Sodium Hydroxide → Methyl 4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate

HRID 72492Notes

Reaction equation

HRID 72492 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:9]

Participants

7

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 66824369Methyl 4-(1-aminocyclopropyl)benzoate hydrochlorideHCID 679581565-Chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinic acid

Product 1

HCID 67958630Methyl 4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoateYield 48.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture of 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinic acid (D104) (200 mg, 0.53 mmol), methyl 4-(1-aminocyclopropyl)benzoate (D7) (144.31 mg, 0.634 mmol) and N,N-diisopropylethylamine (0.291 ml, 1.674 mmol) in dichloromethane (8 ml), ®T3P (1-Propanephosphonic acid cyclic anhydride) (403 mg, 0.633 mmol) was added and the mixture stirred under microwave irradiation at 110° C. for 10 min (2 cycle of 5 min each). 1M NaOH (5 ml) was added and the mixture extracted with dichloromethane (3×20 ml). Collected organics, after solvent evaporation, afforded a crude material that was purified by SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D148) (140 mg)

Workup

  1. additionwas added
  2. extractionthe mixture extracted with dichloromethane (3×20 ml)
  3. customCollected organics, after solvent evaporation
  4. customafforded a crude material that
  5. customwas purified by SPE-Si cartridge (10 g)
  6. washeluting with a mixture cyclohexane/ethyl acetate from 100/0 to 60/40
  7. customCollected fractions, after solvent evaporation

Sources & evidence

ORD record
ord-74c4577e67dc4186892e7abe50f5ec1e
Source dataset
uspto-grants-2014_09
Patent number
US08828987B2

Reaction notes

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