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Ethyl 4-piperidinecarboxylate → 1-[(3-{5-[3-Cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid

HRID 1942736
Notes
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Reaction equation

HRID 1942736 reaction equation
[CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].C([O-])(=O)C.[Na+].[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([O:41]CC)=[O:40])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:33]4[CH2:34][CH2:35][CH:36]([C:39]([OH:41])=[O:40])[CH2:37][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 70770Ethyl 4-piperidinecarboxylateHCID 517045Sodium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 584941545-[3-(2-Ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile

Product 1

HCID 545765021-[(3-{5-[3-Cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid
Yield 33%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), ethyl 4-piperidinecarboxylate (46.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E28) (43 mg). δH (DMSO-d6, 400 MHz): 0.87 (6H, d), 1.03 (3H, t), 1.47 (2H, m), 1.71 (2H, m), 1.92 (3H, m), 2.01 (1H, m), 2.70 (4H, m), 2.93 (2H, q), 3.47 (2H, s), 7.24 (1H, t), 7.39 (1H, dd), 7.66 (2H, m), 8.26 (1H, dd), 8.47 (1H, d).

Workup

  1. stirringthe reaction solution was stirred at room temperature overnight
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in ethyl acetate (30 mL)
  4. washthe organic phase was washed with water
  5. dry with materialdried over sodium sulphate
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in isopropanol/water (10 mL, 1:1)
  8. addition0.5M sodium hydroxide (2.66 mL) was added
  9. stirringThe reaction solution was stirred at room temperature overnight
  10. customThe isopropanol was removed in vacuo
  11. extractionThe resulting solution was extracted with ethyl acetate (2*15 mL)
  12. dry with materialthe combined organic phases were dried over sodium sulphate
  13. concentrationconcentrated
  14. custompurified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-f15400f162504547803643a784d894fc
Source dataset
uspto-grants-2013_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08389508B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes