1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(1-cyanocyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246690Notes

Reaction equation

HRID 246690 reaction equation
[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:44][C:45]1([C:48]#[N:49])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:48]([C:45]1([NH:44][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])[CH2:47][CH2:46]1)#[N:49]

Participants

8

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 145863631-Amino-1-cyclopropanecarbonitrile hydrochlorideHCID 712798942-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

Product 1

HCID 71280047N-(1-cyanocyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 4.1%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DIEA (200 mg, 1.55 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added 1-aminocyclopropanecarbonitrile hydrochloride (100 mg, 0.84 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (5 mg, 4.1%) as a yellow solid. MS: (M+H)+=358; 1H NMR (300 MHz, DMSO): δ 13.40 (s, 1H), 13.00 (s, 1H), 9.19 (s, 1H), 8.98 (s, 1H), 8.56 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=8.1 Hz), 7.46 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 2.53 (s, 3H), 1.78-1.74 (m, 2H), 1.48-1.44 (m, 2H).

Workup

  1. filtrationfiltered
  2. customthe filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm
  3. wait35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.

Sources & evidence

ORD record
ord-41dbfae37c454713bc11d203f6541877
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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