4-Formylbenzoic acid → Bavisant

Temperature

60 °C

4-(4-Cyclopropyl-piperazine-1-carbonyl)-benzaldehyde. A mixture of 4-formyl-benzoic acid (54.4 g), toluene (500 mL), N,N-dimethylformamide (DMF) (3.6 mL), and thionyl chloride (30.4 mL) was heated at 60° C. for 2 h and then was cooled to 5° C. In a separate flask, a 5° C. mixture of NaOH (50.7 g), water (550 mL), and toluene (150 mL) was treated with 1-cyclopropyl-piperazine dihydrochloride (70.0 g) in portions while the temperature was maintained below 10° C. After the addition was complete, the mixture was cooled to 5° C. and treated with the crude acyl chloride solution prepared as above at a rate such that the temperature did not exceed 10° C. After the addition was complete, the mixture was allowed to warm to rt and was stirred overnight. The biphasic mixture was basified to pH ˜10 with 1 N NaOH (300 mL). The layers were separated and the aqueous layer was extracted with toluene (100 mL×2). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to give the title compound as pale yellow viscous oil (56.0 g, 62%). HPLC: RT=5.19 min. MS (ESI): mass calcd. for C15H18N2O2, 258.14; m/z found, 258.9 [M+H+]. 1H NMR (400 MHz, CDCl3): 10.1 (s, 1H), 7.94 (pseudo d, J=8.2 Hz, 2H), 7.56 (pseudo d, J=8.1 Hz, 2H), 3.77 (br s, 2H), 3.33 (br s, 2H), 2.71 (br s, 2H), 2.55 (br s, 2H), 1.66 (ddd, J=10.2, 6.6, 3.7 Hz, 1H), 0.52-0.46 (m, 2H), 0.45-0.40 (br s, 2H). Step D. (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone. To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise over 5 min. The mixture was cooled to 10° C. and was treated with NaB(OAc)3H (64.3 g) in portions over 1 h. After a further 2 h, the mixture was warmed to rt, and a water bath was used to keep the temperature below 20° C. After 18 h, water (60 mL) was added while the temperature was kept under 20° C. by the addition of small amounts of ice. After 20 min, the mixture was basified to pH ˜10 with 1 N NaOH (450 mL) and the mixture was stirred for 10 min. The layers were separated, and the organic layer was washed with 1 N NaOH (150 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to give the title compound as pale yellow viscous oil (68.0 g, 95%). HPLC: RT=4.39 min. MS (ESI): mass calcd. for C19H27N3O2, 329.21; m/z found, 330.2 [M+H+]. 1H NMR (400 MHz, CDCl3): 7.35 (br s, 4H), 3.73 (br s, 2H), 3.69 (t, J=4.6 Hz, 4H), 3.50 (s, 2H), 3.37 (br s, 2H), 2.67 (br s, 2H), 2.53 (br s, 2H), 2.43 (t, J=4.2 Hz, 4H), 1.63 (ddd, J=10.3, 6.7, 3.7 Hz, 1H), 0.49-0.43 (m, 2H), 0.42-0.39 (br s, 2H). 13C NMR (101 MHz, CDCl3): 170.6, 140.0, 135.1, 129.5, 127.5, 67.4, 63.4, 54.0, 38.7, 6.3.

1. temperaturewas cooled to 5° C
2. temperaturewas maintained below 10° C
3. additionAfter the addition
4. temperaturethe mixture was cooled to 5° C.
5. customdid not exceed 10° C
6. additionAfter the addition
7. temperatureto warm to rt
8. customThe layers were separated
9. extractionthe aqueous layer was extracted with toluene (100 mL×2)
10. washThe combined organic layers were washed with brine (200 mL)
11. dry with materialdried (Na2SO4)
12. concentrationconcentrated

ORD record

ord-6ddc56db8a9d47109a29e505f6f5965b

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026242B2