Acetic Acid → 5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(N'-methyl-N'-pyridin-2-yl-hydrazino)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

HRID 39300ノート

反応式

HRID 39300 の反応式
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]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].[CH3:33][N:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[NH2:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Li+].C(O)(C(F)(F)F)=O>ClCCCl.[Cl-].[Na+].O.O.CO>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:18]([CH:20]2[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[CH:11]2[CH2:12][CH2:13][CH:14]([NH:35][N:34]([CH3:33])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:15][CH2:16]2)[CH:8]=1

参加物

12

反応物 7

HCID 176Acetic AcidHCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 77911Pyridine, 2-(1-methylhydrazinyl)-HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 581140005-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester

生成物 1

HCID 533289305-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(N'-methyl-N'-pyridin-2-yl-hydrazino)-cyclohexyl]-amino}-thiophene-2-carboxylic acid収率 38.1%

試薬・触媒・溶媒 4

HCID 111,2-Dichloroethane溶媒HCID 887Methanol溶媒HCID 962Water溶媒HCID 57417360Sodium chloride; water溶媒

実験手順

A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (412 mg, 0.90 mmol) and N-Methyl-N-pyridin-2-yl-hydrazine (222 mg, 1.8 mmol) in DCE (6 mL) was treated with AcOH (200 μL, 3.0 mmol) followed by NaBH(OAc)3 (300 mg, 4.08 mmol) in two or three portions. 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 (20 mL), treated with lithium hydroxide (4.5 mmol, 188 mg) 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 189 mg (37% yield) of the title compound as its trans isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.39 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid) and 71 mg (14% yield) of the title compound as its cis isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.52 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

後処理

  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)

出典と根拠

ORDレコード
ord-9cbb35eefc984c35b9cdaff40857f283
出典データセット
uspto-grants-2013_09
特許番号
US08524764B2

反応ノート

読み込み中…