Hydrochloric Acid → HCID 69002085, compound

Temperature

85 °C

To a mixture of 4-(4-Thiophen-3-yl-benzyl)-phenol (9 g, 33.8 mmol, 1 eq.) and (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.6 g, 35.5 mmol, 1.05 eq.) in DMF (80 ml) was added sodium hydride (60% in mineral oil, 1.62 g, 40 mmol, 1.2 eq.) at 0° C. in one portion. The mixture was stirred at 85° C. overnight. Since (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was consumed with about 15% of 4-(4-thiophen-3-yl-benzyl)-phenol remaining (by TLC and 1H NMR analysis), 1.23 g of additional of (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.46 mmol, 0.1 eq.) was added and the mixture was stirred for overnight. After cooling to room temperature, the mixture was poured into NaHCO3 aq. (500 ml). The mixture was extracted with EtOAc (150 ml×3). The combined EtOAc layers were washed with water (50 ml×3), dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave the crude product as oil (15 g), of which 1H NMR indicated existence of 13% of starting 4-(4-Thiophen-3-yl-benzyl)-phenol. Then the crude product thus obtained was treated with 4N HCl in dioxane (40 ml) overnight to form a solid, which was suspended in THF (3.5 L) and stirred at room temperature overnight. The solid was filtered off and washed with ether. After drying on a vacuum line at 65° C. overnight, 7 g of desired product was obtained as off-white solid. The mother liquid (THF) was evaporated under reduced pressure to 500 ml and the suspension was collected by filtration and washed with ether to give 2.5 g of product; m.p. 187.6˜188.3° C.; LC-MS. 99% purity; HPLC: 99% purity; ee: 99%, determined by chiral HPLC; Elemental analysis (C22H25ClNOS): Calculated (%): C, 68.29; H, 6.51; N, 3.62; S, 8.29. Found (%): C, 67.97; H, 6.36; N, 3.49; S, 8.36. 1H NMR (400 MHz, DMSO-d6) δ 1.70 (m, 1H), 1.90 (m 2H), 2.1 (m, 1H), 3.2 (m, 2H), 3.86 (m, 1H), 3.89 (S, 2H), 4.08 (dd, J=8.0 J2=10.4 Hz, 1H), 4.20 (dd, J1=3.6 Hz, J2=10.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.51 (dd, J=1.6, 4.8 Hz, 1H), 7.62 (m, 3H), 7.79 (d, J=1.6, 3.2 Hz, 1H).

1. additionwas added
2. stirringthe mixture was stirred for overnight
3. temperatureAfter cooling to room temperature
4. extractionThe mixture was extracted with EtOAc (150 ml×3)
5. washThe combined EtOAc layers were washed with water (50 ml×3)
6. dry with materialdried over anhydrous MgSO4
7. customEvaporation of solvent under reduced pressure
8. customgave the crude product as oil (15 g)
9. customThen the crude product thus obtained
10. customto form a solid, which
11. stirringstirred at room temperature overnight
12. filtrationThe solid was filtered off
13. washwashed with ether
14. customAfter drying on a vacuum line at 65° C. overnight

ORD record

ord-f8c7a46a1b9841f2a060c6b01f02db67

Source dataset

uspto-grants-2008_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07402684B2