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 1160621Notes

Reaction equation

HRID 1160621 reaction equation
ClC1C=C(F)C(C2N=NN(C)N=2)=C(C2C=C([F:17])C([C@H](N)C)=NC=2)C=1.FC1CCC(O)(C(O)=O)CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:94])=[CH:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1>ClCCl.CCOC(C)=O>[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:17])([F:94])[CH2:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 57608302N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4-fluoro-1-hydroxycyclohex-3-ene-1-carboxamideHCID 68714852((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)amineHCID 687169194-Fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid

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 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a mixture of the compound of Reference Example 4 (0.192 g, 0.547 mmol), 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid (0.114 g, 0.71 mmol), (1H-1,2,3-benzotriazol-1-yloxy)[tris-(dimethylamino)]phosphonium hexafluorophosphate (0.339 g, 0.77 mmol) in 5 mL of dichloromethane was added triethylamine (0.138 g, 1.37 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc and washed in succession with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-50% EtOAc in hexanes to yield a mixture of diastereomers of N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4-fluoro-1-hydroxycyclohex-3-ene-1-carboxamide, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 493.1 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.03 (bd, J=7.1 Hz, NH), 7.35 (d, J=8.9 Hz, 1H), 7.28-7.25 (m, 2H), 5.43 (quint, J=6.7 Hz, 1H), 5.16 (d, J=13.4 Hz, 1H), 4.35 (s, 3H), 2.79 (d, J=17.8 Hz, 1H), 2.68 (s, OH), 2.43 (m, 1H), 2.26 (m, 1H), 2.21-2.10 (m, 2H), 1.91 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).

Workup

  1. washwashed in succession with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution
  2. dry with materialto drying over sodium sulfate
  3. filtrationFiltration and solvent removal
  4. customprovided material which
  5. customto yield
  6. customgave a proton NMR spectrum consistent with theory

Sources & evidence

ORD record
ord-8765388ab8f04bbf8ae9dcc4babbb652
Source dataset
uspto-grants-2010_10
Patent number
US07816380B2

Reaction notes

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