2-Amino-4-methylphenol → 2-{2-[3-(5-Cyano-pyrazin-2-yl)-ureido]-4-methyl-phenoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester

HRID 418009Notes

Reaction equation

HRID 418009 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([CH2:23][OH:24])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](O)=[C:28]([N+:33]([O-])=O)[CH:27]=1.ClC(Cl)(O[C:40](=[O:46])OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[NH2:57][C:58]1[N:59]=[CH:60][C:61]([C:64]#[N:65])=[N:62][CH:63]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([CH2:23][O:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH2:1])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([CH2:23][O:24][C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][C:28]=2[NH:33][C:40]([NH:57][C:58]2[CH:63]=[N:62][C:61]([C:64]#[N:65])=[CH:60][N:59]=2)=[O:46])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]

Participants

11

Reactant 7

HCID 72642-Amino-4-methylphenolHCID 83914-Methyl-2-nitrophenolHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 2733832Lithium HexamethyldisilazideHCID 5201202tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylateHCID 139252945-Aminopyrazine-2-carbonitrile

Product 2

HCID 666486682-{2-[3-(5-Cyano-pyrazin-2-yl)-ureido]-4-methyl-phenoxymethyl}-morpholine-4-carboxylic acid tert-butyl esterHCID 666489632-(2-Amino-4-methyl-phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

2-(2-Amino-4-methyl-phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (0.087 g, 0.270 mmol) was prepared from 2-amino-4-methyl-phenol according to methods of Compound 3, Steps 1 and 2 using 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (prepared according to the procedure for Compound 2, Step 1 using the corresponding acid) and 4-methyl-2-nitro-phenol. It was combined with triphosgene (0.029 g, 0.10 mmol), toluene (2 mL) and Hunig's base (0.15 mL, 0.86 mmol), and stirred at room temperature for 25 min. The suspension then was transferred through a cannula to a cold solution (−78° C.) containing 5-amino-pyrazine-2-carbonitrile (0.032 g, 0.27 mmol), and lithium bis(trimethylsilyl)amide (0.27 mmol) in THF (1 mL), which had been stirring at −78° C. for 30 min. The reaction was allowed to warm, then was stirred for 16 h at room temperature. A precipitate formed and was collected by filtration to yield the desired product (0.043 g).

Workup

  1. customprepared
  2. customthen was transferred through a cannula to a cold solution (−78° C.)
  3. stirringhad been stirring at −78° C. for 30 min
  4. temperatureto warm
  5. stirringwas stirred for 16 h at room temperature
  6. customA precipitate formed
  7. filtrationwas collected by filtration

Sources & evidence

ORD record
ord-61a2bbade1e247088e592229fc70a6c3
Source dataset
uspto-grants-2012_01
Patent number
US08093244B2

Reaction notes

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