Hydrochloric Acid → (3R)-4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanal

HRID 41022Notes

Reaction equation

[F:1][C:2]([F:30])([F:29])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]

Participants

Conditions

Temperature: -47.5 °C

Procedure

To a −70° C. solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield).

Workup

temperatureafter which the reaction was cooled back at −70° C
filtrationInsoluble material was then filtered from the reaction mixture
washThe organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl
dry with materialThe washed organic phase was dried over sodium sulfate
concentrationwas concentrated
customa rotory evaporator
customto give 0.58 g of the crude product as a pale yellow foam/solid
customThe crude product was chromatographed with 0-80% ethyl acetate/hexanes

Sources & evidence

ORD record: ord-d940b73ed76343f6a4ce0f0463c7b67b
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08530485B2

Reaction notes

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