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

HRID 1046431Notes

Reaction equation

HRID 1046431 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.Cl[C:35]1[CH:40]=[C:39]([C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][N:36]=1.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:33][C:4]([CH3:32])([CH3:3])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([O-:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([O:31][C:37]3[CH:38]=[C:39]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[O:42])[CH:40]=[CH:35][N:36]=3)[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.[Na+:2]

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 24798764VX-222HCID 25219248(2-Chloropyridin-4-yl)(pyrrolidin-1-yl)methanone

Product 1

HCID 66849716Sodium 5-(3,3-dimethylbut-1-ynyl)-3-(4-methyl-N-(4-(4-(pyrrolidine-1-carbonyl)pyridin-2-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylateYield 16%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

NaH (50 mg of a 60% oil dispersion, 1.14 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 (128 mg, 0.287 mmol) and (2-chloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone from the previous step (300 mg, 1.42 mmol) in THF (5.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 85° C. overnight. 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 suspended in ethyl ether and sonicated for several minutes. The ether layer was removed to give an orange solid that was dried under vacuum and 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 (30 mg, 16%). MS (m/z): 618.0 [M−H]−; HPLC retention time: 6.43 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Workup

  1. temperatureheated at 85° C. overnight
  2. temperatureThe reaction was cooled
  3. customthe reaction evaporated to dryness
  4. customto give a solid residue
  5. customsonicated for several minutes
  6. customThe ether layer was removed
  7. customto give an orange solid
  8. customthat was dried under vacuum
  9. custompurified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water)
  10. additionFractions containing product

Sources & evidence

ORD record
ord-49dce2864139486d8e3538a65f2f62ac
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

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