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Acetaldehyde → N-(4-(2-(1-Ethylpiperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676407
Notes
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Reaction equation

HRID 1676407 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH:41](=O)[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:41]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1)[CH3:42]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 177AcetaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 58949489N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

Product 1

HCID 58949468N-(4-(2-(1-Ethylpiperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 2.9%

Reagents, catalysts & solvents

1
HCID 8028TetrahydrofuranSolvent

Procedure

A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 43.4 mg, 0.0776 mmol), acetaldehyde (17.1 mg, 0.388 mmol), NaBH(OAc)3 (82 mg, 0.388 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified with preparative HPLC to afford product (1.3 mg, 2.14%). LRMS (APCI neg): >97% purity, 254 nm, m/e 587 (M). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 8.36 (d, 1H), 8.31 (d, 1H), 8.03 (dd, 1H), 7.67 (m, 2H), 7.49 (m, 1H), 7.39 (t, 1H), 7.29 (m, 3H), 6.62 (d, 1H), 2.60 (q, 2H), 2.32 (m, 2H), 2.19 (m, 2H), 1.94 (m, 1H), 1.18 (t, 3H), 0.90 (m, 4H).

Workup

  1. customhad been consumed (overnight)
  2. customThen the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×100 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a crude product
  9. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1
  10. customv/v) to afford crude product
  11. customThe crude product was further purified with preparative HPLC

Sources & evidence

ORD record
ord-3df2eb845fb148e6acfedcb60c3b29e6
Source dataset
uspto-grants-2011_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08003662B2

Reaction notes

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