Water → 5-[3,3-Dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

HRID 1046441Notes

Reaction equation

HRID 1046441 reaction equation
[H-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:41])([CH3:40])[CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CN(C=O)C>[CH3:41][C:31]([CH3:40])([CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([OH:4])=[O:6])=[C:11]([N:12]([C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:22]2[CH2:23][CH2:24][CH:25]([O:28][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:26][CH2:27]2)[CH:10]=1

Participants

6

Reactant 4

HCID 962WaterHCID 97462-FluoropyridineHCID 24758Sodium hydrideHCID 581141265-[3,3-Dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester

Product 1

HCID 509061505-[3,3-Dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acidYield 43.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (45 mg of a 60% oil dispersion, 1.12 mmol) was added in one portion to a solution of 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (124 mg, 0.221 mmol) and 2-fluoropyridine (0.095 mL, 1.1 mmol) in dry DMF (2.0 mL). After several minutes, the reaction was placed in a 85° C. oil bath and heated for 4 h. The reaction was cooled, water (0.50 mL) was added and the reaction mixture evaporated to dryness to provide a solid residue. The solid was washed with ethyl ether/hexanes then water, collected by centrifugation and washed with ethyl ether followed by water. The solid was collected and dried under vacuum to provide 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 311) (60 mg, 42%) as an off-white solid. MS (m/z): 528.3 [M+H-(2-hydroxypyridine)]+; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Workup

  1. waitAfter several minutes
  2. customwas placed in a 85° C.
  3. temperatureheated for 4 h
  4. temperatureThe reaction was cooled
  5. customthe reaction mixture evaporated to dryness
  6. customto provide a solid residue
  7. washThe solid was washed with ethyl ether/hexanes
  8. customwater, collected by centrifugation
  9. washwashed with ethyl ether
  10. customThe solid was collected
  11. customdried under vacuum

Sources & evidence

ORD record
ord-922dd2e28b424d1eaf48643323f0b8d4
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

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