Triethylamine → HCID 60194461, compound

HRID 1498775Notes

Reaction equation

HRID 1498775 reaction equation
S(C1C=CC=CC=1)([O-])(=O)=O.[CH3:11][S:12]([CH2:15][C:16]([OH:18])=O)(=[O:14])=[O:13].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([C:47]2([C:64]([F:67])([F:66])[F:65])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:63][NH:62][CH2:61]3)[O:56][CH2:55]4)[CH2:48]2)[CH:42]=[C:43]([Cl:46])[C:44]=1[F:45]>C(OCC)(=O)C>[Cl:46][C:43]1[CH:42]=[C:41]([C:47]2([C:64]([F:65])([F:67])[F:66])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:61][N:62]([C:16](=[O:18])[CH2:15][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:63]3)[O:56][CH2:55]4)[CH2:48]2)[CH:40]=[C:39]([Cl:38])[C:44]=1[F:45]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 91526BenzenesulfonateHCID 37328412-Methanesulfonylacetic acid2×HCID 77140585HCID 77140585, compound

Product 1

HCID 60194461HCID 60194461, compoundYield 70%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
35 °C

Procedure

Alternatively, the besylate salt of the chiral 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]can be coupled with methanesulfonylacetic acid using n-propylphosphonic anhydride via a simplified one-pot process instead of the CDI two-pot method. Triethylamine (0.825 g, 1.3 eq.) was added drop-wise over 1 minute at about 18-22° C. to methanesulfonylacetic acid (0.615 g, 1.3 eq.) and chiral-5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran] (Preparation 8, 2.1 g, 3.39 mmol) in 9.3 mL ethyl acetate (EtOAc). The addition funnel was rinsed with 0.5 mL EtOAc and the resulting mixture stirred for a minimum of 2 hours and cooled to <10° C. To this mixture, 50% n-propylphosphonic anhydride in EtOAc (4.313 g, 2.0 eq) was added drop-wise over 15 minutes at <10° C. The addition funnel was then rinsed with 1.5 mL EtOAc. The reaction mixture was warmed to 35° C. and stirred overnight. (HPLC >97% with <1% starting material). To the reaction was added 1.0 g Celite filter aid and filtered through a 1 g celite plug in a 15 mL coarse frit glass funnel and rinsed with 4 mL EtOAc (2×). In process chiral HPLC was 98.8% S-enantiomer and 1.2% R-enantiomer; HPLC >97%. Filtrate was washed with 4 mL water (3×), 4 mL 10% NH4Cl, 4 mL water and the organic layer concentrated to the amorphous S form of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone (foam, 70-80% yield). 1H NMR, 600 MHz (d6-CDCl3) δ ppm: 7.65 (m, 5H), 5.19 (br s, 2H), 4.70 (m, 2H), 4.48 (d, 1H), 4.38 (d, 1H), 4.12 (d, 1H), 3.90 (d, 2H), 3.72 (d, 1H), 3.23 (s, 3H); m/z (CI) 581 [M+H].

Workup

  1. washThe addition funnel was rinsed with 0.5 mL EtOAc
  2. temperaturecooled to <10° C
  3. washThe addition funnel was then rinsed with 1.5 mL EtOAc
  4. stirringstirred overnight
  5. additionTo the reaction was added 1.0 g Celite
  6. filtrationfilter aid
  7. filtrationfiltered through a 1 g celite plug in a 15 mL coarse frit glass funnel
  8. washrinsed with 4 mL EtOAc (2×)
  9. washFiltrate was washed with 4 mL water (3×), 4 mL 10% NH4Cl, 4 mL water

Sources & evidence

ORD record
ord-ddc1ba413fd64424b139e9ab2d5ba806
Source dataset
uspto-grants-2015_12
Patent number
US09200003B2

Reaction notes

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