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 39300Notes

Reaction equation

HRID 39300 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]=[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

Participants

12

Reactant 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

Product 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 acidYield 38.1%

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 (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).

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 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)

Sources & evidence

ORD record
ord-9cbb35eefc984c35b9cdaff40857f283
Source dataset
uspto-grants-2013_09
Patent number
US08524764B2

Reaction notes

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