1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R)-2-(3,5-dichlorophenylamino)-1-(3-(methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanone

HRID 919568Notes

Reaction equation

HRID 919568 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][N:36]([C@@H:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)[C:37]1[N:42]=[CH:41][N:40]=[C:39]2[NH:43][N:44]=[CH:45][C:38]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:48]2[CH2:49][CH2:50][CH2:51][C@@H:46]([N:36]([CH3:35])[C:37]3[N:42]=[CH:41][N:40]=[C:39]4[NH:43][N:44]=[CH:45][C:38]=34)[CH2:47]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 13138167(3,5-Dichlorophenyl)glycineHCID 86706447(R)-N-methyl-N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 86706448(R)-2-(3,5-dichlorophenylamino)-1-(3-(methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanoneYield 15%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 2-(3,5-dichlorophenylamino)acetic acid (170 mg, 0.77 mmol) in DMF (5 mL) was added HOBt (156 mg, 1.16 mmol) at 0° C. and the reaction mixture was stirred for 10 min, followed by the addition of EDCI (222 mg, 1.16 mmol), (R)—N-methyl-N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (180 mg, 0.77 mmol) and DIEA (150 mg, 1.16 mmol). The reaction mixture was allowed to warm to rt and was stirred overnight, diluted with EtOAc (50 mL) and washed with water (3×20 mL). The EtOAc layer was dried over Na2SO4 and evaporated in vacuo to give a residue that purified by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (50 mg, 14.8%). 1H NMR (400 MHz, DMSO-d6): δ 13.50 (d, J=10.8 Hz, 1H), 8.22 (s, 1H), 8.17 (m, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 6.32 (m, 1H), 4.40 (d, J=12.4 Hz, 1H), 4.00 (m, 3H), 3.28 (s, 3H), 3.02 (t, J=7.8 Hz, 1H), 2.80 (m, 1H), 2.62 (t, J=7.8 Hz, 1H), 2.00 (m, 2H), 1.82 (m, 2H). LC-MS: m/z [M+1]=434.

Workup

  1. stirringwas stirred overnight
  2. washwashed with water (3×20 mL)
  3. dry with materialThe EtOAc layer was dried over Na2SO4
  4. customevaporated in vacuo
  5. customto give a residue
  6. customthat purified by column chromatography (silica gel, gradient MeOH in DCM)

Sources & evidence

ORD record
ord-a1fe99586ffb4b0c9012bd5bff6bc2cd
Source dataset
uspto-grants-2016_03
Patent number
US09273028B2

Reaction notes

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