Hydrochloric Acid → HCID 86684902, compound

To a stirred suspension of 1-trifluoromethylcyclopropane-1-carboxylic acid (40.4 g, 263 mmol) and DMF (0.4 mL, 5.25 mmol) in dichloromethane (50 mL) was added oxalyl chloride (36.7 g, 289 mmol) under stirring at room temperature over 2 h (vigorous gas evolution!). After additional stirring for 0.5 h (the gas evolution has stopped), the clear acid chloride solution was transferred into an 100 mL addition funnel and added under vigorous stirring at 0° C. over 0.5 h to a suspension of hydroxyproline methyl ester hydrochloride (45.4 g, 250 mmol) and triethylamine (101 g, 1000 mmol) in dichloromethane (950 mL). After additional stirring at 0° C. for 1 h, methanesulfonyl chloride (31.5 g, 275 mmol) was added over 0.5 h, stirring at 0° C. was continued for 0.5 h and the cold suspension was hydrolyzed with 1 M HCl (500 mL, pH=1). After warming to room temperature the organic layer was washed with 5% brine (500 mL) and the two aqueous layers were extracted with dichloromethane (250 mL). The combined organic layers were dried (Na2SO4) and evaporated (35-45° C./≧10 mbar) affording beige, crystalline crude product (91.4 g) which was dissolved in isopropyl acetate (360 mL) at ˜70° C. Crystallization, which started upon cooling and seeding, was completed by stirring at room temperature, followed by drop wise addition of heptane (540 mL) and stirring at −20° C. for 4 h. Filtration and washing with cold isopropyl acetate-heptane 2:3 gave after drying (10 mbar/55° C./4 h) the product (83.2 g, 92.6%) as an off-white, crystalline powder, mp. 123-124° C. [α]D20=−26.6 (c 1.0; CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.10-1.42 (m, 4H), 2.18-2.30 (m, 1H), 2.58-2.70 (m, 1H), 3.06 & 3.76 (s, each 3H), 3.90 (dd, J1=12.8 Hz, J2=3.2 Hz, 1H), 4.32 (d, J=12.8 Hz, 1H), 4.68 (t, J=8.3 Hz, 1H), 5.33 (s, 1H). ESI-MS (m/z) [M+H]+ 360 (100).

1. stirringAfter additional stirring for 0.5 h (the gas evolution
2. additionwas transferred into an 100 mL addition funnel
3. additionadded
4. stirringAfter additional stirring at 0° C. for 1 h
5. stirringstirring at 0° C.
6. waitwas continued for 0.5 h
7. temperatureAfter warming to room temperature the organic layer
8. washwas washed with 5% brine (500 mL)
9. extractionthe two aqueous layers were extracted with dichloromethane (250 mL)
10. dry with materialThe combined organic layers were dried (Na2SO4)
11. customevaporated (35-45° C./≧10 mbar)
12. customaffording beige
13. customCrystallization, which
14. temperatureupon cooling
15. stirringby stirring at room temperature
16. additionfollowed by drop wise addition of heptane (540 mL)
17. stirringstirring at −20° C. for 4 h
18. filtrationFiltration
19. washwashing with cold isopropyl acetate-heptane 2:3
20. customgave
21. dry with materialafter drying (10 mbar/55° C./4 h) the product (83.2 g, 92.6%) as an off-white, crystalline powder, mp. 123-124° C. [α]D20=−26.6 (c 1.0; CHCl3)

ORD record

ord-fb8a19316c644f0a82244b8e437d1d86

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796471B2