Diisopropylethylamine → N-[(1S, 2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid benzyl ester

The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (1.45 g, 3.8 mmol, prepared as described in WO PCT 0250019) was dissolved in 38 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with mono-benzyl malonate (745 mg, 3.8 mmol), N,N-diisopropylethylamine (6.7 mL, 38 mmol) and HATU (1.75 g, 4.6 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid benzyl ester (1.5 g, 91% yield). MS found: (M+H)+=439.4. The entirity of this material was dissolved in THF (18 mL). This solution was charged sequentially with MeOH (6 mL) and aq. LiOH (84 mg LiOH in 6 mL water) and stirred for 12 h at RT. The mixture was concentrated in vacuo, and the residue was lyophilized from 1:1 acetonitrile/water to provide the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid. MS found: (M+H)+=355.3. (21b) The compound 3-nitro-5-trifluoromethylbenzoic acid (500 mg, 2.1 mmol) was dissolved in 20 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with dimethylamine hydrochloride (174 mg, 2.1 mmol), N,N-diisopropylethylamine (3.7 mL, 21 mmol) and HATU (970 mg, 2.6 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. A portion (107 mg) of this product was dissolved in MeOH (6 mL). This solution was charged with 5% Pd/C, Degussa style (21 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in 6 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid (141 mg, 0.4 mmol, see procedure 21a), N, N-diisopropylethylamine (0.35 mL, 2.0 mmol) and HATU (182 mg, 0.5 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester as a colorless oil (186 mg, 81% yield). MS found: (M+Na)+=585.3. (21c) A solution of {(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (186 mg, 0.33 mmol) in MeOH (6 mL) was charged with 5% Pd/C, Degussa style (37 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (46 mg, 0.33 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=551.3.

1. concentrationconcentrated in vacuo
2. custompartitioned between EtOAc and sat. NH4Cl
3. extractionThe aqueous phase was extracted with EtOAc (1×)
4. washThe combined organic extracts were washed with sat. NaHCO3 and brine
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue was purified by flash chromatography

ORD record

ord-3795f7ff67314c72b57635f8bcc5b22b

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07468440B2