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

HRID 39302Notes

Reaction equation

HRID 39302 reaction equation
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]=[N: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+]>ClCCCl.[Cl-].[Na+].O.O.CO>[CH3:30][C:29]([CH3:31])([CH3:32])[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[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH:11]2[CH2:16][CH2:15][CH:14]([NH:35][N:34]([CH3:33])[C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[CH2:13][CH2:12]2)[CH:8]=1

Participants

11

Reactant 6

HCID 176Acetic AcidHCID 3939Lithium HydroxideHCID 516892Sodium BicarbonateHCID 27663012-(1-Methylhydrazin-1-yl)pyrazineHCID 5049666Sodium triacetoxyborohydrideHCID 581140005-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester

Product 1

HCID 533283795-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(N'-methyl-N'-pyrazin-2-yl-hydrazino)-cyclohexyl]-amino}-thiophene-2-carboxylic acidYield 9.1%

Reagents, catalysts & solvents 4

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) and N-Methyl-N-pyrazin-2-yl-hydrazine (41 mg, 0.33 mmol) in DCE (2 mL) was treated with AcOH (100 μL, 1.5 mmol) followed by NaBH(OAc)3 (120 mg, 0.5 mmol) in two portions. After 5 h, NaHCO3 (saturated aqueous solution, 2 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 (1.1 mmol, 46 mg) and heated to 60 deg C. for 1 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 11 mg of the title compound as its trans isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 26.05 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient) and 7 mg of the title compound as its cis isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 24.38 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient).

Workup

  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 1 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)

Sources & evidence

ORD record
ord-de0d04db59cb493d9b9a94c37d9250ff
Source dataset
uspto-grants-2013_09
Patent number
US08524764B2

Reaction notes

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