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 254007Notes

Reaction equation

HRID 254007 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 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 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-eba380fda8384edd8c0d7b129b3cac47
Source dataset
uspto-grants-2011_01
Patent number
US07872031B2

Reaction notes

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