Sulfuric Acid → 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester

HRID 2261717Notes

Reaction equation

HRID 2261717 reaction equation
OS(O)(=O)=O.C(OC([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@:20]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][C@H:21]2[CH:23]=[CH2:24])[CH2:16][C@@H:15]([O:31][C:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[F:43])[CH2:35]2)=[O:33])[CH2:14]1)=O)(C)(C)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([C@@:20]1([NH:19][C:18]([C@H:17]2[NH:13][CH2:14][C@H:15]([O:31][C:32]([N:34]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][C:40]=4[F:43])[CH2:35]3)=[O:33])[CH2:16]2)=[O:30])[CH2:22][C@H:21]1[CH:23]=[CH2:24])=[O:26])[CH3:29]

Participants

4

Reactant 2

HCID 1118Sulfuric AcidHCID 576892124-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester

Product 1

HCID 670391124-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl esterYield 76.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
60 °C

Procedure

A solution of 64.4 g (630 mmol) of H2SO4 in 120 mL of EtOAc was added to a suspension of 1.7 L of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester (theoretical amount: 600 mmol; as obtained from example 8) in EtOAc at 50-60° C. The dropping funnel was rinsed with 80 mL of EtOAc and the reaction mixture was stirred for 3 h at 60° C. To the reaction mixture 800 mL of an aqueous solution of Na2CO3 (10 wt %) was added. The phases were separated and the organic layer was washed with 400 mL of water. The organic layer was concentrated at a jacket temperature of 105° C. to a residual volume of 450 mL. To the residue 1000 mL of toluene was added. To initiate crystallization the temperature was decreased to 60° C. and maintained for 30 min at this value. The suspension is cooled to −2° C. and stirred for 1 h at this temperature. The crystals were collected on a suction filter and washed three times with a total of 400 mL of toluene. After drying at 53° C. under reduced pressure there was obtained 198.2 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as colorless crystals in a purity of 98.0 wt % and a yield of 75% over 4 steps.

Workup

  1. washThe dropping funnel was rinsed with 80 mL of EtOAc
  2. additionTo the reaction mixture 800 mL of an aqueous solution of Na2CO3 (10 wt %) was added
  3. customThe phases were separated
  4. washthe organic layer was washed with 400 mL of water
  5. concentrationThe organic layer was concentrated at a jacket temperature of 105° C. to a residual volume of 450 mL
  6. additionTo the residue 1000 mL of toluene was added
  7. customcrystallization the temperature
  8. customwas decreased to 60° C.
  9. temperaturemaintained for 30 min at this value
  10. temperatureThe suspension is cooled to −2° C.
  11. stirringstirred for 1 h at this temperature
  12. customThe crystals were collected on a suction
  13. filtrationfilter
  14. washwashed three times with a total of 400 mL of toluene
  15. customAfter drying at 53° C. under reduced pressure

Sources & evidence

ORD record
ord-59b45e9eea7a466c9b0a3e57b362b54b
Source dataset
uspto-grants-2010_12
Patent number
US07847106B2

Reaction notes

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