Benzaldehyde → HCID 71760913, compound

Temperature

50 °C

To a stirring solution of benzaldehyde (43 mg, 0.40 mmol) in methanol (3.5 mL) was added (1S,2S,4S)-1-acetamido-4-(aminomethyl)-N-(tert-butyl)-2-(3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (148 mg, 0.35 mmol) and glacial acetic acid (one drop). The reaction mixture was stirred at 50° C. for 1 h, then cooled using an ice bath prior to adding sodium borohydride (17 mg, 0.45 mmol). After stirring for an additional hour (1 h) at 3° C., the reaction was allowed to warm to room temperature, and stirred for another 20 minutes. Following quenching of the reaction with water (1 mL)., the crude product mixture was treated with a 2:1:1 mixture of concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle, stirred for 2 h at 60° C., and then capped and stirred for an additional 18 h at 130° C. The reaction mixture was then cooled to room temperature prior to uncapping of the pressure bottle. The crude mixture was diluted with water (20 mL), extracted with methylene chloride (20 mL) and concentrated in vacuo. The residue obtained was treated with water (20 mL) and concentrated three times to remove excess HCl. The crude reaction mixture was then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol prior to use. After stirring for 40 min, the reaction mixture was filtered and the resin washed successively with water, methanol and methylene chloride twice. Following washing, the resin was stirred with 1N HCl (15 mL×4) and filtered. The combined filtrates were concentrated and the residue was treated with water (20 mL) followed by concentration of the aqueous mixture three times to remove excess HCl. Purification of the crude product by HPLC followed by formation of the hydrochloride salt afforded the subject compound (71.4 mg, 50%) as a hygroscopic white foam. NMR (D2O) δ 7.40 (br s, 5 H), 4.17 (br s, 2 H), 3.02 (d, J=5.5 Hz, 2 H), 2.70 (m, 1 H), 2.51 (m, 1 H), 2.15 (m, 1 H), 1.80 (m, 2 H), 1.55 (m, 1 H), 1.30-1.45 (m, 2 H), 1.20 (m, 1 H), 1.05 (m, 1 H), 0.60-0.75 (m, 2 H). MS (M+1): 335.5; MS (M−H2O+1): 317.4; MS (M−2H2O+1): 299.3.

1. temperaturecooled
2. stirringAfter stirring for an additional hour (1 h) at 3° C.
3. temperatureto warm to room temperature
4. stirringstirred for another 20 minutes
5. customFollowing quenching of the reaction with water (1 mL)
6. addition, the crude product mixture was treated with a 2:1:1 mixture of concentrated HCl
7. stirringglacial acetic acid:water (8 mL) in a pressure bottle, stirred for 2 h at 60° C.
8. customcapped
9. stirringstirred for an additional 18 h at 130° C
10. temperatureThe reaction mixture was then cooled to room temperature
11. additionThe crude mixture was diluted with water (20 mL)
12. extractionextracted with methylene chloride (20 mL)
13. concentrationconcentrated in vacuo
14. customThe residue obtained
15. concentrationconcentrated three times
16. customto remove excess HCl
17. customThe crude reaction mixture
18. washhad been rinsed with methanol
19. stirringAfter stirring for 40 min
20. filtrationthe reaction mixture was filtered
21. washthe resin washed successively with water, methanol and methylene chloride twice
22. washFollowing washing
23. stirringthe resin was stirred with 1N HCl (15 mL×4)
24. filtrationfiltered
25. concentrationThe combined filtrates were concentrated
26. additionthe residue was treated with water (20 mL)
27. customto remove excess HCl
28. customPurification of the crude product by HPLC

ORD record

ord-941d386637254bf2bb168ecb4df3cab4

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09200011B2