Diisopropylethylamine → HCID 178512397, compound

HRID 1696827Notes

Reaction equation

HRID 1696827 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:46])=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=2)[OH:36])=[CH:25][CH:24]=1.I.[NH2:48][C:49]1[C:50]([C:57]([NH:59][C:60](=[NH:63])SC)=[O:58])=[N:51][C:52]([Cl:56])=[C:53]([NH2:55])[N:54]=1>C(O)C>[OH-:12].[NH4+:4].[NH2:48][C:49]1[C:50]([C:57]([N:59]=[C:60]([NH2:63])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][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:46])=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=3)[OH:36])=[CH:27][CH:28]=2)=[O:58])=[N:51][C:52]([Cl:56])=[C:53]([NH2:55])[N:54]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 86649682HCID 86649682, compoundHCID 140329753methyl N-(3,5-diamino-6-chloropyrazine-2-carbonyl)carbamimidothioate;hydroiodide

Product 2

HCID 14923Ammonium HydroxideYield 0.05%HCID 178512397HCID 178512397, compoundYield 46%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
70 °C

Procedure

Diisopropylethylamine (0.13 mL, 0.72 mmol) was added to a solution of N-[5-(2-{4-[4-(4-aminobutyl)phenyl]butylamino}-1-(R)-hydroxyethyl)-2-hydroxyphenyl]formamide diacetic acid salt (11) (65 mg, 0.13 mmol) in absolute ethanol (5 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 (53 mg, 0.14 mmol) was added in two portions over 45 min. The reaction mixture was stirred at that temperature for 3 h and cooled to rt. 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 1% to 15%), and further purified by semi-preparative HPLC eluting with a gradient acetonitrile and water, each containing 0.05% 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)formamide (12) as a greenish yellow solid (35 mg, 46%): 1H NMR (500 MHz, DMSO-d6) δ 1.50 (m, 8H), 2.51 (m, 4H), 3.15 (m, 6H), 4.42 (m, 1H), 5.00 (br, 1H), 6.58 (br, 2H), 6.72 (m, 1H), 6.80 (m, 1H), 7.08 (m, 4H), 8.00 (s, 1H), 8.25 (s, 1H); m/z (ESI) 612 [C29H38ClN9O4+H]+; [α]D25 −3.3° (c 0.15, MeOH); mp 138-140° C.

Workup

  1. stirringThe reaction mixture was stirred at that temperature for 3 h
  2. temperaturecooled to rt
  3. customSolvent 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 1% to 15%), and
  5. customfurther purified by semi-preparative HPLC
  6. washeluting with a gradient acetonitrile and water

Sources & evidence

ORD record
ord-9b934a864b4d4238a3eb7b3467f06e93
Source dataset
uspto-grants-2012_04
Patent number
US08163758B2

Reaction notes

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