O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate → Methyl 4-(1-(5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate

HRID 72507Notes

Reaction equation

HRID 72507 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].F[P-](F)(F)(F)(F)F.ClC1C=CC2N=NN(OC(N(C)C)=[N+](C)C)C=2C=1.Cl.[NH2:50][C:51]1([C:54]2[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52]1>[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:50][C:51]1([C:54]2[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52]1)=[O:8]

Participants

5

Reactant 3

HCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 66824369Methyl 4-(1-aminocyclopropyl)benzoate hydrochlorideHCID 679583595-Chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinic acid

Product 1

HCID 67958882Methyl 4-(1-(5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinamido)cyclopropyl)benzoateYield 64.1%

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

A mixture of 5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinic acid (D113) (55.4 mg, 0.161 mmol), O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU) (66.8 mg, 0.161 mmol) and N,N-disopropylethylamine (0.072 ml, 0.403 mmol) was stirred 30 min at room temperature. Methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (37.8 mg, 0.161 mmol) was added and the reaction mixture stirred overnight at room temperature. NH4Cl saturated solution (20 ml) was added and the mixture was extracted with ethylacetate (3×10 ml). The residue obtained after solvent evaporation was purified by SPE-Si cartridge (10 g) eluting dichloromethane. Collected fractions, after solvent evaporation, afforded the title compound (D163) (52.6 mg).

Workup

  1. stirringthe reaction mixture stirred overnight at room temperature
  2. extractionthe mixture was extracted with ethylacetate (3×10 ml)
  3. customThe residue obtained
  4. customafter solvent evaporation
  5. customwas purified by SPE-Si cartridge (10 g)
  6. washeluting dichloromethane
  7. customCollected fractions, after solvent evaporation

Sources & evidence

ORD record
ord-f08ec3ba944541f6b35c32226025d65e
Source dataset
uspto-grants-2014_09
Patent number
US08828987B2

Reaction notes

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