Hydrochloric Acid → HCID 19903194, compound

To a suspension of 1.23 g of the benzazepinone of Example 1 (5.18 mmol) in 30 mL of benzene was added 0.14 g of NaH (5.7 mmol, ~1.1 eq.) in 2 portions, followed after 30 minutes by 0.21 g of KI (1.3 mmol, ~0.25 eq.). To this mixture was added a solution derived from 1.42 g of bromopropylamine HBr (6.48 mmol, 1.25 eq.). The free base utilized was prepared as follows: 1.42 g of amine HBr (6.48 mmol, 1.25 eq.) was dissolved in H2O, made basic with 2N NaOH, and extracted with C6H6 (3×10 mL). The C6H6 layers were then washed with saturated NaCl, dried (K2CO3), and added dropwise to the aforementioned anion solution. The reaction was heated 24 hr at 40°, then an additional 0.5 g of KI was added and heated at reflux for 4 hr. The reaction was cooled to 25°, and an additional 0.14 g of NaH (5.7 mmol, ~1.1 eq.) and bromopropyl amine (from 1.42 amine HBr, 6.48 mmol, 1.25 eq.) solution were added. The mixture was further refluxed for 48 hr, cooled to 25°, and 75 mL of H2O and 75 mL of EtOAc were added. The phases were separated, the aqueous phase was reextracted with EtOAc, and the combined organic phases were extracted with 2N HCl (2×150 mL). The combined acidic layers were then basified with conc. NH4OH, extracted with EtOAc, and the EtOAc layers in turn washed with saturated NaCl, dried (K2CO3), and the solvents removed in vacuo to yield 1.32 of crude 2-(3-aminopropyl)benzazepinone as a yellow oil. This oil was immediately dissolved in 175 mL of PhCH3, 0.87 g of p-TSA (4.6 mmol, 1 eq.) was added, and the reaction heated at reflux with a Dean-Stark water separator for 72 hr. The reaction was then cooled to 25°, an additional 0.87 g p-TSA (4.6 mmol, 1 eq.) was added and the reaction refluxed a further 48 hr. The reaction was finally cooled to 25°, the volatiles were removed in vacuo and the residue partitioned between saturated NaHCO3 and EtOAc. The EtOAc layers were washed with saturated NaCl, dried (Na2SO4), and evaporated to yield 0.75 g of a waxy solid. This solid was converted to the crude HCl salt and chromatographed on neutral activity III Al2O3 eluting with 6% MeOH in CH2Cl2 to furnish 0.70 g of 1,2,3,5,6,11-hexahydro-11-phenylpyrimido[1,2-b][2]benzazepine as a white crystalline solid, mp 227°-228°.

1. additionTo this mixture was added a solution
2. customThe free base utilized was prepared
3. extractionextracted with C6H6 (3×10 mL)
4. washThe C6H6 layers were then washed with saturated NaCl
5. dry with materialdried (K2CO3)
6. additionadded dropwise to the aforementioned anion solution
7. temperatureThe reaction was heated 24 hr at 40°
8. additionan additional 0.5 g of KI was added
9. temperatureheated
10. temperatureat reflux for 4 hr
11. temperatureThe reaction was cooled to 25°
12. temperatureThe mixture was further refluxed for 48 hr
13. temperaturecooled to 25°
14. customThe phases were separated
15. extractionthe combined organic phases were extracted with 2N HCl (2×150 mL)
16. extractionextracted with EtOAc
17. washthe EtOAc layers in turn washed with saturated NaCl
18. dry with materialdried (K2CO3)
19. customthe solvents removed in vacuo
20. customto yield 1.32 of crude 2-(3-aminopropyl)benzazepinone as a yellow oil
21. temperaturethe reaction heated
22. waitseparator for 72 hr
23. temperatureThe reaction was then cooled to 25°
24. temperaturethe reaction refluxed a further 48 hr
25. temperatureThe reaction was finally cooled to 25°
26. customthe volatiles were removed in vacuo
27. customthe residue partitioned between saturated NaHCO3 and EtOAc
28. washThe EtOAc layers were washed with saturated NaCl
29. dry with materialdried (Na2SO4)
30. customevaporated
31. customto yield 0.75 g of a waxy solid
32. customchromatographed on neutral activity III Al2O3 eluting with 6% MeOH in CH2Cl2

ORD record

ord-c033e947609f4d0c8cf522833a92fdf1

Source dataset

uspto-grants-1992_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05098901