Lithium Hydroxide → 5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-amino}-thiophene-2-carboxylic acid

HRID 39314

Reaktionsgleichung

Reaktionsgleichung von HRID 39314
CO[C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1C(Cl)=O.CCN(C(C)C)C(C)C.[C:51]([O-])(O)=[O:52].[Na+].[OH-:56].[Li+]>C(Cl)Cl.[Cl-].[Na+].O.O.CO>[CH3:31][C:28]([CH3:29])([CH3:30])[C:27]#[C:26][C:7]1[S:6][C:5]([C:3]([OH:56])=[O:4])=[C:9]([N:10]([C:17]([CH:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[O:18])[CH:11]2[CH2:12][CH2:13][N:14]([C:51]([C:37]3[CH:38]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:52])[CH2:15][CH2:16]2)[CH:8]=1

Komponenten

10

Edukt 5

HCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 135033Picolinoyl Chloride HydrochlorideHCID 516892Sodium BicarbonateHCID 583558385-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester

Produkt 1

HCID 583558265-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-amino}-thiophene-2-carboxylic acid

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 57417360Sodium chloride; waterLösungsmittel

Versuchsvorschrift

A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (63 mg, 0.141 mmol) and pyridine-2-carbonyl chloride HCl salt (33 mg, 0.184 mmol) in DCM (2 mL) was treated with DIEA (124 μL, 0.7 mmol). After 30 min, NaHCO3 (saturated aqueous solution, 4-8 mL) was added to the mixture, followed by brine (20 mL), and the crude product was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated and the crude material was dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide (42 mg, 1 mmol,) and heated to 60 deg C. for 2 hours. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 40 mg of the title compound as its TFA salt: MS (m/z): 536.9 [M−H]+; HPLC retention time: 4.17 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Aufarbeitung

  1. extractionthe crude product was extracted with ethyl acetate (2×20 mL)
  2. concentrationThe combined organic layers were concentrated
  3. dissolutionthe crude material was dissolved in a 3:2:1 mixture of THF
  4. temperatureheated to 60 deg C
  5. waitfor 2 hours
  6. customThe residue was purified by HPLC (Gemini column, 35% acetonitrile
  7. additionwater, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid)

Quellen und Nachweise

ORD-Eintrag
ord-4b6280c9b7a843eeac5bc5f89389c691
Quelldatensatz
uspto-grants-2013_09
Patentnummer
US08524764B2

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