Acryloyl chloride → evobrutinib

HRID 1522091Notes

Reaction equation

HRID 1522091 reaction equation
[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=2)[CH2:24][CH2:25]1)(=[O:37])[CH:35]=[CH2:36]

Participants

6

Reactant 3

HCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 710928091415824-88-2

Product 1

HCID 71479709evobrutinibYield 37%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Into a 20 mL reaction vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70.00 mg; 0.19 mmol), sodium bicarbonate (23.49 mg; 0.28 mmol) suspended in THF (3.00 ml) and water (0.30 ml). The mixture was cooled to 0° C. Acryloyl chloride (0.02 ml; 0.22 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting 0-50% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine as a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665 min. MS: m/z=430 [M+H]+, RT=1.53 min. 1H-NMR (DMSO-d6) δ 7.93 (s, 1H), 7.40 (t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H), 5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).

Workup

  1. customInto a 20 mL reaction
  2. customThe crude mixture was purified
  3. washeluting 0-50% MeOH/EtOAc
  4. additionFractions containing the desired product
  5. concentrationconcentrated under reduced pressure
  6. waitThe residue was lyophilized overnight

Sources & evidence

ORD record
ord-6a385cb55df547dbbdab18ff4e5a5658
Source dataset
uspto-grants-2015_07
Patent number
US09073947B2

Reaction notes

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