Urea → HCID 9923121, compound

To a solution of 27B (500 mg, 1.83 mmol) in CH2Cl2 (1.5 mL) was added TFA (1.5 mL). The reaction mixture was stirred at RT for 1 h, then concentrated under reduced pressure to give an oily residue, which was stripped with toluene (3×) and dried in vacuo overnight. The oily residue was dissolved in CH2Cl2 (10 mL) and to the solution was added N,N-diisopropylethylamine (0.35 mL, 2.01 mmol), followed by a solution of 6B (355 mg, 1.83 mmol) in CH2Cl2 (5 mL) and 4 Å molecular sieves (1 g). The reaction mixture was stirred at RT for 1 h, the resulting turbid solution (formation of the urea intermediate) was treated with DBU (0.41 mL, 2.745 mmol), and stirred at RT for an additional 1 h. The clear reaction solution was partitioned between CH2Cl2 and 5% aqueous KHSO4. The aqueous phase was extracted with CH2Cl2 (2×) and the combined CH2Cl2 extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 4% MeOH in EtOAc/hexane (1:1) to give 330 mg of the desired product as a racemic mixture. The title compound (8 mg) was isolated by using preparative HPLC with a chiral column (CHIRALPAK® AD, 5×50 cm, 20μ) and 10% of isopropanol/hexane as an eluate. Chiral HPLC: 99% at 20.6 min (retention time) (CHIRALPAK® AD column 4.6×250 mm; 20% isopropanol in hexane over 30 minutes, 1 mL/min, monitoring at 220 nM); MS (ES): m/z 322 [M+1]+.

1. concentrationconcentrated under reduced pressure
2. customto give an oily residue, which
3. customdried in vacuo overnight
4. dissolutionThe oily residue was dissolved in CH2Cl2 (10 mL) and to the solution
5. stirringThe reaction mixture was stirred at RT for 1 h
6. stirringstirred at RT for an additional 1 h
7. customThe clear reaction solution was partitioned between CH2Cl2 and 5% aqueous KHSO4
8. extractionThe aqueous phase was extracted with CH2Cl2 (2×)
9. washthe combined CH2Cl2 extracts were washed with brine
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationThe filtrate was concentrated under reduced pressure
13. customto give a crude product, which
14. customwas chromatographed (silica gel)
15. washeluting with 4% MeOH in EtOAc/hexane (1:1)

ORD record

ord-4f2eee46b2294948a30697f2656b0387

Source dataset

uspto-grants-2003_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06670386B2