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 604812Notes

Reaction equation

HRID 604812 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

8

Reactant 5

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 62493Pivaloyl chlorideHCID 670391124-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl esterHCID 131728566(s)-2-Tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt

Product 1

HCID 250544334-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 esterYield 110.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

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) N-methylmorpholine 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. 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 sodium carbonate (5% w/w) and dried over sodium sulfate. 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% m/m.

Workup

  1. temperaturecooled to 0° C
  2. stirringThe mixture was first stirred for 2.5 h at 2° C.
  3. waitfor 19 h at 26° C
  4. customThe phases were separated
  5. extractionthe aqueous layer was extracted with toluene (3×3 mL)
  6. washThe combined organic layers were washed with 2 mL of water, 5 mL of aqueous sodium carbonate (5% w/w)
  7. dry with materialdried over sodium sulfate
  8. customThe solvent was removed at 50° C. under reduced pressure
  9. customa rotary evaporator
  10. customThe resulting oil was finally dried under oil pump vacuum

Sources & evidence

ORD record
ord-8f45e2a078694b00b996bcd733b6d864
Source dataset
uspto-grants-2011_03
Patent number
US07910728B2

Reaction notes

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