Tetrahydrofuran → HCID 71537773, compound

HRID 1519312Notes

Reaction equation

HRID 1519312 reaction equation
C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C1COCC1.O.[OH-].[Li+]>CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:37]5[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]5)=[O:32])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 79341Piperidin-4-olHCID 168937Lithium hydroxide, monohydrateHCID 86679835HCID 86679835, compound2×

Product 1

HCID 71537773HCID 71537773, compoundYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-hydroxypiperidine (available from Aldrich Chemical Company, Inc.; 42 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-hydroxy-piperidine-1-carbonyl)-biphenyl-2-carboxylic acid (48 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 8.47 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42-7.49 (m, 4H), 3.73-3.79 (m, 1H), 3.36-3.52 (m, 2H+water peak), 3.15-3.27 (m, 2H), 1.70-1.82 (m, 2H), 1.32-1.47 (m, 2H).

Workup

  1. customto give the crude amide product
  2. concentrationThe reaction mixture was concentrated to dryness under vacuum at 40° C
  3. addition1 M HCl (3 mL) was added
  4. stirringthe mixture was stirred
  5. concentrationconcentrated to dryness
  6. custompurified
  7. customHPLC Purification Conditions

Sources & evidence

ORD record
ord-d0d410a041144ea3b68047f987addb4e
Source dataset
uspto-grants-2015_07
Patent number
US09073881B2

Reaction notes

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