HCID 57677755, compound → HCID 86602170, compound

HRID 492886Notes

Reaction equation

HRID 492886 reaction equation
[CH3:1][N:2]([CH3:41])[CH:3]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29]C(=O)OCC5C=CC=CC=5)=[C:25]([F:40])[CH:24]=4)[CH:19]=[CH:18][N:17]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:4]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:5]4[CH2:6][CH:3]([N:2]([CH3:41])[CH3:1])[CH2:4]4)[CH2:8][CH2:9]3)=[O:14])[CH:21]=2)=[CH:24][C:25]=1[F:40]

Participants

4

Reactant 1

HCID 57677755HCID 57677755, compound

Product 1

HCID 86602170HCID 86602170, compound

Reagents, catalysts & solvents 2

HCID 178502593HCID 178502593, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

After adding 20% palladium hydroxide-carbon (50 mg) to a solution of benzyl {4-[2-({4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carbonyl}amino)pyridin-4-yloxy]-2-fluorophenyl}carbamate (135 mg) in tetrahydrofuran (10.0 ml), the mixture was stirred for 8 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated to 3 ml of solvent to provide a crude product of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide (ESI-MS (m/z): 429[M+H]+). Ethanol (3.0 ml) and (1S)-(+)-10-camphorsulfonic acid (68.3 mg) were added to the crude product. After stirring at room temperature for 10 minutes, 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 3.15 ml) was added and the mixture was stirred at room temperature. After 30 minutes, 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 4.26 ml) was added and stirring was continued at room temperature for 3.5 hours. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were then added to the reaction solution, and the mixture was stirred at room temperature for 2 hours and then partitioned. The aqueous layer was extracted with ethyl acetate, and then the separated organic layer was washed with brine. It was then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated. Diethyl ether and hexane were added thereto, and the produced precipitate (41.3 mg) was filtered. After removing 12 mg of the powder, the remaining 29.3 mg was again purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were combined and concentrated. Diethyl ether and hexane were added thereto, and the produced precipitate was filtered. It was then subjected to aeration drying to provide the title compound (12.8 mg) as white powder.

Workup

  1. filtrationThe catalyst was filtered
  2. concentrationthe filtrate was concentrated to 3 ml of solvent

Sources & evidence

ORD record
ord-acc3f22385b7477990bb37b24d9bbcde
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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