Diisopropylethylamine → 4-(2-{6-[4-(2-Hydroxy-2-methylpropylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}ethyl)piperidine-1-carboxylic acid tert-butyl ester

HRID 1867997Notes

Reaction equation

HRID 1867997 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:18])C(O)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:22]([O:26]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:59][C:60]1[S:61][C:62]2[CH:68]=[C:67]([O:69][S:70]([C:73]3[CH:78]=[CH:77][C:76]([NH:79][CH2:80][C:81]([OH:84])([CH3:83])[CH3:82])=[CH:75][CH:74]=3)(=[O:72])=[O:71])[CH:66]=[CH:65][C:63]=2[N:64]=1>CN(C)C=O.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:18][C:22](=[O:26])[NH:59][C:60]2[S:61][C:62]3[CH:68]=[C:67]([O:69][S:70]([C:73]4[CH:74]=[CH:75][C:76]([NH:79][CH2:80][C:81]([OH:84])([CH3:82])[CH3:83])=[CH:77][CH:78]=4)(=[O:71])=[O:72])[CH:66]=[CH:65][C:63]=3[N:64]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 177818912-[1-(Tert-butoxycarbonyl)piperidin-4-yl]propanoic acidHCID 86612154(2-Amino-1,3-benzothiazol-6-yl) 4-[(2-hydroxy-2-methylpropyl)amino]benzenesulfonate;2,2,2-trifluoroacetic acid2×

Product 1

HCID 579808274-(2-{6-[4-(2-Hydroxy-2-methylpropylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}ethyl)piperidine-1-carboxylic acid tert-butyl esterYield 53.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of 1-Boc-piperidin-4-ylpropionic acid (176 mg, 0.686 mmol), HBTU (260 mg, 0.686 mmol) and N,N-diisopropylethylamine (185 mg, 1.435 mmol) in 10 ml of dimethylformamide is stirred for 10 minutes. 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester; compound with trifluoroacetic acid (intermediate 82) (130 mg, 0.33 mmol) is added and the reaction medium is stirred for 48 hours at room temperature. Water is added to the reaction medium and the resulting mixture is then extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated to dryness. The dry residue is purified by reverse-phase chromatography on a 300×20 mm Dynamax C18 column, with a gradient over 5 minutes of 5% to 40% acetonitrile in water supplemented with 0.07% trifluoroacetic acid, and then from 40% to 80% over 30 minutes. The fractions containing the product are evaporated to dryness, to give 111 mg of 4-(2-{6-[4-(2-hydroxy-2-methylpropylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}ethyl)piperidine-1-carboxylic acid tert-butyl ester in a yield of 51%.

Workup

  1. extractionthe resulting mixture is then extracted 3 times with ethyl acetate
  2. dry with materialThe organic phase is dried over magnesium sulfate
  3. concentrationconcentrated to dryness
  4. customThe dry residue is purified by reverse-phase chromatography on a 300×20 mm Dynamax C18 column, with a gradient over 5 minutes of 5% to 40% acetonitrile in water
  5. waitfrom 40% to 80% over 30 minutes
  6. additionThe fractions containing the product
  7. customare evaporated to dryness

Sources & evidence

ORD record
ord-9d9fe33621f540bb997bae3befa0e1f5
Source dataset
uspto-grants-2009_12
Patent number
US07632952B2

Reaction notes

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