Triethylamine → (R)-N-(1-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2-yl)ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide

HRID 1160618Notes

Reaction equation

HRID 1160618 reaction equation
[F:1][C:2]1([F:12])[CH2:7][CH2:6][C:5]([OH:11])([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([F:36])[C:17]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:18]([C:20]2[CH:21]=[C:22]([F:29])[C:23]([C@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=2)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([F:36])[C:17]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:18]([C:20]2[CH:21]=[C:22]([F:29])[C:23]([C@H:26]([NH:28][C:8]([C:5]3([OH:11])[CH2:4][CH2:3][C:2]([F:1])([F:12])[CH2:7][CH2:6]3)=[O:10])[CH3:27])=[N:24][CH:25]=2)[CH:19]=1

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 401519704,4-Difluoro-1-hydroxycyclohexane-1-carboxylic acidHCID 68714852((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)amine

Product 1

HCID 24884552(R)-N-(1-(5-(5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-fluoropyridin-2-yl)ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of 4,4-difluoro-1-hydroxy-cyclohexanecarboxylic acid (324 mg, 1.8 mmol) and the compound of Reference Example 4 (632 mg, 1.8 mmol) was dissolved in 3.6 ml of degassed DMF. HOBT (58 mg, 0.43 mmol) and EDCI (449 mg, 2.34 mmol) were added, and the reaction mixture was made basic with triethylamine (182 mg, 1.8 mmol). After 1 hour at ambient temperature, 20 ml of water and 2 ml of 10% aqueous sodium bicarbonate solution were added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, and dried over sodium sulfate, filtered, and concentrated. The crude material was subjected to silical gel chromatography eluting with 10 to 30% EtOAc in hexanes to provide the title compound as a white solid which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 513.0 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.67 (d, J=7 Hz, 1H), 7.35 (d, J=10 Hz, 1 H), 7.28 (m, 2H), 5.41 (m, 1H), 4.36 (s, 3H), 2.88 (s, 1H), 2.12 (m, 6H), 1.76 (m, 2H), 1.44 (d, J=7 Hz, 3H).

Workup

  1. extractionthe mixture was extracted with EtOAc
  2. washThe combined organic extracts were washed with water and brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. washeluting with 10 to 30% EtOAc in hexanes

Sources & evidence

ORD record
ord-b2a27bfd229a4e18acb7a073ad03e435
Source dataset
uspto-grants-2010_10
Patent number
US07816380B2

Reaction notes

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