Sodium Hydroxide → Sodium 3-(N-(4-(4-(azetidine-1-carbonyl)pyridin-2-yloxy)cyclohexyl)-4-methylcyclohexanecarboxamido)-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate

HRID 1046432Notes

Reaction equation

HRID 1046432 reaction equation
[H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42](Cl)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[OH-].[Na+]>CN(C=O)C>[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([O:31][CH:28]3[CH2:29][CH2:30][CH:25]([N:15]([C:9]4[CH:8]=[C:7]([C:6]#[C:5][C:4]([CH3:32])([CH3:3])[CH3:33])[S:11][C:10]=4[C:12]([O-:14])=[O:13])[C:16]([CH:18]4[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH2:26][CH2:27]3)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[Na+:2]

Participants

6

Reactant 4

HCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 24798764VX-222HCID 58113908Azetidin-1-yl-(2-chloro-pyridin-4-yl)-methanone

Product 1

HCID 66850076Sodium 3-(N-(4-(4-(azetidine-1-carbonyl)pyridin-2-yloxy)cyclohexyl)-4-methylcyclohexanecarboxamido)-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylateYield 77%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (60 mg of a 60% oil dispersion, 1.50 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.291 mmol) and azetidin-1-yl-(2-chloro-pyridin-4-yl)-methanone from the previous step (290 mg, 1.47 mmol) in DMF (3.0 mL) at 0° C. After 30 min the reaction was warmed to room temperature and then heated at 85° C. for 3.5 h. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (140 mg, 77%). HPLC retention time: 6.41 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Workup

  1. temperatureheated at 85° C. for 3.5 h
  2. temperatureThe reaction was cooled
  3. customthe reaction evaporated to dryness
  4. customto give a solid residue
  5. customThe solid was purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water)
  6. additionFractions containing product

Sources & evidence

ORD record
ord-172d448c86424989bf41970c114f0f17
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

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