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1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → Masilukast

HRID 1198299
ノート
印刷プレビュー

反応式

HRID 1198299 の反応式
[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])(=[O:24])=[O:23])=[O:20])=[CH:17][C:16]=1[O:34][CH3:35])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:49][C@H:50]([CH2:53][C:54]([F:57])([F:56])[F:55])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[F:55][C:54]([F:57])([F:56])[CH2:53][C@@H:50]([CH3:49])[CH2:51][NH:52][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])(=[O:23])=[O:24])=[O:20])=[CH:17][C:16]=1[O:34][CH3:35])=[O:2]
参加物実験手順後処理出典と根拠反応ノート

参加物

7

反応物 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 12004108(R)-2-methyl-4,4,4-trifluorobutylamine hydrochlorideHCID 151044754-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide

生成物 1

HCID 204056Masilukast収率 90.5%

試薬・触媒・溶媒 3

HCID 14284
4-(Dimethylamino)pyridine
触媒
HCID 8028Tetrahydrofuran溶媒
HCID 8857Ethyl Acetate溶媒

実験手順

To a mixture of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (103.5 g), 4-dimethylaminopyridine (112.4 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride (51.8 g) in tetrahydrofuran (distilled from sodium benzophenone ketyl) (2.0 L), which had been stirred for 2 hours, was added (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (42.6 g); and the reaction mixture was stirred overnight (about 18 hours, incomplete reaction) then heated to reflux for two hours (complete reaction). The cooled reaction mixture was diluted with ethyl acetate (2 L) washed with 1N hydrochloric acid (twice) and brine, dried (MgSO4) and evaporated. The residue (138.6 g) was combined with impure product from similar procedures (28.0 g) and purified by flash chromatography, eluting with methylene chloride:ethyl acetate (sequentially, 1:0, 9:1 and 3:1) to afford a solid which was triturated twice with ether to give the crude title compound (135.2 g) which was recrystallized from ethanol (1.2 L) and acetone (0.3 L) (concentrated by boiling to about 0.9 L and refrigerated) and dried under vacuum to provide the title compound (117.1 g, 65% recovery) as a white crystalline solid; m.p. 141.5°-143.5° C.; NMR (300 MHz, DMSO-d6): 1.01 (d, 3H, CH3), 2.0-2.2 (m, 2H, CF3CH2), 2.3-2.5 (m, 1H, CHCH3), 2.61 (s, 3H, ArCH3), 3.23 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.13 (s, 1H), 7.17 (d, 2H), 7.38-7.69 (m, 6H), 7.72 (d, 1H), 8.05 (d, 1H), 8.11 (s, 1H), 8.46 (br t, 1H, NHCO); analysis for C31H32F3N3O5S: calculated: C, 60.48; H, 5.24; N, 6.83%, found: C, 60.47; H, 5.27; N, 6.67%

後処理

  1. stirringand the reaction mixture was stirred overnight
  2. custom(about 18 hours, incomplete reaction)
  3. temperaturethen heated
  4. temperatureto reflux for two hours
  5. custom(complete reaction)
  6. customThe cooled reaction mixture
  7. washwashed with 1N hydrochloric acid (twice) and brine
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. custompurified by flash chromatography
  11. washeluting with methylene chloride
  12. customethyl acetate (sequentially, 1:0, 9:1 and 3:1) to afford a solid which
  13. customwas triturated twice with ether
  14. customto give the crude title compound (135.2 g) which
  15. customwas recrystallized from ethanol (1.2 L) and acetone (0.3 L) (concentrated by boiling to about 0.9 L and refrigerated)
  16. customdried under vacuum

出典と根拠

ORDレコード
ord-6aea0aaf4f134ffc901cc83e32d771e4
出典データセット
uspto-grants-1994_01
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US05280125

反応ノート

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