Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Definitions

• This invention relates to a new process for making derivatives of 1,4-benzodioxan and, more specifically, to a process for preparing derivatives of 1,4-benzodioxan compounds which are substituted in their two-position by amino(lower) alkyl moieties.
• R denotes hydrogen, lower alkyl; aralkylparticularly, benzyl and aryl particularly phenyl; but it may also represent heterocyclic radicals, such as, pyridyl, piperidyl, morpholinyl, etc.;
• R stands for hydrogen, halogen-particularly, chlorine and bromine; hydroxy; lower alkyl and lower alkoxy;
• X represents halogen, preferably, chlorine or bromine and n ranges from 0 to 4.
• lower alkyl as used herein per se and as included in die term lower alkoxy means saturated monovalent aliphatic radicals of the general formula C H wherein n designates an integer of less than six and is inclusive of both straight-chain and branchedchain radicals.
• the 1,4-benzodioxan compounds referred to above, and particularly, many of their derivatives have been found to possess outstanding pharmacological properties, such as sympatholytic properties [Fourneau et al., Arch. intern. pharmacodynamie, 46, 178 (1933); Bovet et al., Arch. intern. pharmacodynamie, 55, 15 (1937); Goldenberg et al., J. Am. Med. Assoc., 135, 971 (1947)], Central depressant properties (Mills, Abstracts, 132nd Meeting, Am. Chem. Soc., New York, Sept. 1957, 7-0; U.S. Patent 2,906,757 and U.S.
• 2-amino(lower) alkyl- 1,4-benzodioxan 2-aminomethyl-1,4-benzodioxan, for instance, can be synthesized by the three-step procedure carried out by G. B. Marini-Betolo et al. in Gazz. Chirn. Ital., 83, 144 (1953). Catechol was refluxed with epichlorohydrin to yield l,4-benzodioxan-Z-methanol. This was obtained in 90% yield crude and 60% yield pure.
• Patent 2,366,102 there is obtained 2-aminomethyl-l,4- benzodioxan. No yield is given for this conversion. But it has been found when following this procedure that this is obtained only in 15% yield from 2-chloromethyl- 1,4-benzodioxan. This last step, in addition to affording only low yields of the desired product, must be carried out under high pressure and is by no means a simple conversion. The overall yield for this three-step process, as described in the literature, is 5.8%
• 2-aminornethyl-1,4-benzodioxan has also been synthesized in somewhat better yield in three steps in accordance with a method described in Koo et al., J.
• 3-aminomethyl-2-methyl-1,4-benzodioxan was also synthesized in three steps by Koo et al., J. Org. Chem., 26, 339 (1961) by condensing catechol with ethyl 2,3-dibromobutyrate in the presence of potassium carbonate giving, in 30% yield, ethyl 3-methyl-1,4-benz0dioXan-2- carboxylate. Ammoniation of this ester afforded 3- methyl-1,4-benzodioXan-2-carboxamide in yield. Reduction of the carboxamide with lithium aluminum hydride gave 2-aminomethyl-3-methyl-1,4-benzodioxan in 70% yield.- The overall yield for this process was 16.8%.
• this method involves reacting catechol or a substituted catechol with an appropriate dihalo alkanoic acid nitrile to produce the corresponding cyano derivative of 1,4-benzodioxan in yields as high as Reduction of the cyano derivative proceeds readily to 2- amino (lower)alkyl 3-substituted or unsubstituted-1,4- benzodioxanin yields as high as 77%.
• the process of this invention contemplates as first step refluxing for several hours of catechol or a substituted catechol, dissolved in, preferably, dry acetone as inert solvent, with a dibrorno (lower)alkanoic acid Patented Sept.
• binding agents as potassium hydroxide, sodium carbonate and sodium hydroxide, calcium carbonate and their equivalents may be employed.
• acetone as inert solvent for the catechol, it is practicable to use such organic solvents as, benzene, toluene, dibutylether, etc., while as diluent for lithium aluminum hydride in addition to ether, also tetrahydrofuran, dioxan, and their equivalents may be employed.
• the starting materials, substituted or unsubstituted catechols and dibromo(lower)alkanoic acid nitriles are respectively, commercially available or available by synthesis, e.g., according to the following literature references: Moureau, Annales de Chimie et de Physique [7] 2, 189 (2,3-dibromopropionitrile)-; Lespieau, Comptes rendus de lAcademie des Sciences, 137, 262 (3,4-dibromobutyronitrile); Palmer, American Chemical Journal, 11, 91 (2,3-dibromobutyronitrile); etc.
• benzodioxan which comprises the steps of adding to a solution of a catechol of the formula wherein R is a member selected from the group consisting of hydrogen, chlorine, bromine, hydroxy, lower alkyl and lower alkoxy, in dry acetone, anhydrous potassium carbonate as acid binding agent and a dibromo(lower)a1- kanoic acid nitrile of the formula XOH-R wherein R is selected from the groupconsisting of hydrogen and lower alkyl, benzyl, phenyl, pyridyl, piperidyl and morpholinyl, X is taken from the group consisting of chlorine and bromine, and n has a value of 0 to 4, refluxing the reaction mixture thus obtained for from 18 to 36 hours, recovering and purifying the resulting cyano 1,4- benzodioxan of the formula 2) n N R1 References Cited in the file of this patent Koo et al.: J. Am. Chem. Soc., vol.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)

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Cited By (3)

• 1961
  • 1961-10-30 US US148704A patent/US3149108A/en not_active Expired - Lifetime
• 1962
  • 1962-01-29 ES ES0274335A patent/ES274335A1/es not_active Expired
  • 1962-01-29 ES ES0274332A patent/ES274332A1/es not_active Expired

Non-Patent Citations (1)

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