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

HRID 1198299
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1198299
[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]
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Komponenten

7

Edukt 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

Produkt 1

HCID 204056MasilukastAusbeute 90,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 14284
4-(Dimethylamino)pyridine
Katalysator
HCID 8028TetrahydrofuranLösungsmittel
HCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

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%

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-6aea0aaf4f134ffc901cc83e32d771e4
Quelldatensatz
uspto-grants-1994_01
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US05280125

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