Potassium Carbonate → 1,1-Dimethylethyl N-[1-(6-chloro-2-pyrazinyl)-4-piperidinyl]carbamate

HRID 1529255Notes

Reaction equation

HRID 1529255 reaction equation
Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C:10]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].C[Sn](C)(C)C1N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)C=NC=1>CN(C=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[O:13][C:10]([CH3:11])([CH3:9])[CH3:12])[CH2:22][CH2:21]2)[CH:7]=[N:6][CH:5]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 785042,6-DichloropyrazineHCID 7238334-(N-Boc-amino)piperidineHCID 67958144HCID 67958144, compound

Product 1

HCID 534860761,1-Dimethylethyl N-[1-(6-chloro-2-pyrazinyl)-4-piperidinyl]carbamateYield 98%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

A suspension of 2,6-dichloropyrazine (223.5 g, 1.5 mol, 1.0 eq), 4-N-boc-aminopiperidine (300 g, 1.5 mol, 1.0 eq) and K2CO3 (228 g, 1.65 mol, 1.1 eq) in DMF (900 mL) was heated to 85° C. for 20 h. LC-MS analysis showed that tert-butyl 1-(6-(trimethylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate was formed as the major product. The reaction mixture was cooled to RT and poured into ice-water (3 L). The resulting precipitate was collected by filtration, washed with water (1 L×2) and hexane (1 L×2), and dried at 50° C. under vacuum affording tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (252 g, >98% purity) in 54% yield. MS (ESI, pos. ion) m/z: 393.0 (M+1). A suspension of tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (245 g, 0.75 mol, 1.0 eq), hexamethylditin (492 g, 1.5 mol, 2.0 eq) and Pd(PPh3)4 (87 g, 0.075 mol, 0.1 eq) in anhydrous toluene (2 L) was degassed with N2 for 30 min and heated to 110° C. for 24 h. LC-MS analysis showed around 50% conversion and no more further reaction. The reaction mixture was cooled to RT, quenched with water (2 L), and stirred well. After filtration through a celite pad and phase separation, the aqueous layer was extracted with EtOAc (1 L×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography eluting with DCM/EtOAc (20/1), affording title compound 1d (150 g, >96% purity) in 45% yield. MS (ESI, pos. ion) m/z: 443.2 (M+1)

Workup

  1. customwas formed as the major product
  2. temperatureThe reaction mixture was cooled to RT
  3. filtrationThe resulting precipitate was collected by filtration
  4. washwashed with water (1 L×2) and hexane (1 L×2)
  5. customdried at 50° C. under vacuum

Sources & evidence

ORD record
ord-250dfd14e00a48afa2e23b77c1e68957
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

Loading…