Phenyl chloroformate → 1-[2-Fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester

HRID 409934Notes

Reaction equation

HRID 409934 reaction equation
Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:18][C:19]([C:21]1([C:24](=[O:41])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=3)=[CH:28][C:27]=2[F:40])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC(OC1C=CC=CC=1)=O.C(#N)C.C(OC(C1(C(=O)NC2C=CC(OC3C=CN=C(N)C=3)=CC=2F)CC1)=O)C1C=CC=CC=1.O1CCCC1>C(#N)C.O1CCCC1.O.O1CCCC1.N1C=CC=CC=1.N1C=CC=CC=1>[CH2:11]([O:18][C:19]([C:21]1([C:24](=[O:41])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH:34]=3)=[CH:28][C:27]=2[F:40])[CH2:22][CH2:23]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

10

Reactant 4

HCID 15891Phenyl chloroformateHCID 59459707HCID 59459707, compoundHCID 86707875HCID 86707875, compoundHCID 86707876HCID 86707876, compound

Product 1

HCID 247886951-[2-Fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl esterYield 99.1%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6342AcetonitrileSolvent2×HCID 8028TetrahydrofuranSolvent2×HCID 16069498Pyridine tetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

Pyridine (50 ml) was mixed with tetrahydrofuran (40 ml) and cooled to 10° C. A solution of phenyl chloroformate (4.83 g) in acetonitrile (50 ml) and a solution of 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (10.00 g) in tetrahydrofuran (80 ml) were added dropwise to the tetrahydrofuran-pyridine solution over a period of 2 hours at 10° C. At this time, the amounts of the phenyl chloroformate-acetonitrile solution and the 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester/tetrahydrofuran solution added dropwise were adjusted to the constant rate so that each solution was added dropwise over a period of 2 hours. The crystals were precipitated while the solutions were added dropwise. After completing the dropwise addition, the completion of reaction was confirmed using an HPLC apparatus. Subsequently, a mixed solution of water (10 ml) and acetonitrile (50 ml) was added to the reaction mixture. The crystals were collected by filtration and washed with a mixed solution of tetrahydrofuran (15 ml)-acetonitrile (15 ml) and dried under reduced pressure to give the title compound (12.74 g). Apparent yield 98.0%, purity 94.6% (HPLC area percentage).

Workup

  1. additionwas added dropwise over a period of 2 hours
  2. customThe crystals were precipitated while the solutions
  3. additionwere added dropwise
  4. additionthe dropwise addition
  5. customthe completion of reaction
  6. filtrationThe crystals were collected by filtration
  7. washwashed with a mixed solution of tetrahydrofuran (15 ml)-acetonitrile (15 ml)
  8. customdried under reduced pressure

Sources & evidence

ORD record
ord-9bd1752451df4aecb56345e090f1f0e9
Source dataset
uspto-grants-2014_06
Patent number
US08759530B2

Reaction notes

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