Hydrochloric Acid → (5S)-N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

HRID 1642758Notes

Reaction equation

HRID 1642758 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])OC(C)(C)C.Cl.[OH-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([OH:43])[C:33]([N:35]2[C@H:39](C(O)=O)[CH2:38][CH:37]=[N:36]2)=[O:34])=[CH:28][CH:27]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C.CCOC(C)=O.CC(OC)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9]([C@H:39]1[N:35]([C:33](=[O:34])[C@@H:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[OH:43])[N:36]=[CH:37][CH2:38]1)=[O:15]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 14798Sodium HydroxideHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 57425264HCID 57425264, compoundHCID 58017528HCID 58017528, compound

Product 1

HCID 44537923(5S)-N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamideYield 88%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

In an open vessel, tert-butyl 5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamate (14 g, 45.20 mmol, prepared as described in J. Med. Chem. 2004, 47, 2995, was suspended in acetonitrile (80 mL). HCl (6 M aqueous solution, 37.7 mL, 225.99 mmol) was added and the mixture was then stirred at room temperature for 4 hours. Water (200 mL) and TBME (100 mL) were added. To the aqueous phase and under ice-cooling was added EtOAc (200 mL) followed by slow addition of 2 M NaOH (aq., 130 mL). The organic phase was then washed with water (100 mL). To the EtOAc solution (220 mL) containing the crude (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine was then added (5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (7.53 g, 28.28 mmol) followed by the addition of N-methylmorpholine (4.66 mL, 42.43 mmol). To this clear homogenous solution was then added TBTU (10.90 g, 33.94 mmol) in one portion. The mixture was then stirred at room temperature over night. The precipitate formed was filtrated and then washed with TBME (100 mL). After drying in vacuo, the desired compound was obtained as a solid (7.65 g, 59%). The mother liquor was diluted with EtOAc and washed with Na2CO3 (aq., sat), water and 1 M HCl (aq.). Crystallization from CH3CN/water gave 4.59 g of the title compound. Total yield 88%. 1H NMR (600 MHz, CD3CN) δ 2.93 (ddd, 1H), 3.10 (ddd, 1H), 4.15-4.19 (m, 2H), 4.25 (dd, 1H), 4.60 (dd, 1H), 5.73-5.76 (m, 1H), 6.97-6.99 (m, 1H), 7.07-7.10 (m, 2H), 7.28-7.30 (m, 1H), 7.42-7.46 (m, 3H), 7.54-7.56 (m, 1H), 7.71 (d, 1H), 9.20 (s, 1H).

Workup

  1. temperatureTo the aqueous phase and under ice-cooling
  2. washThe organic phase was then washed with water (100 mL)
  3. additionTo the EtOAc solution (220 mL) containing the crude (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine
  4. stirringThe mixture was then stirred at room temperature over night
  5. customThe precipitate formed
  6. filtrationwas filtrated
  7. washwashed with TBME (100 mL)
  8. customAfter drying in vacuo

Sources & evidence

ORD record
ord-993755b02a484d65b6f3aef32bc22974
Source dataset
uspto-grants-2012_02
Patent number
US08119673B2

Reaction notes

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