Hydrochloric Acid → HCID 86684918, compound

HRID 2402913Notes

Reaction equation

HRID 2402913 reaction equation
[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][N:10]2[C:15]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:10]([C:15]([C:17]3([CH3:20])[CH2:19][CH2:18]3)=[O:16])[CH2:11][C@@H:12]([O:14][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH2:13]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 7369Benzenesulfonyl chlorideHCID 8471TriethylamineHCID 86684903HCID 86684903, compound

Product 1

HCID 86684918HCID 86684918, compoundYield 85.5%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

(2S,4S)-4-Hydroxy-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (62.0 g, 224 mmol) and 4-(dimethylamino)pyridine (98%, 1.5 g, 12.0 mmol) were dissolved in dichloromethane (370 mL), benzenesulfonyl chloride (31.1 mL, 242 mmol), followed by triethylamine (49.8 mL, 358 mmol) were added at room temperature and the mixture was stirred for 16 h. After that, it was diluted with water (140 mL) and acidified by addition of hydrochloric acid (25% m/m, 21.4 mL). The phases were separated and the organic layer was washed with water (160 mL). The combined aqueous phases were extracted with dichloromethane (160 mL), the combined organic extracts were concentrated in vacuo to a volume of 430 mL. The solvent was exchanged via continuous distillation in vacuo (internal temperature 40° C., 670-170 mbar) to ethanol (670 mL added), the overall volume was kept constant (430 mL). The resulting solution was allowed to cool to room temperature and seed crystals (ca. 10 mg) were added to initiate crystallization. After crystallization had started, the suspension was stirred for 30 min at room temperature, heptane (430 mL) was added within 50 min and it was stirred for 12 h. The suspension was then filtered, the precipitate was washed with heptane/ethanol 2:1 (v/v, 321 mL) and heptane (107 mL) and dried in vacuo at 40° C. to yield the title compound as a white crystalline solid (80.0 g, 85%). MS (ESI & APCI): m/z=418.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ 0.59-0.64 (m, 1H), 0.65-0.69 (m, 1H), 0.80-0.90 (m, 1H), 0.99-1.05 (m, 1H), 1.12-1.21 (m, 2H), 1.30 (s, 3H), 1.47-1.53 (m, 2H), 2.15 (ddd, J=5.8 Hz, 9.2 Hz, 14.6 Hz, 1H), 2.70 (br d, J=14.0 Hz, 1H), 3.83 (dd, J=3.8 Hz, 12.3 Hz, 1H), 4.08 (dd, J=5.3 Hz, 12.4 Hz, 1H), 4.55 (br s, 1H), 5.04-5.08 (m, 1H), 7.49 (br s, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H).

Workup

  1. additionwere added at room temperature
  2. customThe phases were separated
  3. washthe organic layer was washed with water (160 mL)
  4. extractionThe combined aqueous phases were extracted with dichloromethane (160 mL)
  5. concentrationthe combined organic extracts were concentrated in vacuo to a volume of 430 mL
  6. distillationThe solvent was exchanged via continuous distillation in vacuo (internal temperature 40° C., 670-170 mbar) to ethanol (670 mL added)
  7. additionseed crystals (ca. 10 mg) were added
  8. customcrystallization
  9. customAfter crystallization
  10. stirringthe suspension was stirred for 30 min at room temperature
  11. additionheptane (430 mL) was added within 50 min
  12. stirringit was stirred for 12 h
  13. filtrationThe suspension was then filtered
  14. washthe precipitate was washed with heptane/ethanol 2:1 (v/v, 321 mL) and heptane (107 mL)
  15. customdried in vacuo at 40° C.

Sources & evidence

ORD record
ord-0be2675251a14e6987f42d82d3e911e5
Source dataset
uspto-grants-2014_08
Patent number
US08796471B2

Reaction notes

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