Diisobutylaluminum hydride → HCID 58204562, compound

HRID 1799995Notes

Reaction equation

HRID 1799995 reaction equation
C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][C:20]4[N:16]([N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[CH:19]=4)[C:15]=3[CH:32]=2)[CH2:8]1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[CH:19]=[C:20]3[N:16]([C:15]4[CH:32]=[C:11]([CH:9]5[CH2:10][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8]5)[CH:12]=[CH:13][C:14]=4[O:23][CH2:22][CH2:21]3)[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]

Participants

4

Reactant 2

HCID 14487Diisobutylaluminum hydride2×HCID 67050689HCID 67050689, compound

Product 1

HCID 58204562HCID 58204562, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (200 mg, 0.55 mmol), 2-bromo-2-methyl propionate (71 L, 0.55 mmol), triethylamine (75 L, 0.55 mmol) in DMF was heated at 55° C. for 30 h before concentrating in vacuo. The residue was partitioned between 10% MeOH in DCM and water, the aqueous extracted with 10% MeOH in DCM and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 23%). To a solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 0.12 mmol) in THF (1.5 mL) at −78° C. was added DIBAL (1.5 M solution in toluene, 0.24 mL, 0.36 mmol) and the mixture allowed to warm to RT over 18 h. The mixture was cooled to 0° C., further DIBAL (0.12 mL, 0.18 mmol) added dropwise and stirring continued for 45 min. The reaction was quenched by the addition of MeOH (0.5 mL) followed by Rochelle's salt saturated aqueous solution (0.5 mL), then diluted with ethyl acetate and filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH (+2M NH3) in DCM) to give 170 as a white solid, as illustrated in FIG. 13 (27 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.85 (d, J=2.18 Hz, 1H); 7.23 (d, J=2.23 Hz, 1H); 7.17 (d, J=8.29 Hz, 1H); 6.87 (s, 1H); 5.74-5.66 (m, 1H); 4.55 (t, J=6.02 Hz, 2H); 3.71 (s, 3H); 3.43 (s, 2H); 3.28 (s, 2H); 3.16 (t, J=6.03 Hz, 2H); 1.59 (d, J=6.62 Hz, 6H); 1.04 (s, 6 H). 1 Exchangeable proton not observed. LCMS: RT=6.43 min, M+H+=423

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. customThe reaction was quenched by the addition of MeOH (0.5 mL)
  3. additiondiluted with ethyl acetate
  4. filtrationfiltered through Celite®
  5. washwashing with ethyl acetate
  6. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-fdfcdd1f8df04c33906479bb490e7a21
Source dataset
uspto-grants-2013_01
Patent number
US08343955B2

Reaction notes

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