2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl → HCID 66670528, compound

HRID 1896208Notes

Reaction equation

HRID 1896208 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[C:28](Cl)[CH:27]=[CH:26][C:25]=34)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:60][N:61](C=O)C.O>[OH-].[Na+].C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[C:28]([C:60]#[N:61])[CH:27]=[CH:26][C:25]=34)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 3

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 21962138N,N-Dimethylformamide--water (1/1)HCID 58303367HCID 58303367, compound

Product 1

HCID 66670528HCID 66670528, compound

Reagents, catalysts & solvents 4

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of (R)-3-[6-(6-Chloro-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (129 mg, 0.3 mmol), zinc cyanide (40 mg, 0.342 mmol), S-Phos (11.1 mg, 0.027 mmol) and Pd2(dba)3 (11 mg, 0.012 mmol) in DMF-water (1.36 ml, 99:1 DMF:water) was degassed for 5 min then back filled with nitrogen. The reaction mixture was then heated to 150° C. in a microwave reactor for 30 min. The crude reaction mixture was diluted with 2N NaOH (1 ml) and ethyl acetate (10 ml). The aqueous layer was back extracted with ethyl acetate (10 ml), then the pooled ethyl acetate phases were washed with brine and dried with sodium sulfate and concentrated in vacuo to an oil. The crude oil was purified by column chromatography (0-100% ethyl acetate in heptane) which gave (R)-3-[6-(6-cyano-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a greenish oil (70 mg). (R)-3-[6-(6-cyano-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.167 mmol) was dissolved in anhydrous DCM (2 ml) then 4 N HCl in dioxane (0.417 mL, 10 eq.) was added. The resulting mixture was capped and stirred at 23° C. After 4 h the reaction mixture was concentrated which gave the title compound 21 as a light yellow solid (64 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.68 (m, 1H) 1.79-2.01 (m, 2H) 2.01-2.16 (m, 1H) 2.78-3.05 (m, 2H) 3.19-3.30 (m, 1H) 3.44 (none, 1H) 4.27 (br. s., 1H) 7.68 (d, J=8.59 Hz, 1H) 7.84 (s, 1H) 8.38 (s, 1H) 8.54 (d, J=9.35 Hz, 1H) 8.98 (s, 1H) 9.67 (s, 1H); LCMS M+1 320.2.

Workup

  1. customwas degassed for 5 min
  2. additionthen back filled with nitrogen
  3. customThe crude reaction mixture
  4. extractionThe aqueous layer was back extracted with ethyl acetate (10 ml)
  5. washthe pooled ethyl acetate phases were washed with brine
  6. dry with materialdried with sodium sulfate
  7. concentrationconcentrated in vacuo to an oil
  8. customThe crude oil was purified by column chromatography (0-100% ethyl acetate in heptane) which

Sources & evidence

ORD record
ord-336b76e0628f4201b0bed66976d4fdea
Source dataset
uspto-grants-2013_08
Patent number
US08518952B2

Reaction notes

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