1,2-Dichloroethane → N-(Cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

HRID 427395Notes

Reaction equation

HRID 427395 reaction equation
[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.O[N:26]1[C:30]2C=CC=CC=2N=N1.[NH2:35][C:36]1(C#N)[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>CN(C=O)C>[C:30]([CH:38]1[CH2:37][CH:36]([NH:35][C:9](=[O:11])[CH:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH2:41][CH2:40][N:39]1[CH3:42])#[N:26]

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 114349914-Amino-1-methylpiperidine-4-carbonitrileHCID 59972959(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid

Product 1

HCID 18768938N-(Cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (0.20 g, 0.71 mmol) (see Example 1-part a and b) was dissolved in 5 mL of DMF and cooled to 0° C. by an ice-water bath. EDC (0.18 g, 0.92 mmol) and 1-hydroxybenzotriazole (0.12 g, 0.92 mmol) were added and stirring, under argon, continued for 25 min. Then 4-amino-4-cyano-1-methylpiperidine (0.098 g, of the mixture of aminonitrile:cyanohydrin:ketone) was dissolved in 1 mL of DMF and added to the solution of the active ester. The resulting mixture was stirred at ambient temperature for 4 h. The volatiles were removed in vacuo and the resulting residue was dissolved in 100 mL of EtOAc and washed sequentially with 2×100 mL of saturated sodium bicarbonate and 1×100 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated to a thick oil. The oil was purified by column chromatography on SiO2 using as eluent 5% MeOH in CH2Cl2 to give the title compound as a clear oil (0.005 g): 1H NMR (CDCl3) 6.64 (1H, m), 3.73-3.37 (8H, m), 2.95-2.85 (1H, m), 2.75-2.55 (2H, m), 2.5-2.37 (2H, m), 2.34-2.25 (3H, m), 1.98-1.82 (2H, m), 1.80-1.58 (6H, m), 1.32-1.10 (8H, m), 0.95-0.78 (3H,m). MS: m/z=405 M+1.

Workup

  1. stirringThe resulting mixture was stirred at ambient temperature for 4 h
  2. customThe volatiles were removed in vacuo
  3. dissolutionthe resulting residue was dissolved in 100 mL of EtOAc
  4. washwashed sequentially with 2×100 mL of saturated sodium bicarbonate and 1×100 mL of brine
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to a thick oil
  8. customThe oil was purified by column chromatography on SiO2 using as eluent 5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-a84eedec4157407184ffc6479cd9e1a2
Source dataset
uspto-grants-2001_11
Patent number
US06313117B1

Reaction notes

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