Bromide ion → 5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

HRID 1046424Notes

Reaction equation

HRID 1046424 reaction equation
C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23](Br)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[SH:39].C1CCN2C(=NCCC2)CC1.[Br-].[OH-].[K+].Cl>O1CCOCC1>[CH3:31][C:29]([CH3:30])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[CH:20]2[CH2:25][CH2:24][CH:23]([S:39][C:35]3[N:34]([CH3:33])[CH:38]=[N:37][N:36]=3)[CH2:22][CH2:21]2)[CH:8]=1

Participants

8

Reactant 6

HCID 259Bromide ionHCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 581141653-[(4-Bromo-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl esterHCID 178481306HCID 178481306, compound

Product 1

HCID 581139105-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

3-[(4-Bromo-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (75 mg, 0.143 mmol, 1.0 eq.) was weighed into a round-bottomed flask containing 1,4-dioxane (2 mL) and purged with N2. 4-Methyl-4H-[1,2,4]triazole-3-thiol (83 mg, 0.718 mmol, 5.0 eq.) and DBU (107 μL, 0.718 mmol, 5 eq.) were then added to the solution. The reaction was stirred at 80° C. until the complete consumption of bromide. The solution was then cooled to room temperature and 50% KOH (1.0 mL) was added to the flask. The reaction was heated at 40° C. for 2 h. The reaction was cooled to 0° C. and acidified with 2 N HCl. After removing volatiles, the residue was purified by reverse phase preparative HPLC to afford Example 1 (5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid, 32 mg, 41%).

Workup

  1. custompurged with N2
  2. temperatureThe reaction was heated at 40° C. for 2 h
  3. temperatureThe reaction was cooled to 0° C.
  4. customAfter removing volatiles
  5. customthe residue was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-34f845bf6856441ab0601e4423002851
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

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