Sodium Bicarbonate → tert-butyl 2-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

HRID 1518559Notes

Reaction equation

HRID 1518559 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)=[N:12][N:11]=[N:10]1.Br[C:31]1[S:46][C:34]2[CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38][C:33]=2[CH:32]=1.C([O-])(O)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:29][C:15]1[N:16]=[CH:17][C:18]([C:31]2[S:46][C:34]3[CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][CH2:38][C:33]=3[CH:32]=2)=[CH:19][C:14]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:10]=[N:11][N:12]=1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 17389889tert-butyl 2-bromo-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylateHCID 581794573-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Product 1

HCID 58180103tert-butyl 2-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (250 mg, 0.63 mmol), tert-butyl 2-bromo-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (198 mg, 0.63 mmol), and NaHCO3 (1.56 mL, saturated solution in H2O) in N,N-dimethylformamide (8.3 mL) was degassed with a nitrogen stream for 20 min. To this mixture was added [1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloride (46 mg, 0.06 mmol) and the reaction was stirred in a microwave for 10 min at 120° C. The resulting crude mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with H2O (2×15 mL) and brine (1×15 mL), concentrated under reduced pressure, and purified via silica gel chromatography to provide tert-butyl 2-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate. This material (137 mg, 0.27 mmol) was treated with HCl (4 mL, 4.0 N in dioxane) for 1 hr, and solvent was removed under reduced pressure. The residue was dissolved in MeOH (500 mL) and treated with cold diethyl ether (˜15 mL). The resulting precipitate was collected and dried in vacuo to provide the hydrochloride salt of 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)pyridin-2-amine as a bright yellow solid (103 mg, 37% yield over two steps); 1H NMR (DMSO-d6): 9.50 (s, 2H), 8.44 (d, J=2.4 Hz, 1H), 7.85-7.46 (m, 4H), 7.05 (s, 1H), 4.29 (s, 2H), 3.39-3.25 (m, 2H), 2.85-2.81 (m, 2H); ES-MS: m/e=412.2 (M+H).

Workup

  1. customwas degassed with a nitrogen stream for 20 min
  2. filtrationfiltered
  3. washThe filtrate was washed with H2O (2×15 mL) and brine (1×15 mL)
  4. concentrationconcentrated under reduced pressure
  5. custompurified via silica gel chromatography

Sources & evidence

ORD record
ord-570aa382fef4433597c7fc355527a798
Source dataset
uspto-grants-2012_07
Patent number
US08232406B2

Reaction notes

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