GB587244A - Improvements relating to the synthesis of amino acid derivatives and salts thereof - Google Patents

Improvements relating to the synthesis of amino acid derivatives and salts thereof

Info

Publication number
GB587244A
GB587244A GB1399844A GB1399844A GB587244A GB 587244 A GB587244 A GB 587244A GB 1399844 A GB1399844 A GB 1399844A GB 1399844 A GB1399844 A GB 1399844A GB 587244 A GB587244 A GB 587244A
Authority
GB
United Kingdom
Prior art keywords
methyl
hydroxy
alaninium
ethyl
ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB1399844A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
Burroughs Wellcome Co USA
Burroughs Wellcome and Co USA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Burroughs Wellcome Co USA, Burroughs Wellcome and Co USA Inc filed Critical Burroughs Wellcome Co USA
Priority to GB1399844A priority Critical patent/GB587244A/en
Publication of GB587244A publication Critical patent/GB587244A/en
Expired legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58Radicals substituted by nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Phenalkyl compounds of general formula <FORM:0587244/IV/1> wherein R1 represents H or alkyl (1 to 2 carbon atoms), R2 represents alkyl (1 to 5 carbon atoms), R3 represents alkoxy or hydroxyalkylamino (1 to 5 carbon atoms), R4 and R5 each represent H, alkyl (1 to 2 carbon atoms) or alkoxy (1 to 5 carbon atoms), or R4 and R5 together are methylenedioxy, R6 represents H or halogen, n is either zero or 1 and X represents alkylene (2 to 5 carbon atoms of which at least 2 are in the direct chain connecting the nitrogen atom with the COR3 group), and salts thereof, are obtained by treating a secondary phenalkyl amino alcohol having at least 2 carbon atoms in the chain between the phenyl group and the nitrogen atom and with the OH- group attached to the carbon atom in said chain next the ring, with an aliphatic acid ester (3 to 6 carbon atoms) which acid is either substituted by halogen on a carbon atom at least once removed from the carboxy group, or which is an a b -unsaturated acid. Preferably, the reactants are dissolved in a mutual solvent, being refluxed after standing for at least 2 hours; and the desired amino-ester salt is isolated by adding an alkyl alcohol (1 to 5 carbon atoms) and a strong acid to the mixture after refluxing. Conversion of the foregoing esters to the corresponding amides is effected by customary methods, e.g. by treatment with an alkylolamine; advantageously, b -alanine derivatives are amidated by the Stoll method, viz., converting the ester to the corresponding azide, prior to treating with an alkylolamine. Specified compounds obtained according to the invention are: N - methyl - N - (b - hydroxy - b - phenyl) isopropyl b -alanine methyl ester hydrochloride, l - N - methyl - N - (b - hydroxy - b - phenyl) isopropyl b -alanine ethyl ester hydrochloride, N - methyl - N - (b - hydroxy - b - 2 : 5 - dimethoxyphenyl) ethyl b -alanine methyl ester hydrochloride, N - methyl - N - (b - hydroxy - b - 2 : 5 - dimethoxyphenyl) ethyl-b -alanine n-amyl ester hydrochloride, N - methyl - N - (g -carbomethoxypropyl - b - hydroxy - b - 2 : 5 - dimethoxyphenyl) ethylamine hydrochloride, N - methyl - N - (b - hydroxy - b - 2 : 5 - dimethoxyphenyl) ethyl - b - alanine hydroxy ethyl amide acid oxalate, N - methyl - N - (b - hydroxy - b - 3 : 4 - dimethoxyphenyl) ethyl-b -alanine methyl ester hydrochloride, N - methyl - N - (g - carbethoxypropyl - b - hydroxy - b - 3 : 4 - methylenedioxy - 6 - bromo - phenyl) isopropylamine hydrochloride, N - ethyl - N - (b - hydroxy - a - ethyl - b - p - tolyl) ethyl b -alanine-methyl ester hydroiodide, N-methyl-N-(b -hydroxy-b -2-methoxy-5-methyl phenyl) ethyl b -alanine hydrochloride, N-n-amyl-N-(g -hydroxy - g - 3 : 4 - diethoxyphenyl) propyl b -alanine methyl ester phosphate, N-ethyl-N-(e -carbethoxy - n - amyl - b - hydroxy - 4 - methoxy - phenyl) ethyl amine sulphate, N-methyl-N-(g -hydroxy-g -3-amyloxyphenyl) propyl b -alanine methyl ester malate. Many examples are given of the process. The Provisional Specification describes also compounds of general formula <FORM:0587244/IV/2> wherein A represents an anion corresponding to an acid, X represents alkylene (2 to 6 carbon atoms) of which at least 2 are in the direct chain connecting N and -CO-, n is an integer (1 to 5), R1 represents hydroxy or methoxy and alkyl (1 to 5 carbon atoms), R3 represents alkyl (1 to 5 carbon atoms), R4 represents H or alkyl (1 to 5 carbon atoms), R5 represents alkoxy (1 to 5 carbon atoms), R6 represents H or -OH, or alkoxy or alkyl (1 to 5 carbon atoms), R6 represents H, -OH, halogen or alkoxy or alkyl (1 to 5 carbon atoms) or R6 and R7 together represent methylenedioxy, and R8 represents H, halogen or alkyl (1 to 5 carbon atoms). Quaternary salts are obtained by treating the corresponding tertiary bases with alkyl halides or sulphates. Specified phenalkyl ammonium compounds are: N - methyl - N - phenethyl - b - alaninium ethyl ester bromide, N-methyl-N-(b -hydroxy-b -phenylisopropyl)-b -alaninium ethyl- and the corresponding methyl-ester chlorides, N-ethyl-N-(b -2 : 5-dimethylphenylisopropyl)-b -alaninium methyl ester chloride, methyl n-butyl-b - (2 - methyl - 5 - isopropylphenyl) - isopropyl-g -carbomethoxypropyl ammonium iodide, N-ethyl - N - benzyl - N - (b - 3 : 4 - dimethoxyphenylpropyl) - b - alaninium methyl ester chloride, N - methyl - N - (3 : 4 - dimethoxyphenethyl) - b - alaninium ethyl ester chloride, N-methyl-N-(2 : 5 - dimethoxyphenethyl) - b - alaninium ethyl ester chloride, N - methyl - N - homopiperonyl - b - alaninium ethyl ester acid oxalate, methyl-2 : 5-dimethoxyphenethyl - g - carbomethoxypropyl ammonium chloride, l-N-methyl-N-(b -hydroxy-b - 3 : 4 - dimethoxyphenyl) - ethyl - b - alaninium methyl ester chloride, d - N - methyl - N - (b - hydroxy-b -3 : 4-dimethoxyphenyl) isopropyl-b -alaninium methyl ester bromide, N-ethyl-N-methyl-N-(b -hydroxy-b -3 : 4-dimethoxyphenyl) isopropyl b -alaninium ethyl ester iodide, N,N-dimethyl-N-(b -hydroxy-b -3 : 4-dimethoxy-6-chlorophenylisopropyl) - b - alaninium methyl ester chloride, dimethyl-g -carbethoxypropyl-b -hydroxy-b -(3 : 4-methylenedioxy-6-bromophenyl) isopropyl ammonium iodide, N,N-diethyl-N-p-chlorophenethyl - b - alaninium ethyl ester chloride, N-methyl-N-n-propyl-N-(g -hydroxy-g - p - bromophenyl - n - propyl) - b - alaninium methyl ester chloride, N-n-amyl-N-(#s-hydroxy-#s - p - tolylbutyl) - b - alaninium methyl ester malate, l-N-methyl-N-(b -2-hydroxy-5-bromophenylheptyl) - b - alaninium ethyl ester d-tartrate, N-methyl-N-(a -3 : 4-dihydroxybenzyl-n-hexyl)-b -alaninium methyl ester sulphate, methyl - a - (3 - methoxy - 4 - hydroxy - 5 - bromobenzyl) - n - propyl, e - carbethoxy amyl ammonium acid phosphate, N-methyl-N-(3 : 4-dimethoxyphenethyl)-b -alaninium n-amyl ester acid oxalate, N - methyl - N - (4 - methoxy - 3 - chlorophenethyl) - b - alaninium - n - butyl ester chloride, methyl-2 : 3-dimethoxyphenethyl-a -methyl - b - carboisobutoxyethyl ammonium bromide, N - methyl - N - (b - 3 : 4 - dimethoxyphenylisopropyl) - b - alaninium, ethanolamide acid oxalate, N : N - dimethyl - N - (b - hydroxy - b - 3 : 4 - dimethoxyphenylethyl) - b - alaninium b -hydroxyisopropylamide chloride, N-n-butyl-N - (4 - methoxy - 3 - bromophenylisopropyl) - b - alaninium ethanolamide bromide, N-n-propyl-N - (b - methoxy - b - 4 - n - butylphenylethyl) - b - alaninium ethyl ester chloride, N-methyl-N-(#z - hydroxy - #z - 3 : 4 - diethoxyphenylhexyl)-b -alaninium methyl ester bromide, methyl-g -hydroxy - g - mesityl - n - propyl - b - methyl - b -carbomethoxy ethyl ammonium chloride, methyl-2 : 5-dimethylphenethyl-a -n-butyl-b -carbethoxy ethyl ammonium bromide, N - methyl-N-(b -methoxy-b -4-n-propoxyphenylethyl) - b - alaninium methyl ester bromide, methyl - 3 : 4 - dimethoxyphenethyl - #z - carbo - methoxy hexyl ammonium bromide, N-methyl-N-(2-methoxy-5-n-amylphenethyl)-b -aluminium methyl ester nitrate, g - (ethyl - 3 : 4 - dimethoxyphenethylamino) - butyric acid ethanolamide ethochloride, N-methyl-N-(b -4-hydroxy - 3 : 5 - diiodophenylisopropyl) - b - alaninium ethyl ester chloride, dimethyl-3-hydroxy-4-methoxy-6-iodophenethyl-g -carbomethoxy - n - propyl ammonium bromide, N - methyl - N - (p-hydroxyphenethyl) - b - alaninium ethyl ester chloride, N : N - dimethyl - N - (p - hydroxyphenethyl) - b - alaninium ethyl ester chloride. Many examples of the process are also included.
GB1399844A 1944-07-21 1944-07-21 Improvements relating to the synthesis of amino acid derivatives and salts thereof Expired GB587244A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB1399844A GB587244A (en) 1944-07-21 1944-07-21 Improvements relating to the synthesis of amino acid derivatives and salts thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1399844A GB587244A (en) 1944-07-21 1944-07-21 Improvements relating to the synthesis of amino acid derivatives and salts thereof

Publications (1)

Publication Number Publication Date
GB587244A true GB587244A (en) 1947-04-18

Family

ID=10033156

Family Applications (1)

Application Number Title Priority Date Filing Date
GB1399844A Expired GB587244A (en) 1944-07-21 1944-07-21 Improvements relating to the synthesis of amino acid derivatives and salts thereof

Country Status (1)

Country Link
GB (1) GB587244A (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2786045A (en) * 1953-01-21 1957-03-19 Tee Pak Inc Hydroxyacyl-amino acids and their polymers
US2886594A (en) * 1954-12-27 1959-05-12 Sterling Drug Inc N-(2-carbamylalkyl)-aralkylamines
US3936492A (en) * 1969-10-20 1976-02-03 The Kendall Company Monomeric emulsion stabilizers
EP0289070A1 (en) * 1987-04-10 1988-11-02 Duphar International Research B.V Tertiary arylethyl amine derivatives having opiate-antagonistic activity
US5393788A (en) * 1990-07-10 1995-02-28 Smithkline Beecham Corporation Phenylalkyl oxamides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2786045A (en) * 1953-01-21 1957-03-19 Tee Pak Inc Hydroxyacyl-amino acids and their polymers
US2886594A (en) * 1954-12-27 1959-05-12 Sterling Drug Inc N-(2-carbamylalkyl)-aralkylamines
US3936492A (en) * 1969-10-20 1976-02-03 The Kendall Company Monomeric emulsion stabilizers
EP0289070A1 (en) * 1987-04-10 1988-11-02 Duphar International Research B.V Tertiary arylethyl amine derivatives having opiate-antagonistic activity
US5393788A (en) * 1990-07-10 1995-02-28 Smithkline Beecham Corporation Phenylalkyl oxamides

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