Dimethylamine → N-(4-(2-(4-(Dimethylamino)cyclohexyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676377Notes

Reaction equation

HRID 1676377 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[C:29](=[O:41])[N:30]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[N:31]=[CH:32][CH:33]=2)=[O:27])[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][C:21](=O)[CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:42][NH:43][CH3:44].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:42][N:43]([CH3:44])[CH: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:25][C:26]([C:28]4[C:29](=[O:41])[N:30]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:31]=[CH:32][CH:33]=4)=[O:27])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1

Participants

5

Reactant 3

HCID 674DimethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 58949495N-(3-Fluoro-4-(2-(4-oxocyclohexyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

Product 1

HCID 58949473N-(4-(2-(4-(Dimethylamino)cyclohexyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 62.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A round-bottomed flask was charged with N-(3-fluoro-4-(2-(4-oxocyclohexyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 162, Step C, 3.2 mg, 0.0056 mmol), dimethylamine (1.3 mg, 0.028 mmol), NaBH(OAc)3 (3.6 mg, 0.017 mmol) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (30 mL) and H2O (30 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×30 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 50/1 to 10/1, v/v) to afford product (2.1 mg, 62%). LRMS (APCI pos): m/e 602 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.43 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.60 (m, 2H), 7.38 (m, 1H), 7.21-7.32 (m, 4H), 6.45 (d, 1H), 3.22 (m, 1H), 2.30 (s, 6H), 2.22 (m, 1H), 1.55-1.94 (m, 8H).

Workup

  1. customhad been consumed (overnight)
  2. customThen the reaction was partitioned between EtOAc (30 mL) and H2O (30 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×30 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 50/1 to 10/1

Sources & evidence

ORD record
ord-f193eae54ae0402ba4a56508fff21ee1
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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