Diisopropylethylamine → HCID 178505027, compound

HRID 1696843Notes

Reaction equation

HRID 1696843 reaction equation
C([N:4](C(C)C)CC)(C)C.C(O)(=[O:12])C.C(O)(=O)C.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C@@H:35]([C:37]2[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=2)[OH:36])=[CH:25][CH:24]=1.I.[NH2:50][C:51]1[C:52]([C:59]([NH:61][C:62](=[NH:65])SC)=[O:60])=[N:53][C:54]([Cl:58])=[C:55]([NH2:57])[N:56]=1>C(O)C>[OH-:12].[NH4+:4].[NH2:50][C:51]1[C:52]([C:59]([N:61]=[C:62]([NH2:65])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C@@H:35]([C:37]3[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=3)[OH:36])=[CH:25][CH:24]=2)=[O:60])=[N:53][C:54]([Cl:58])=[C:55]([NH2:57])[N:56]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 66860779HCID 66860779, compoundHCID 140329753methyl N-(3,5-diamino-6-chloropyrazine-2-carbonyl)carbamimidothioate;hydroiodide

Product 2

HCID 14923Ammonium HydroxideYield 0.01%HCID 178505027HCID 178505027, compoundYield 48%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
70 °C

Procedure

Diisopropylethylamine (0.54 mL, 3.11 mmol) was added to a solution of N-[5-(2-{4-[4-(4-aminobutyl)phenyl]butylamino}-1-(R)-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide diacetic acid salt (39) (0.30 g, 0.52 mmol) in absolute ethanol (8 mL). The mixture was stirred at 70° C. (oil bath) for 10 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.2) g, 0.54 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and cooled to rt. The solvent was removed by rotary evaporation. The residue was purified by Biotage silica gel column chromatography (A=dichloromethane, B=10% concentrated aqueous ammonium hydroxide in methanol, gradient B/A 0% to 15%), and further purified by semi-preparative HPLC eluting with a gradient acetonitrile and water, each containing 0.01% concentrated ammonium hydroxide, to give N-(5-{2-[4-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenyl)butylamino]-1-(R)-hydroxyethyl}-2-hydroxyphenyl)methanesulfonamide (40) as a greenish yellow solid (0.17 g, 48%): 1H NMR (500 MHz, CD3OD) δ 1.60 (m, 8H), 2.60 (m, 6H), 2.72 (m, 1H), 2.80 (m, 1H), 2.88 (s, 3H), 3.23 (m, 2H), 4.65 (m, 1H), 6.80 (d, 1H), 6.98 (d, 1H), 7.06 (m, 4H), 7.30 (s, 1H), m/z (ESI) 662 [C29H40ClN9O5S+H]+; [α]D25 −7.5° (c 0.60, MeOH); mp 108-110° C.

Workup

  1. stirringThe reaction mixture was stirred at that temperature for 3 h
  2. temperaturecooled to rt
  3. customThe solvent was removed by rotary evaporation
  4. customThe residue was purified by Biotage silica gel column chromatography (A=dichloromethane, B=10% concentrated aqueous ammonium hydroxide in methanol, gradient B/A 0% to 15%), and
  5. customfurther purified by semi-preparative HPLC
  6. washeluting with a gradient acetonitrile and water

Sources & evidence

ORD record
ord-a9a2565623e840e3aee6480011547180
Source dataset
uspto-grants-2012_04
Patent number
US08163758B2

Reaction notes

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