Sodium Bicarbonate → tert-butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

HRID 446744Notes

Reaction equation

HRID 446744 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[C:15]=3[F:23])[N:12]=[N:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[CH:36]=2)O1.C(=O)(O)[O-].[Na+]>Cl[Pd]Cl.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.[Fe+2].COCCOC>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)[CH:36]=2)=[CH:3][C:4]=1[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[C:15]=2[F:23])[N:12]=[N:11][N:10]=1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 45480279tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate2×HCID 582937635-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine2×

Product 1

HCID 58293836tert-butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateYield 50.6%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
70 °C

Procedure

To a round-bottom flask charged with 5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1078, 3.832 g, 10 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1098, 4.150 g, 11.00 mmol) and DME (100 mL) was flushed with N2 for 20 min. An aqueous solution of sodium bicarbonate (25 mL of 1.2 M, 30.00 mmol) was added. Nitrogen flow was continued for another 40 min before the addition of PdCl2 dppf (731.7 mg, 1.00 mmol). The resulting suspension was heated at 70° C. for 15 hours, filtered though a layer of diatomaceous earth, and washed with brine. The volatiles were removed in vacuo to afford a residue, which was purified by silica gel chromatography, eluting with 20-100% EtOAc/hexanes to yield tert-butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1103, 2.8 g, 50.6%) as yellow solid; ESMS (M+H)=554.

Workup

  1. customwas flushed with N2 for 20 min
  2. filtrationfiltered though a layer of diatomaceous earth
  3. washwashed with brine
  4. customThe volatiles were removed in vacuo
  5. customto afford a residue, which
  6. customwas purified by silica gel chromatography
  7. washeluting with 20-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-35eccede60fc4900b4e728b3a9709e64
Source dataset
uspto-grants-2013_07
Patent number
US08481524B2

Reaction notes

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