Hydrochloric Acid → 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

HRID 604811Notes

Reaction equation

HRID 604811 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].Cl.[F:40][C:41]1[CH:49]=CC=[C:46]2[C:42]=1CN[CH2:45]2.Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:14](=[O:26])[NH:15][C@:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]2[CH:19]=[CH2:20])[CH2:10][C@@H:11]([O:13][C:27]([N:34]2[CH2:35][C:49]3[C:37](=[CH:45][CH:46]=[CH:42][C:41]=3[F:40])[CH2:38]2)=[O:28])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 426096434-Fluoro-1H-isoindoline hydrochlorideHCID 57892908(2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

Product 1

HCID 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 esterYield 82.5%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8471TriethylamineSolvent

Procedure

8.19 g of crude (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 60 mL of toluene and 4.25 g carbonyldiimidazole (26.2 mmol) was added in portions at a temperature of 22° C. to 25° C. The reaction mixture was stirred for 1.5 h at ambient temperature. Then 3.66 g (21.0 mmol) of 4-fluoroisoindoline hydrochloride was added in portions followed by 3.1 mL of triethylamine. The resulting suspension was heated to 52° C. bath temperature. After stirring for 3 h at this temperature the reaction mixture was cooled with an ice bath and 70 mL of aqueous HCl (1M) were added. The mixture was extracted with 50 mL of toluene. The separated aqueous layer was extracted twice with 50 mL toluene. The combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of sodium carbonate (5% w/w). The toluene extract was dried with sodium sulfate, filtered, and the solvent was completely removed to afford 9.21 g 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 as a grey solid, which was used in the next step without further purification.

Workup

  1. temperatureThe resulting suspension was heated to 52° C. bath temperature
  2. stirringAfter stirring for 3 h at this temperature the reaction mixture
  3. temperaturewas cooled with an ice bath
  4. extractionThe mixture was extracted with 50 mL of toluene
  5. extractionThe separated aqueous layer was extracted twice with 50 mL toluene
  6. washThe combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of sodium carbonate (5% w/w)
  7. extractionThe toluene extract
  8. dry with materialwas dried with sodium sulfate
  9. filtrationfiltered
  10. customthe solvent was completely removed

Sources & evidence

ORD record
ord-a28ba3d9b5a94ffc8dcdcbf1f2152f64
Source dataset
uspto-grants-2011_03
Patent number
US07910728B2

Reaction notes

Loading…