Hydrochloric Acid → 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropyl-carbamoyl)-pyrrolidin-3-yl ester

HRID 2261713Notes

Reaction equation

C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([O-:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:47]([O:49][C:50]([C@@:52]1([NH:57][C:58]([C@H:60]2[NH:64][CH2:63][C@H:62]([O:65][C:66]([N:68]3[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[CH:73][C:74]=4[F:77])[CH2:69]3)=[O:67])[CH2:61]2)=[O:59])[CH2:54][C@H:53]1[CH:55]=[CH2:56])=[O:51])[CH3:48].Cl>C1COCC1.O>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([N:64]1[C@H:60]([C:58](=[O:59])[NH:57][C@:52]2([C:50]([O:49][CH2:47][CH3:48])=[O:51])[CH2:54][C@H:53]2[CH:55]=[CH2:56])[CH2:61][C@@H:62]([O:65][C:66]([N:68]2[CH2:76][C:75]3[C:70](=[CH:71][CH:72]=[CH:73][C:74]=3[F:77])[CH2:69]2)=[O:67])[CH2:63]1)=[O:25])=[O:20])([CH3:15])([CH3:16])[CH3:17]

Participants

Conditions

Temperature: 22.5 °C

Procedure

A solution of 1.15 g (2.55 mmol) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) and 469 mg (4.64 mmol) NMM in 9.0 mL of THF was added dropwise to a solution of 302 mg (2.53 mmol) pivaloyl chloride in 1.5 mL of THF while maintaining the temperature at 20-25° C. The suspension was stirred for 45 min, then cooled to 0° C. A solution of 1.00 g (2.32 mmol) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester in 13 mL of THF was added to the mixed anhydride at 0° C. within 25 min. The mixture was first stirred for 2.5 h at 2° C., then for 19 h at 26° C. after which 9.5 mL water and 14.8 mL aqueous HCl (0.5 N) were added. The phases were separated and the aqueous layer was extracted with toluene (3×3 mL). The combined organic layers were washed with 2 mL of water, 5 mL of aqueous Na2CO3 (5 wt %) and dried (Na2SO4). The solvent was removed at 50° C. under reduced pressure using a rotary evaporator. The resulting oil was finally dried under oil pump vacuum yielding 1.75 g (88.3%) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as a brown resin with an assay of 80.5 wt %.

Workup

temperaturecooled to 0° C
stirringThe mixture was first stirred for 2.5 h at 2° C.
customThe phases were separated
extractionthe aqueous layer was extracted with toluene (3×3 mL)
washThe combined organic layers were washed with 2 mL of water, 5 mL of aqueous Na2CO3 (5 wt %)
dry with materialdried (Na2SO4)
customThe solvent was removed at 50° C. under reduced pressure
customa rotary evaporator
customThe resulting oil was finally dried under oil pump vacuum

Sources & evidence

ORD record: ord-9ce0a3dac56d4dc3851a731a70d28b61
Source dataset: uspto-grants-2010_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07847106B2

Reaction notes

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