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

HRID 1707268
Notes
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Reaction equation

HRID 1707268 reaction equation
[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>[CH3:35][O:34][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:2])[NH:52][CH2:51][C@H:50]([CH3:49])[CH2:53][C:54]([F:57])([F:56])[F:55])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])(=[O:24])=[O:23])=[O:20]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 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

Product 1

HCID 204056MasilukastYield 104.5%

Reagents, catalysts & solvents 3

HCID 14284
4-(Dimethylamino)pyridine
Catalyst
HCID 8028TetrahydrofuranSolvent
HCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of 4-(5-carboxy-l-methylindol-3-yl-methyl) -3-methoxy-N-(2-methylphenylsulfonyl)benzamide (103.5 g), 4-dimethylaminopyridine (112.4 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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 (MgS04) 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 crude (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)-indol -3-ylmethyl]-N-(2-methylphenylsulphonyl)benzamide (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 form B (117.1 g, 65% recovery) as a white crystalline solid; mp 141.5°-143.5 ° C.; NHR (300 MHz, DMSO-d6): 1.01 (d, 3H, CH3), 2.0-2.2 (m, 2H, CF3C2), 2.3-2.5 (m, 1H, CHCH3), 2.61 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.

Workup

  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. customdried (MgS04)
  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

Sources & evidence

ORD record
ord-f9d9accbca3d4a5c97499427e82d0027
Source dataset
uspto-grants-1994_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05352694

Reaction notes

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