Trimethyl orthoformate → HCID 67045111, compound

HRID 2203835Notes

Reaction equation

HRID 2203835 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.C(OC)(OC)OC.CCN(C(C)C)C(C)C.[CH:44]1([CH:47]=O)[CH2:46][CH2:45]1.[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][CH2:47][CH:44]3[CH2:46][CH2:45]3)[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 9005Trimethyl orthoformateHCID 81531DiisopropylethylamineHCID 123114CyclopropanecarboxaldehydeHCID 4311764Sodium borohydrideHCID 67045442HCID 67045442, compound

Product 1

HCID 67045111HCID 67045111, compoundYield 70.6%

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), trimethyl orthoformate (0.32 mL, 2.9 mmol), and DIEA (0.100 mL, 0.57 mmol; d 0.742) were placed in MeOH (3 mL). Cyclopropanecarbaldehyde (0.022 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% 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-(cyclopropylmethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride salt (0.050 g, 60% yield). 1H NMR (400 MHz, D2O) δ 8.98-8.98 (m, 1H), 8.65-8.64 (m, 1H), 8.52-8.50 (m, 1H), 8.12 (s, 1H), 7.74-7.71 (m, 1H), 7.27 (s, 1H), 3.54-3.51 (m, 1H), 3.18-3.04 (m, 3H), 2.97-2.92 (m, 1H), 2.69-2.55 (m, 2H), 1.82-1.78 (m, 1H), 1.55-1.52 (m, 1H), 1.40-1.30 (m, 1H), 1.21-1.17 (m, 1H), 0.74-0.68 (m, 1H), 0.36-0.32 (m, 2H), 0.05-0.00 (m, 2H); LCMS (APCI+) m/z 469, 471 (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% 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-c826b215dbe2438982aec0288e525585
Source dataset
uspto-grants-2016_06
Patent number
US09365568B2

Reaction notes

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