Benzenesulfonic Acid → Omarigliptin

Temperature

32.5 °C

Benzenesulfonic acid (32.95 kg, 271 mol) was dissolved in dichloromethane (1020 kg) under nitrogen. Then, 880 g of water was added such that the solution KF was 0.2%. Next, tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate (38.4 kg, 100 mol) was added in three equal portions over 30 min. The reaction was then aged overnight at room temperature. Next, water (733 kg) was added over 1 h and the reaction stirred rapidly for 1 h. The layers were then separated, discarding the resulting organics layer. To the aqueous layer was charged dichloromethane (510 kg) followed by triethylamine (22.4 kg, 592 mol). After agitation, the layers were separated and the aqueous extracted with dichloromethane (510 kg). The combined organics were washed with 7% aqueous NaHCO3 (2×410 kg) and 5% brine (386 kg). The organics were then dried with Na2SO4, filtered, and treated with activated carbon (6.2 kg of C-941). The carbon was filtered off and the filtrate was concentrated under vacuum to 154-193 L. This solution was then warmed to 30-35° C. to dissolve solids (additional dichloromethane may be added to dissolve solids). Next, iso-propylacetate (338 kg) was added and the solution stirred at room temperature for 1.5 h. Then, n-heptane (159 kg) was charged to the vessel drop-wise and stirred for 3 h. The slurry was then filtered and the cake washed with n-heptane. This wet cake was then recrystallized again by dissolving it into dichloromethane and adding iso-propylacetate and n-heptane as before, filtering, and washing with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine was washed with cold 2:1EtOAc/hexanes to give the title compound as an off-white solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88(s, 1H). LC-MS: 399.04 [M+1].

1. customThe layers were then separated
2. additionTo the aqueous layer was charged dichloromethane (510 kg)
3. customAfter agitation, the layers were separated
4. extractionthe aqueous extracted with dichloromethane (510 kg)
5. washThe combined organics were washed with 7% aqueous NaHCO3 (2×410 kg) and 5% brine (386 kg)
6. dry with materialThe organics were then dried with Na2SO4
7. filtrationfiltered
8. additiontreated with activated carbon (6.2 kg of C-941)
9. filtrationThe carbon was filtered off
10. concentrationthe filtrate was concentrated under vacuum to 154-193 L
11. dissolutionto dissolve
12. additionsolids (additional dichloromethane may be added to dissolve solids)
13. additionNext, iso-propylacetate (338 kg) was added
14. stirringthe solution stirred at room temperature for 1.5 h
15. additionThen, n-heptane (159 kg) was charged to the vessel drop-wise
16. stirringstirred for 3 h
17. filtrationThe slurry was then filtered
18. washthe cake washed with n-heptane
19. customThis wet cake was then recrystallized again
20. dissolutionby dissolving it into dichloromethane
21. additionadding iso-propylacetate and n-heptane as before,
22. filtrationfiltering
23. washwashing with n-heptane
24. customThe solids were dried under vacuum at 40-50° C. overnight

ORD record

ord-05a2890319554764afc9aba78ca1beb9

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08895603B2