反应详情

温度

90 °C

2-(3-{[7-(3-Chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-(ethylamino)ethanol (ideally 12 molar equivalents) were added to N,N-dimethylacetamide under an inert atmosphere (such as provided by nitrogen) and the mixture heated to 90° C. with stirring. After a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C. and water added in a controlled manner to maintain the temperature between 80-85° C. The batch is adjusted to 80° C. and seeded with crystals of the preferred form of the product (ideally an amount of about 1% of the expected yield). The mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as to crystallise the product in the required form and of a size sufficient to afford a good filtration rate. The product is then filtered and washed with a mixture of water/N,N-dimethylacetamide and acetonitrile and suitably deliquored to afford a hydrated form of the product. Following this, the cake is slurried in situ for a period (ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered, washed with more acetonitrile and then dried (in vacuo or under a stream of nitrogen) to afford the almost anhydrous 2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide as an off-white solid in a yield of 85-90%.

1. temperatureAfter a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C.
2. temperatureto maintain the temperature between 80-85° C
3. customis adjusted to 80° C.
4. customexpected yield)
5. temperatureThe mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as
6. customto crystallise the product in the required form
7. customof a size sufficient to afford a good filtration rate
8. filtrationThe product is then filtered
9. washwashed with a mixture of water/N,N-dimethylacetamide and acetonitrile
10. customto afford a hydrated form of the product
11. waitis slurried in situ for a period
12. filtration(ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered
13. washwashed with more acetonitrile
14. customdried (in vacuo