Triethylamine → HCID 68107563, compound

5% Palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 330116) was placed in a Parr bottle under nitrogen, followed by MeOH (70 mL, JT-Baker 909333). The crude mixture of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15A & 15B) (186.6 g, 892.1 mmol) dissolved in MeOH (117 mL) was added to the Parr bottle, followed by NEt3 (124.3 mL, 892.1 mmol, Sigma-Aldrich 471283). The bottle was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the starting material was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving brown oil, which was dissolved in Et2O and washed with water (2×). The ether phase was extracted with aqueous 1 N HCl (5×250 mL), which was washed with Et2O (3×) and then basified with aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with dichloromethane (CH2Cl2, 4×), and the combined organic extract was washed with saturated aqueous NH4Cl, dried over Mg504, and filtered through a pad of silica eluting with CH2Cl2 to 25% EtOAc/hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 m×250 μm×0.25 μm column heating at 60° C. for 2 min to 300° C. over 15 min with a 1 mL/min flow rate) M+1: 182.0 (11.44 min). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.61 min). 1H NMR (300 MHz, CDCl3) δ 6.97 (td, J=8.1, 6.3 Hz, 1H), 6.43-6.35 (m, 2H), 5.21-5.13 (m, 1H), 4.54 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 torr) collecting the distillate at 101-108° C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2° C. was slowly added 5 M HCl (1 eq) in iPrOH. The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. A white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HCl salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HCl salt as a third crop of the product. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.58 min). 1H NMR (300 MHz, CDCl3) δ 10.73 (br.s, 3H), 7.66 (d, J=8.1 Hz, 1H), 7.33 (td, J=8.2, 5.9 Hz, 1H), 7.13-7.05 (m, 1H), 5.26 (dd, J=9.0, 6.5 Hz, 1H), 4.38-4.28 (m, 1H), 4.00-3.91 (m, 1H), 2.59-2.46 (m, 1H), 2.30-1.95 (m, 3H) ppm. The overall yield from the three crops was 76%.

1. additionwas added to the Parr bottle
2. additionAfter adding 45 psi H2
3. custom(HPLC and LCMS showed complete reaction)
4. customThe reaction mixture was purged with nitrogen
5. filtrationfiltered through Celite™
6. washrinsed with EtOAc
7. concentrationThe filtrate was concentrated on a rotary evaporator
8. customgiving brown oil, which
9. washwashed with water (2×)
10. extractionThe ether phase was extracted with aqueous 1 N HCl (5×250 mL), which
11. washwas washed with Et2O (3×)
12. extractionThe basic aqueous phase was extracted with dichloromethane (CH2Cl2, 4×)
13. extractionthe combined organic extract
14. washwas washed with saturated aqueous NH4Cl
15. customdried over Mg504
16. filtrationfiltered through a pad of silica eluting with CH2Cl2 to 25% EtOAc/hexane
17. concentrationThe desired filtrate was concentrated under reduced pressure

ORD record

ord-e86131dc3b98456b82ed78de0d2cd270

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08912326B2