Triethylamine → Methyl 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinate

HRID 72445Notes

Reaction equation

HRID 72445 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1.FC(F)(F)C(O)=O.ClCCl.C(N(CC)CC)C.ClC1[N:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]>ClCCl.O1CCCC1.CO>[Cl:49][C:46]1[CH:47]=[N:48][C:14]([N:12]2[CH2:11][CH:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:13]2)=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 2764318Methyl 2,5-DichloronicotinateHCID 21863450Trifluoroacetic acid methylene chlorideHCID 63303164Tert-butyl 3-((2,4-difluorophenyl)amino)azetidine-1-carboxylate

Product 1

HCID 67958025Methyl 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinateYield 42.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a cooled (0° C.) solution of tert-butyl 3-((2,4-difluorophenyl)amino)azetidine-1-carboxylate (D31) (90 mg, 0.316 mmol) in dichloromethane, a mixture of trifluoroacetic acid/dichloromethane (3 ml/1 ml) was added and the reaction mixture was stirred 1 h. The solvents were evaporated in vacuo and the residue was dissolved in tetrahydrofuran/methanol (3/1 ml) triethylamine (0.132 ml, 0.95 mmol) was added followed by the addition of methyl 2,5-dichloronicotinate (52.33 mg, 0.253 mmol) and the resulting mixture was stirred 12 h at 75° C. The residue abtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with cyclohexane/ethyl acetate from 100/0 to 90/10. Collected fractions afforded the title compound (D85) (0022/086/5) (38 mg).

Workup

  1. additionwas added
  2. customThe solvents were evaporated in vacuo
  3. additionwas added
  4. stirringthe resulting mixture was stirred 12 h at 75° C
  5. customafter solvent evaporation
  6. customwas purified by Biotage SNAP-Si column
  7. washeluting with cyclohexane/ethyl acetate from 100/0 to 90/10

Sources & evidence

ORD record
ord-13b22ee979534379850a65b42e3ebcf9
Source dataset
uspto-grants-2014_09
Patent number
US08828987B2

Reaction notes

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