Diisopropylethylamine → 2-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamide

HRID 252188Notes

Reaction equation

HRID 252188 reaction equation
Cl.Cl.N[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:10][CH:9]=1.C([N:27](C(C)C)CC)(C)C.I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C.CO>[NH2:34][C:35]1[C:36]([C:43]([N:45]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]3[NH:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[CH:10][CH:9]=2)[C:46]([NH2:49])=[NH:27])=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 220544322-[4-(4-Aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamide dihydrochlorideHCID 140329753methyl N-(3,5-diamino-6-chloropyrazine-2-carbonyl)carbamimidothioate;hydroiodide

Product 1

HCID 220544352-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamideYield 32.5%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 887MethanolSolvent

Procedure

A solution of 2-[4-(4-aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamide dihydrochloride 35 (99 mg, 0.27 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) in absolute ethanol (4 mL) and anhydrous methanol (3 mL) was stirred at 70° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) was added in one portion. The reaction mixture was stirred for 3 h and then cooled to room temperature. The yellow insolubles were removed by suction filtration and the liquid filtrate was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, 150:10:1, and 100:10:1, v/v) to give 2-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamide as a yellow solid (44 mg, 29% yield). The free base thus obtained was dissolved in methanol and treated with 4 drops of 4 N aqueous HCl. The solution was concentrated under reduced pressure and further dried under vacuum to give the final compound 36. mp 172-174° C. 1H NMR (300 MHz, CD3OD) δ 1.61-1.77 (m, 4H), 2.58-2.70 (m, 2H), 3.32-3.40 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.20 (s, 2H). m/z (ESI): 501 [C21H25ClN10O3+H]+.

Workup

  1. customThe yellow insolubles were removed by suction filtration
  2. concentrationthe liquid filtrate was concentrated by rotary evaporation
  3. customThe crude residue was purified by flash silica gel column chromatography
  4. washeluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, 150:10:1, and 100:10:1

Sources & evidence

ORD record
ord-91eb65f144424d8394f964b56854d775
Source dataset
uspto-grants-2011_01
Patent number
US07868010B2

Reaction notes

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