Ethyl cyanoacetate → Tofacitinib

HRID 2069003Notes

Reaction equation

HRID 2069003 reaction equation
[C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].C(N(CC)CC)C.[CH3:16][N:17]([C@@H:27]1[C@H:32]([CH3:33])[CH2:31][CH2:30][NH:29][CH2:28]1)[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1>C1(C)C=CC=CC=1>[CH3:33][C@@H:32]1[CH2:31][CH2:30][N:29]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:28][C@@H:27]1[N:17]([CH3:16])[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1

Participants

5

Reactant 3

HCID 7764Ethyl cyanoacetateHCID 8471TriethylamineHCID 23401507N-Methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Product 1

HCID 9926791TofacitinibYield 55.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Ethyl 2-cyanoacetate (140 mg, 1.23 mmol, 6.00 equiv.) and triethylamine (40 mg, 0.39 mmol, 2.00 equiv.) were added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 12 (50 mg, 0.19 mmol, 1.00 equiv.) in toluene (10 mL). The resulting solution was stirred at about 110° C. for about 16 hours and then was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol (50:1)) to give the title product as a light yellow solid (33 mg; yield=52%). 1H NMR (300 MHz, CD3OD) δ: 8.10 (s, 1H), 7.10 (d, J=4.0 Hz, 1H), 6.65 (d, J=4.0 Hz, 1H), 5.00-5.10 (m, 1H), 3.80-4.00 (m, 2H), 3.55-3.75 (m, 1H), 3.40-3.55 (m, 1H), 3.30-3.40 (m, 5H), 2.40-2.55 (m, 1H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 1H), 1.05-1.20 (m, 3H). LC-MS: m/z=313 (M+H)+.

Workup

  1. concentrationwas concentrated in vacuo
  2. customThe resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol (50:1))

Sources & evidence

ORD record
ord-dfbc5798fe4447ccb9a6162183bdb230
Source dataset
uspto-grants-2012_10
Patent number
US08299084B2

Reaction notes

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