US3313842A - Phenylcyclopropane carboxylic acids and esters - Google Patents
Phenylcyclopropane carboxylic acids and esters Download PDFInfo
- Publication number
- US3313842A US3313842A US281037A US28103763A US3313842A US 3313842 A US3313842 A US 3313842A US 281037 A US281037 A US 281037A US 28103763 A US28103763 A US 28103763A US 3313842 A US3313842 A US 3313842A
- Authority
- US
- United States
- Prior art keywords
- acid
- amino
- ethyl
- cis
- esters
- 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 - Lifetime
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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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1047267D GB1047267A (ru) | 1963-05-16 | ||
GB1047268D GB1047268A (ru) | 1963-05-16 | ||
US281037A US3313842A (en) | 1963-05-16 | 1963-05-16 | Phenylcyclopropane carboxylic acids and esters |
FR974711A FR3520M (fr) | 1963-05-16 | 1964-05-15 | Médicament hypotenseur a base de nouveaux aminoacides. |
BE648020D BE648020A (ru) | 1963-05-16 | 1964-05-15 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US281037A US3313842A (en) | 1963-05-16 | 1963-05-16 | Phenylcyclopropane carboxylic acids and esters |
Publications (1)
Publication Number | Publication Date |
---|---|
US3313842A true US3313842A (en) | 1967-04-11 |
Family
ID=23075695
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US281037A Expired - Lifetime US3313842A (en) | 1963-05-16 | 1963-05-16 | Phenylcyclopropane carboxylic acids and esters |
Country Status (4)
Country | Link |
---|---|
US (1) | US3313842A (ru) |
BE (1) | BE648020A (ru) |
FR (1) | FR3520M (ru) |
GB (2) | GB1047267A (ru) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954158A (en) * | 1983-08-16 | 1990-09-04 | University Of Georgia Research Foundation, Inc. | 2,3-methanoproline |
US20050222146A1 (en) * | 2003-12-15 | 2005-10-06 | Fryer Andrew M | N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof |
US20060199826A1 (en) * | 2003-12-15 | 2006-09-07 | Takashi Inaba | Cyclopropane compounds and pharmaceutical use thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2936038A1 (de) * | 1979-09-06 | 1981-03-26 | Bayer Ag, 51373 Leverkusen | Verfahren zur herstellung von 1-aminocyclopropan-carbonsaeure und deren derivaten |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3050559A (en) * | 1962-08-21 | Substituted phenylcyclopropylamjnes | ||
US3068283A (en) * | 1960-12-05 | 1962-12-11 | Smith Kline French Lab | (2-phenylcyclopropyl)-ureas, and 2-phenylcyclopropylcarbamoylamines |
-
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
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3050559A (en) * | 1962-08-21 | Substituted phenylcyclopropylamjnes | ||
US3068283A (en) * | 1960-12-05 | 1962-12-11 | Smith Kline French Lab | (2-phenylcyclopropyl)-ureas, and 2-phenylcyclopropylcarbamoylamines |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954158A (en) * | 1983-08-16 | 1990-09-04 | University Of Georgia Research Foundation, Inc. | 2,3-methanoproline |
US20050222146A1 (en) * | 2003-12-15 | 2005-10-06 | Fryer Andrew M | N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof |
US20060199826A1 (en) * | 2003-12-15 | 2006-09-07 | Takashi Inaba | Cyclopropane compounds and pharmaceutical use thereof |
US7351825B2 (en) | 2003-12-15 | 2008-04-01 | Japan Tobacco Inc. | Cyclopropane compounds and pharmaceutical use thereof |
US20080242656A1 (en) * | 2003-12-15 | 2008-10-02 | Japan Tobacco Inc. | N-Substituted-N-Sulfonylaminocyclopropane Compounds and Pharmaceutical Use Thereof |
Also Published As
Publication number | Publication date |
---|---|
GB1047267A (ru) | |
GB1047268A (ru) | |
BE648020A (ru) | 1964-11-16 |
FR3520M (fr) | 1965-09-06 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SMITHKLINE BECKMAN CORPORATION Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 |