Hydrochloric Acid → (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile

HRID 1409312Notes

Reaction equation

HRID 1409312 reaction equation
O[CH2:2][C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:40]=[C:39]([C:41]2[CH:45]=[CH:44][NH:43][N:42]=2)[CH:38]=[C:37]([F:46])[C:34]=1[C:35]#[N:36].CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>CCOC(C)=O.C(Cl)Cl.O>[NH2:5][C@@H:3]([CH3:4])[CH2:2][N:43]1[CH:44]=[CH:45][C:41]([C:39]2[CH:38]=[C:37]([F:46])[C:34]([C:35]#[N:36])=[C:33]([Cl:32])[CH:40]=2)=[N:42]1

Participants

9

Reactant 5

HCID 313Hydrochloric Acid2×HCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 70231031,1-Dimethylethyl N-((1S)-2-hydroxy-1-methylethyl)carbamateHCID 178510273HCID 178510273, compound

Product 1

HCID 67170587(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrileYield 66.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-tert-Butyl (1-hydroxypropan-2-yl)carbamate (259 mmol, 45.4 g) and triphenylphosphine (259 mmol, 68.0 g) were mixed in dry EtOAc (380 ml) under nitrogen atmosphere. 2-Chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (130 mmol, 35.9 g) was added and the resulting mixture was stirred for 10 min. DIAD (259 mmol, 52.4 g) was added slowly while keeping the temperature between 15-25° C. with an ice bath. After the addition the mixture was allowed to warm to RT and stirred for 4 h. Water and concentrated HCl (1296 mmol, 106 ml) was added to the mixture and stirred for 6 days during which more HCl (107 ml in total) was added. Water and DCM was added and the mixture was stirred for a while before separating the phases. The organic phase was extracted twice with water. The water phases were combined and washed twice with DCM. DCM was added to the water phase and the pH of the water phase was adjusted to 12.5 with 50% NaOH. The phases were separated and the water phase was extracted once more with DCM. The DCM phases were combined and washed once with water. The separated DCM phase was evaporated and dried under vacuum. 24.0 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 0.96 (d, 3H), 1.18 (bs, 2H), 3.19-3.29 (m, 1H), 3.97-4.08 (m, 2H), 7.03 (d, 1H), 7.85-7.92 (m, 2H), 7.98-8.02 (m, 1H).

Workup

  1. custombetween 15-25° C.
  2. additionAfter the addition the mixture
  3. stirringstirred for 4 h
  4. additionwas added
  5. stirringthe mixture was stirred for a while
  6. custombefore separating the phases
  7. extractionThe organic phase was extracted twice with water
  8. washwashed twice with DCM
  9. additionDCM was added to the water phase
  10. customThe phases were separated
  11. extractionthe water phase was extracted once more with DCM
  12. washwashed once with water
  13. customThe separated DCM phase was evaporated
  14. customdried under vacuum

Sources & evidence

ORD record
ord-54b31004a07449e18c4eca375ff981e1
Source dataset
uspto-grants-2014_12
Patent number
US08921378B2

Reaction notes

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