1,2-Dichloroethane → HCID 52916876, compound

HRID 2360561Notes

Reaction equation

HRID 2360561 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:36][C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][C:33]=1[NH:38][C:21]([C:20]1[CH:24]=[CH:25][C:17]([N:14]2[CH2:13][CH2:12][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:11]3)[CH2:16][CH2:15]2)=[N:18][CH:19]=1)=[O:22]

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 7243O-PhenylenediamineHCID 757711-HydroxybenzotriazoleHCID 67104328HCID 67104328, compound

Product 1

HCID 52916876HCID 52916876, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of tert-butyl 2,7-diazaspiro[3.5]nonane (660 mg, 2.91 mmol), methyl 6-chloronicotinate (500 mg, 2.91 mmol) and Et3N (0.487 mL, 3.50 mmol) in 2 mL of N-methylpyrrolidine was stirred under microwave irradiation for 20 min at a temperature of 180° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated, giving tert-butyl 7-[5-(methoxycarbonyl)pyridine-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate. The methyl ester was dissolved in 2 mL of 1:1 THF/water, treated with LiOH.H2O (26 mg, 0.62 mmol) and stirred for 20 hours. The mixture was poured into EtOAc and washed with 1M HCl followed by brine, dried (MgSO4), filtered and concentrated, providing 6-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl]nicotinic acid. A mixture of the carboxylic acid in 2 mL of DMF was treated with EDC (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol) and phenylenediamine (125 mg, 1.15 mmol), stirred for 15 h at room temperature. The reaction mixture was then diluted with EtOAc and washed with sat.'d NaHCO3, dried (MgSO4), filtered and concentrated. The crude oil was purified by reverse phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) and formation of the desired product, tert-butyl 7-(5-{[(2-aminophenyl)amino]carbonyl}pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, which was confirmed by MS (ESI+): cal'd [M+H]+ 438.2, obs'd 438.3.

Workup

  1. washwashed with sat.'d NaHCO3
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude oil was purified by reverse phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) and formation of the desired product, tert-butyl 7-(5-{[(2-aminophenyl)amino]carbonyl}pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, which

Sources & evidence

ORD record
ord-7fbbb46f83594225bfe4ce9f6676cc55
Source dataset
uspto-grants-2014_04
Patent number
US08686020B2

Reaction notes

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