Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
  • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
  • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

Definitions

• This invention relates to novel organic compounds and to processes for their preparation.
• the present invention pertains to a new class of amino acids which find value as both therapeutic agents and as intermediates for the synthesis of new chemical substances.
• the compounds of the present invention may be represented as follows:
• R2 R1 OOOH wherein each of R R and R is hydrogen, hydroxyl, lower alkyl, lower alkoxy, benzyloxy, chloro, fluoro, bromo or trifluoromethyl.
• the present invention embraces both the dand l-cis isomers and the dand ltrans isomers.
• the cis and trans forms are prepared by different chemical syntheses while the dand l-isomersof either the cis or trans forms can be resolved by the classical methods, as for example, by formation of diastereoisomers.
• the compounds of this invention serve as valuable intermediates in organic preparations representing synthetic amino acids which may for example be employed in the synthesis of new polypeptides or substituted for natural amino acids such as phenylalanine or tyrosine in the synthesis of modified protein molecules.
• the compounds of the instant invention demonstrate hypotensive activity and are therefore useful in the treatment of various hypertensive conditions. While the mechanisms of such activity is by no means clear, it appears that it may be a manifestation of catecholamine release and depletion.
• the compounds ofthis invention may be administered by any of the usual routes, especially oral, in a suitable pharmaceutical form such as tablets, capsules, sustained release preparations, solutions, suspensions or the like.
• R2 R1 COOB H OH O O OK+ (III)
• the requisite phenylcyclopropanedicarboxylic acid monoester is prepared according to our invention by treatment of a dialkyl benzalmalonate (XI) with trimethylsulfoxonium iodide and strong alkali, e.g. sodium hydride, to yield the corresponding dialkyl phenylcyclopropanedicarboxylate (XII). Selective saponification with one mole of potassium hydroxide then yields the monoester potassium carboxylate (III).
• XI dialkyl benzalmalonate
• trimethylsulfoxonium iodide and strong alkali e.g. sodium hydride
• EXAMPLE -1 A solution of 106 g. (1 mole) of benzaldehyde, 176 g. (1.1 mole) of diethyl malonate, 10 m1. of piperidine and 10 g. of 'benzoic acid is refluxed azeotropically for five hours. The solution is cooled, washed three times with dilute hydrochloric acid, twice with aqueous sodium bicarbonate and twice with water, dried over magnesium sulfate and concentrated to an oil. This material is then distilled at 2 mm.-pressure to yield diethyl benzalmalonate as a colorless liquid.
• the isocyanate ester (5.0 g.) is added to a freshly prepared solution of ml. of concentrated sulfuric acid and 25 ml. of water and stirred at 6070 for about minutes. Any insoluble material is removed by filtration and the filtrate cooled to give an ethyl l-amino-Z-phenylcyclopropanecarboxylate as the sulfate.
• This salt is dissolved in 15 ml. of #30 alcohol and an excess of 10% aqueous sodium hydroxide is added. The solution is heated on a steam bath for thirty minutes during which time the alcohol is allowed to evaporate. The alkaline solution is then adjusted to pH 7 with acetic acid and the crystals which form collected by filtration and suspended in ethyl alcohol.
• This suspension is adjusted to pH 2 with alcoholic hydrochloric acid and filtered.
• the filtrate is flooded with ethyl ether to yield cis-1-amino-2- phenylcyclopropanecarboxylic acid hydrochloride, melting point for the hydrated product 224 (dec.).
• This hydrochloride is dissolved in water and the pH adjusted to 7 with aqueous sodium hydroxide. The solid thus formed is collected to give the free amino acid, cis-lamino-2-phenylcyclopropanecarboxylic acid, M.P. 223 (dec.).
• the corresponding trans isomer of 1-amino-2-(3-hydroxyphenyl)cyclopropanecarboxylic acid is obtained by subjecting the potassium salt of ethyl 1-carboxy-2-(3- benzyloxyphenyl)cyclopropanecarboxylate to the procedure of Example 2 followed by treatment with hydrochloric acid an acetic acid as described in this example.
• this compound is converted into the cis-1-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid whereas by fo1lowing the procedures of Examples 2 and 5 the corresponding trans isomer of l-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid is obtained.
• R2 R1 COOH wherein each of R R and R is a member selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, ethoxy, chloro, bromo, fluoro, trifluoromethyl and benzyloxy and the pharmaceuticallyacceptable acid addition and alkali salts thereof.
• each of R R and R is a member selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, chloro, bromo, fiuoro, trifluoromethyl and 5 benzyloxy, and
• each of B and B is a member selected from the group consisting of hydrogen and lower alkyl.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Citations (2)

• 0
  • GB GB1047268D patent/GB1047268A/en active Active
  • GB GB1047267D patent/GB1047267A/en active Active
• 1963
  • 1963-05-16 US US281037A patent/US3313842A/en not_active Expired - Lifetime
• 1964
  • 1964-05-15 FR FR974711A patent/FR3520M/fr active Active
  • 1964-05-15 BE BE648020D patent/BE648020A/xx unknown

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