Triphenylphosphine → 5-Methyl-isoxazole-3-carboxylic Acid [4-((S)-2-amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide

HRID 521632Notes

Reaction equation

HRID 521632 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([CH3:42])[C:25]=1[C:26]1[CH:27]=[C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])[CH:29]=[CH:30][C:31]=1[OH:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:58][C@@H:59]([NH:61]C(=O)OC(C)(C)C)[CH3:60]>C1COCC1>[NH2:61][C@@H:59]([CH3:60])[CH2:58][O:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])=[CH:27][C:26]=1[C:25]1[N:24]([CH3:42])[N:23]=[CH:22][C:21]=1[Cl:20]

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylate2×HCID 70231031,1-Dimethylethyl N-((1S)-2-hydroxy-1-methylethyl)carbamate2×HCID 136388020N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide

Product 1

HCID 578147415-Methyl-isoxazole-3-carboxylic Acid [4-((S)-2-amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amideYield 21.34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq; 1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed with nitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in a rotary shaker for 2 minutes. N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide (30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly then DIAD (diisopropyl azodicarboxylate, 27.94 μl, 144.4 μmol) was added. After 30 minutes in a rotary shaker a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dry THF was added. The resulting suspension was heated to 65° C. and mixed overnight. LCMS showed that the reaction did not go to completion. A fresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to the reaction mixture and the suspension was heated to 65° C. and mixed overnight. The suspension was filtered and the resin washed with THF (3×3 mL). The filtrate and washings were combined and concentrated under vacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL), heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organic solvent was removed under vacuum and the crude residue was dissolved in acetonitrile (0.8 mL), neutralized with saturated NaHCO3 and subjected to purification by preparative LCMS. The desired fractions were pooled, frozen and lyophilized to afford the title compound as an off-white solid (21.34% yield). LCMS m/z=390.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3H), 2.54 (s, 3H), 3.46-3.57 (m, 1H), 3.66 (bs, 3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H), 7.35 (dd, J=9.09, 2.53 Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.95 (dd, J=9.09, 2.53 Hz, 1H), 7.97-8.04 (bs, 2H), 10.76 (s, 1H).

Workup

  1. customcapped
  2. customflushed with nitrogen
  3. additionmixed in a rotary shaker for 2 minutes
  4. additionThe suspension was mixed briefly
  5. additionmixed overnight
  6. temperaturethe suspension was heated to 65° C.
  7. additionmixed overnight
  8. filtrationThe suspension was filtered
  9. washthe resin washed with THF (3×3 mL)
  10. concentrationconcentrated under vacuum
  11. dissolutionThe resulting residue was dissolved in 20% TFA in DCM (2.0 mL)
  12. temperatureheated to 65° C.
  13. additionmixed in a rotary shaker for 1.0 hour
  14. customThe organic solvent was removed under vacuum
  15. dissolutionthe crude residue was dissolved in acetonitrile (0.8 mL)
  16. customsubjected to purification by preparative LCMS
  17. temperaturefrozen

Sources & evidence

ORD record
ord-dbb4eb37d14349bfa8d68180abab38dd
Source dataset
uspto-grants-2016_05
Patent number
US09328107B2

Reaction notes

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