq.). The aqueous layer was separated and re-extracted with dichloromethane (2×). The combined dichloromethane layers were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the two desired fractions was evaporated and the residues were separately crystallized from acetonitrile. The product was filtered off and dried in vacuo at 70° C., yielding a first fraction of 2.22 parts (35.2%) of cis-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl ]-2H-1-benzopyran-8-carboxamide hemihydrate; mp. 142.6° C. and a second fraction of 1.00 part (15.9% ) of cis-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl]-2H-1-benzopyran-8-carboxamide hemihydrate; mp. 143.5° C. Total yield: 3.22 parts (51.1%) of product (comp. 128).

1. temperatureat reflux temperature
2. customThe reaction mixture was evaporated
3. customthe residue was partitioned between dichloromethane and ammonia (aq.)
4. customThe aqueous layer was separated
5. extractionre-extracted with dichloromethane (2×)
6. dry with materialThe combined dichloromethane layers were dried
7. filtrationfiltered
8. customevaporated
9. customThe residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5)
10. customThe eluent of the two desired fractions was evaporated
11. customthe residues were separately crystallized from acetonitrile
12. filtrationThe product was filtered off
13. customdried in vacuo at 70° C.