Tri-o-tolylphosphine → Ispronicline

HRID 909279

Reaktionsgleichung

Reaktionsgleichung von HRID 909279
Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][N:13](C(OC(C)(C)C)=O)[C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][NH:13][C@H:14]([CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1)[CH3:15]

Komponenten

7

Edukt 3

HCID 80271Tri-o-tolylphosphineHCID 105848083-Bromo-5-(propan-2-yloxy)pyridineHCID 54671306(S)-tert-butyl methyl(pent-4-en-2-yl)carbamate

Produkt 1

HCID 9824145Ispronicline

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 23938PalladiumKatalysatorHCID 167845palladium(II) acetateKatalysatorHCID 21895542Acetonitrile triethylamineLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

The halo-substituted pyridine, (e.g., 5-bromo-3-isopropoxypyridine) can be synthesized by two different routes. In one preparation, 3,5-dibromopyridine is heated at 140° C. for 14 hours with 2 molar equivalents of potassium isopropoxide in dry isopropanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube to yield 5-bromo-3-isopropoxypyridine. A second preparation of 5-bromo-3-isopropoxypyridine from 5-bromonicotinic acid can be performed as follows: (i) 5-Bromonicotinic acid is converted to 5-bromonicotinamide by treatment with thionyl chloride, followed by reaction of the intermediate acid chloride with aqueous ammonia. (ii) The resulting 5-bromonicotinamide, previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761 (1970), is subjected to Hofmann degradation by treatment with sodium hydroxide and a 70% solution of calcium hypochlorite. (iii) The resulting 3-amino-5-bromopyridine, previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761 (1970), can be converted to 5-bromo-3-isopropoxypyridine by diazotization with isoamyl nitrite under acidic conditions, followed by treatment of the intermediate diazonium salt with isopropanol to yield 5-bromo-3-isopropoxypyridine. The palladium-catalyzed coupling of 5-bromo-3-isopropoxypyridine and (2S)—N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is carried out in acetonitrile-triethylamine (2:1, v,v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction can be carried out by heating the components at 80° C. for 20 hours to yield (2S)-(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine Removal of the tert-butoxycarbonyl protecting group can be accomplished by treatment with 30 molar equivalents of trifluoroacetic acid in anisole at 0° C. to afford (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Aufarbeitung

  1. customThe reaction
  2. customto yield
  3. custom(2S)-(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine Removal of the tert-butoxycarbonyl protecting group
  4. customcan be accomplished by treatment with 30 molar equivalents of trifluoroacetic acid in anisole at 0° C.

Quellen und Nachweise

ORD-Eintrag
ord-ba824ba69de9484d8aed772c28e0277d
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08017785B2

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