Hydroxyamine hydrochloride → HCID 89158611, compound

Temperature

0 °C

A stirring solution of racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 11 g, 106 mmol), copper(I) chloride (0.20 g, 2.03 mmol), and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (156 mL) was poured into a 1 L jacketed reactor and cooled to 0° C. A solution of 4-(bromoethynyl)benzoic acid (INT-1, 22.81 g, 101 mmol) and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (111 mL) was then added dropwise and the reaction was stirred for 2 hr. The reaction mixture was washed with MTBE (2×230 mL) and the aqueous layer was diluted with methyl THF (460 mL). The solution was cooled to 0° C. and acidified by dropwise addition of 6M HCl (100 ml) to pH 1. The reaction mixture was filtered through Celite, and washed with methyl-THF (230 ml). The two layers were partitioned and the aqueous layer was back-extracted with methyl-THF (230 mL). The organic layers were washed with 2M HCl (2×230 mL), water (230 ml), and brine (230 ml), dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure until the solution turned cloudy, then heptane (230 mL) was added. The resulting solution was concentrated under reduced pressure to 5 volumes and then additional heptane (230 mL) was added. The resulting solution was concentrated to 5 volumes to give a slurry. The solids were collected by filtration, washed with heptane (50 mL), and dried under reduced pressure to yield 4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic acid (3.4, 3.96 g). MS: m/z calcd for C15H12O3 240.08. found [M−H]+ 239.1. 1H NMR (DMSO-d6, 400 MHz) δ 13.18 (s, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 4.72 (t, 1H), 3.39-3.52 (m, 1H), 3.21-3.32 (m, 1H), 1.41-1.51 (m, 2H), 0.81-0.99 (m, 2H).

1. washThe reaction mixture was washed with MTBE (2×230 mL)
2. additionthe aqueous layer was diluted with methyl THF (460 mL)
3. temperatureThe solution was cooled to 0° C.
4. additionacidified by dropwise addition of 6M HCl (100 ml) to pH 1
5. filtrationThe reaction mixture was filtered through Celite
6. washwashed with methyl-THF (230 ml)
7. customThe two layers were partitioned
8. extractionthe aqueous layer was back-extracted with methyl-THF (230 mL)
9. washThe organic layers were washed with 2M HCl (2×230 mL), water (230 ml), and brine (230 ml)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationThe organic layer was concentrated under reduced pressure until the solution
13. additionheptane (230 mL) was added
14. concentrationThe resulting solution was concentrated under reduced pressure to 5 volumes
15. additionadditional heptane (230 mL) was added
16. concentrationThe resulting solution was concentrated to 5 volumes
17. customto give a slurry
18. filtrationThe solids were collected by filtration
19. washwashed with heptane (50 mL)
20. customdried under reduced pressure

ORD record

ord-31a24437e89447169765000be3dbab08

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09403758B2