N-Methyl dicyclohexylamine → HCID 57546104, compound

HRID 913944Notes

Reaction equation

HRID 913944 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C1(N(C)C2CCCCC2)CCCCC1.Cl[CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:7]=2)[CH:3]=1

Participants

5

Reactant 3

HCID 24210N-Methyl dicyclohexylamineHCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl etherHCID 57546202HCID 57546202, compound

Product 1

HCID 57546104HCID 57546104, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 5-chloro-1H-indazole-7-carboxylate (15 g, 30.7 mmol) and N-cyclohexyl-N-methylcyclohexanamine (10.86 mL, 50.7 mmol) in tetrahydrofuran (100 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (8.7 mL, 49 mmol). After 5 min, the ice bath was removed and stirring continued at room temperature for 24 h. The reaction was treated with 25 mL of 2M ammonia in methanol and allowed to stir at room temperature for 20 min. The reaction was diluted with diethyl ether, washed with water, then 1M potassium bisulfate, then water, then brine, dried over magnesium sulfate, and concentrated. TLC shows a slightly less polar impurity. The product was purified by column chromatography. The column was begun with 25% ethyl acetate/n-hexane and continued with that solvent system until the less polar impurity had been removed. The polarity was then ramped to 30% ethyl acetate/n-hexane to give nearly perfect separation. All absolutely pure fractions (by TLC) were combined to give 17.6 g (93%) as an amorphous white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.18 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.44 (dd, J=8.6, 5.6 Hz, 2H), 7.03 (dd, J=8.9, 8.6 Hz, 2H), 5.77 (s, 2H), 4.33 (s, 2H), 3.80 (br, 2H), 3.63 (t, J=8.2 Hz, 2H), 3.07 (m, 2H), 2.28 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.5, 161.7 (d, J=247 Hz), 155.0, 144.4, 137.5, 131.8, 129.1 (d, J=7.7 Hz), 126.8, 125.0, 124.4, 122.7, 121.1, 115.5 (d, J=21 Hz), 82.6, 79.6, 72.7, 68.0, 40.8, 40.1 (br), 32.1, 28.5, 18.1, −1.3. Mass spec.: 618.28 (MH)+.

Workup

  1. customthe ice bath was removed
  2. waitcontinued at room temperature for 24 h
  3. additionThe reaction was treated with 25 mL of 2M ammonia in methanol
  4. stirringto stir at room temperature for 20 min
  5. additionThe reaction was diluted with diethyl ether
  6. washwashed with water
  7. dry with material1M potassium bisulfate, then water, then brine, dried over magnesium sulfate
  8. concentrationconcentrated
  9. customThe product was purified by column chromatography
  10. customhad been removed
  11. customto give nearly perfect
  12. customseparation
  13. customto give 17.6 g (93%) as an amorphous white foam solid

Sources & evidence

ORD record
ord-042c67d5ae0a4debb0cb095f36e9276d
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

Loading…