Isobutyraldehyde → HCID 67045778, compound

HRID 875753Notes

Reaction equation

HRID 875753 reaction equation
[ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[C:10]=23)[CH2:4]1.CCN(C(C)C)C(C)C.C(OC)(OC)OC.[CH:44](=O)[CH:45]([CH3:47])[CH3:46].[BH4-].[Na+]>CO.O>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1

Participants

8

Reactant 5

HCID 6561IsobutyraldehydeHCID 9005Trimethyl orthoformateHCID 81531DiisopropylethylamineHCID 4311764Sodium borohydrideHCID 67045442HCID 67045442, compound

Product 1

HCID 67045778HCID 67045778, compoundYield 70.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.075 g, 0.14 mmol, Example 1A), DIEA (0.100 mL, 0.57 mmol; d 0.742) and trimethyl orthoformate (0.32 mL, 2.9 mmol) were placed in MeOH (3 mL) at room temperature. Isobutyraldehyde (0.026 mL, 0.29 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. NaBH4 (0.014 g, 0.36 mmol) was then added, and the reaction was stirred for 1 hour. The reaction was then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase HPLC (0-50% acetonitrile (“ACN”) in water, Gilson system). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(5-bromo-4-(3-(isobutylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.050 g, 60% yield). 1H NMR (400 MHz, D2O) δ 9.16-9.16 (m, 1H), 8.83-8.82 (m, 1H), 8.77-8.75 (m, 1H), 8.27 (s, 1H), 7.96-7.93 (m, 1H), 7.42 (s, 1H), 3.78-3.75 (m, 1H), 3.34-3.33 (m, 2H), 3.22-3.17 (m, 1H), 3.09-3.03 (m, 1H), 2.77-2.67 (m, 2H), 2.00-1.97 (m, 1H), 1.81-1.75 (m, 1H), 1.68-1.65 (m, 1H), 1.52-1.49 (m, 1H), 1.35-1.32 (m, 1H), 0.80-0.78 (m, 6H); LCMS (APCI+) m/z 471, 473 (M+H)+.

Workup

  1. stirringthe reaction was stirred for 1 hour
  2. extractionextracted with DCM
  3. dry with materialThe combined organic fractions were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the crude product, which
  7. customwas purified by reverse phase HPLC (0-50% acetonitrile (“ACN”) in water, Gilson system)
  8. dissolutionThe purified product was then dissolved in DCM (with minimal MeOH to aid solubility)
  9. additionadded dropwise to a stirring solution of 1M HCl in ether
  10. filtrationThe resulting solid was filtered
  11. customdried
  12. customcollected

Sources & evidence

ORD record
ord-ecdf121cb22c4e9abf4b3e8fe3fb8685
Source dataset
uspto-grants-2015_03
Patent number
US08981085B2

Reaction notes

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