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

HRID 919555Notes

Reaction equation

HRID 919555 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.[NH:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[CH:50][C:43]=23)[CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:48]1[C:44]2=[N:45][CH:46]=[N:47][C:42]([NH:41][C@H:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:11](=[O:13])[CH2:10][NH:9][C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:36]3)=[C:43]2[CH:50]=[N:49]1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 13138167(3,5-Dichlorophenyl)glycineHCID 118890621(S)-N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 118906708(S)-1-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)piperidin-1-yl)-2-(3,5-dichlorophenylamino)ethanoneYield 32.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a cooled solution of 2-(3,5-dichlorophenylamino)acetic acid (102 mg, 0.45 mmol) at 0° C. in anhydrous DMF (5 mL), HOBt (135 mg, 0.68 mmol) was added and the reaction mixture was stirred for 10 min before EDCI (132 mg 0.68 mmol), (S)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.45 mmol) and DIEA (117 mg, 0.90 mmol) were added in succession. The reaction mixture was allowed to warm to rt and stirred overnight. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled intermediate (62 mg, 32%). 1H NMR (400 MHz, CDCl3): δ 11.42 (bs, 1H), 8.58 and 8.49 (2s, 1H), 7.98 (s, 1H), 6.71 and 6.68 (2s, 2H), 6.41 and 6.39 (2s, 2H), 5.29-5.18 (m, 1H), 4.40-4.09 (m, 2H), 3.94-3.42 (m, 3H), 3.18-3.03 (m, 1H), 2.27-2.20 (m, 1H), 1.97-1.56 (m, 4H). LC-MS: m/z [M+1]=420.

Workup

  1. additionwere added in succession
  2. customAfter completion of the reaction
  3. washwas washed with water (3×20 mL)
  4. dry with materialThe EtOAc layer was then dried over Na2SO4
  5. customevaporated in vacuo
  6. customto give a residue that
  7. customwas purified by column chromatography (silica gel, gradient MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-d1054fd8c5364f2fa4182d6bb8a72dc8
Source dataset
uspto-grants-2016_03
Patent number
US09273028B2

Reaction notes

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