1,4-Dioxane → 4-Cyano-3-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]-benzoic acid methyl ester

HRID 1909071Notes

Reaction equation

HRID 1909071 reaction equation
Br[C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C(OC(N1C2=CN=CC([C:37]3[CH:42]=[C:41]([C:43]([O:45][CH3:46])=[O:44])[CH:40]=[CH:39][C:38]=3[C:47]#[N:48])=C2C=C1)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:46][O:45][C:43](=[O:44])[C:41]1[CH:40]=[CH:39][C:38]([C:47]#[N:48])=[C:37]([C:2]2[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]3[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=23)[CH:42]=1

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 665997094-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridineHCID 672864874-(2-Cyano-5-methoxycarbonyl-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester

Product 1

HCID 665995454-Cyano-3-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]-benzoic acid methyl esterYield 69%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridine (0.940 g, 2.63 mmol), 4-Cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-benzoic acid methyl ester (Example 140 Step 1 starting material) (0.840 g, 2.93 mmol, 1.1 eq), Bis(di-tertbutyl-(4-dimethylaminophenyl)-phosphine)-di-chloropalladium (II) (0.046 g, 0.066 mmol, 2 mol %), and tribasic potassium phosphate (1.12 g, 5.26 mmol, 2 eq) in a 10:1 mixture of dioxane and water was heated to 80° C. for 2.5 hr. The reaction was cooled to 23° C., the contents decanted into a separatory funnel and the residue in the vial was washed with copious amounts of ethyl acetate. The organic was washed with water, brine, dried (Na2SO4), and concentrated. The crude mixture was further purified by chromatography eluting with 30% EtOAc/Heptane giving 4-Cyano-3-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]-benzoic acid methyl ester as a yellow amorphous solid (0.790 g, 1.81 mmol, 69%). MS ESI m/z 438.4 (M+H)+. 1NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 6.20 (d, J=3.2 Hz, 1H), 5.54 (d, J=5.0 Hz, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 3.55 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H).

Workup

  1. temperatureThe reaction was cooled to 23° C.
  2. customthe contents decanted into a separatory funnel
  3. washthe residue in the vial was washed with copious amounts of ethyl acetate
  4. washThe organic was washed with water, brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe crude mixture was further purified by chromatography
  8. washeluting with 30% EtOAc/Heptane

Sources & evidence

ORD record
ord-973d72c7056f4c95a5707de4e9ae07fd
Source dataset
uspto-grants-2013_12
Patent number
US08598217B2

Reaction notes

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