3-Chloro-4,7-difluorobenzo[b]thiophene-2-carbonyl chloride → {4-[(3-Chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester

HRID 2389730Notes

Reaction equation

HRID 2389730 reaction equation
[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:37]2[C:38]([F:43])=[CH:39][CH:40]=[C:41]([F:42])[C:36]=2[S:35][C:34]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:44]([C:34]2[S:35][C:36]3[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:37]=3[C:33]=2[Cl:32])=[O:45])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:29][CH3:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 219384153-Chloro-4,7-difluorobenzo[b]thiophene-2-carbonyl chlorideHCID 69231045[4-(2-Methoxy-5-pyridin-4-yl-benzylamino)cyclohexyl]methylcarbamic acid t-butyl ester

Product 1

HCID 86618979{4-[(3-Chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a 3 L 3-neck RB flask equipped with a mechanical stirrer, N2 inlet and addition funnel is added [4-(2-methoxy-5-pyridin-4-yl-benzylamino)cyclohexyl]methylcarbamic acid t-butyl ester P5 (50.3 g, 118.20 mmol) and CH2Cl2 (750 mL). The resulting mixture is cooled in an ice bath and 3-chloro-4,7-difluorobenzothiophene-2-carbonyl chloride P10 (34.7 g, 129.92 mmol) in CH2Cl2 (250 mL) is added over 4 h. The reaction mixture is diluted with CH2Cl2 and washed with 1N HCl (800 mL), 1N NaOH (800 mL), H2O (500 mL) and brine (500 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to an orange-brown solid. The crude product is ground to a fine solid, diluted with EtOAc (450 mL) and the resulting slurry is stirred for 1 h. The mixture is filtered and the filter cake is washed with EtOAc (100 mL), and dried to give {4-[(3-chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester P6 (66.0 g, 85%) as an off-white solid.

Workup

  1. customTo a 3 L 3-neck RB flask equipped with a mechanical stirrer, N2 inlet and addition funnel
  2. temperatureThe resulting mixture is cooled in an ice bath
  3. washwashed with 1N HCl (800 mL), 1N NaOH (800 mL), H2O (500 mL) and brine (500 mL)
  4. dry with materialThe organic layer is dried over anhydrous Na2SO4
  5. concentrationconcentrated in vacuo to an orange-brown solid
  6. additiondiluted with EtOAc (450 mL)
  7. filtrationThe mixture is filtered
  8. washthe filter cake is washed with EtOAc (100 mL)
  9. customdried

Sources & evidence

ORD record
ord-a2da5a5463b84133bd725cfe19aa71ca
Source dataset
uspto-grants-2012_09
Patent number
US08273747B2

Reaction notes

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