Triethylamine → HCID 56932931, compound

HRID 1972349Notes

Reaction equation

HRID 1972349 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([S:20]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:12][CH2:11][N:10]1[C:32]1[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:41])([F:42])[F:40])=[CH:34][CH:33]=1

Participants

10

Reactant 6

HCID 8471TriethylamineHCID 855182-Thiophenesulfonyl chlorideHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 450368332-(2,5-Dichlorophenyl)piperazineHCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 56932931HCID 56932931, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
23 °C

Procedure

To a solution of 2-(2,5-dichlorophenyl)piperazine (316 mg, 1.369 mmol, Ark Pharm, Libertyville, Ill.) in CH2Cl2 (7.0 mL) was added 2-thiophenesulfonyl chloride (250 mg, 1.369 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (572 μL, 4.11 mmol). The reaction was stirred at 23° C. for 18 h, after which time the mixture was concentrated to dryness. To this intermediate was added 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (368.3 mg, 1.369 mmol, Example 27, step 1), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (95.8 mg, 0.734 mmol, Strem Chemical Inc, Newburyport, Mass.) tris(dibenzylideneacetone)dipalladium (0) (62.7 mg, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), 10 mL of toluene (9.78 mL) and sodium tert-butoxide (315.7 mg, 3.28 mmol). The reaction was heated to 90° C. and stirred for 20 h. After that time, the mixture was cooled to room temperature, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (50 g of silica, 10 to 40% EtOAc in hexanes) followed by reverse-phase preparative HPLC using a Phemomenex Gemini-NX C18 110 A column (150×30 mm), eluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 16.5 min) to provide 2-(4-(2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of 4 isomers.

Workup

  1. concentrationafter which time the mixture was concentrated to dryness
  2. temperatureThe reaction was heated to 90° C.
  3. stirringstirred for 20 h
  4. temperatureAfter that time, the mixture was cooled to room temperature
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was absorbed onto a plug of silica gel
  8. custompurified by silica gel chromatography (50 g of silica, 10 to 40% EtOAc in hexanes)
  9. washeluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 16.5 min)

Sources & evidence

ORD record
ord-f3aa0558c0304c53b71a87b0bdfec6f1
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

Loading…