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
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- 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
Links
- 150000002148 esters Chemical class 0.000 title description 3
- IWWCCNVRNHTGLV-UHFFFAOYSA-N 1-phenylcyclopropane-1-carboxylic acid Chemical class C=1C=CC=CC=1C1(C(=O)O)CC1 IWWCCNVRNHTGLV-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000001413 amino acids Chemical class 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- -1 phenylcyclopropanedicarboxylic acid ester Chemical class 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- KXTAOXNYQGASTA-UHFFFAOYSA-N 2-benzylidenepropanedioic acid Chemical compound OC(=O)C(C(O)=O)=CC1=CC=CC=C1 KXTAOXNYQGASTA-UHFFFAOYSA-N 0.000 description 2
- TYTIFABDVSLOJD-UHFFFAOYSA-N 2-phenylcyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1C1=CC=CC=C1 TYTIFABDVSLOJD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- VUWPIBNKJSEYIN-UHFFFAOYSA-N diethyl 2-benzylidenepropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CC1=CC=CC=C1 VUWPIBNKJSEYIN-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 2
- MRUPFDZGTJQLCH-SCZZXKLOSA-N (1s,2r)-1-amino-2-phenylcyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@]1(N)C[C@@H]1C1=CC=CC=C1 MRUPFDZGTJQLCH-SCZZXKLOSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- RNAFMUVOYNVRPK-UHFFFAOYSA-N 1-amino-2-(3,4-dihydroxyphenyl)cyclopropane-1-carboxylic acid Chemical class OC(=O)C1(N)CC1C1=CC=C(O)C(O)=C1 RNAFMUVOYNVRPK-UHFFFAOYSA-N 0.000 description 1
- QJIGJBFNKLGGML-UHFFFAOYSA-N 1-amino-2-(3-hydroxyphenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(N)CC1C1=CC=CC(O)=C1 QJIGJBFNKLGGML-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- XDDLXZHBWVFPRG-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 XDDLXZHBWVFPRG-UHFFFAOYSA-N 0.000 description 1
- JAICGBJIBWDEIZ-UHFFFAOYSA-N 3-phenylmethoxybenzaldehyde Chemical compound O=CC1=CC=CC(OCC=2C=CC=CC=2)=C1 JAICGBJIBWDEIZ-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZCUFTCUMEDALHC-UHFFFAOYSA-N CC[K] Chemical compound CC[K] ZCUFTCUMEDALHC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-M cyclopropanecarboxylate Chemical compound [O-]C(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-M 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001874 trioxidanyl group Chemical group [*]OOO[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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 (enrdf_load_stackoverflow) | 1963-05-16 | ||
| GB1047268D GB1047268A (enrdf_load_stackoverflow) | 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 (enrdf_load_stackoverflow) | 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 (enrdf_load_stackoverflow) |
| BE (1) | BE648020A (enrdf_load_stackoverflow) |
| FR (1) | FR3520M (enrdf_load_stackoverflow) |
| GB (2) | GB1047268A (enrdf_load_stackoverflow) |
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 GB1047267D patent/GB1047267A/en active Active
- GB GB1047268D patent/GB1047268A/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 |
|---|---|
| GB1047268A (enrdf_load_stackoverflow) | |
| GB1047267A (enrdf_load_stackoverflow) | |
| BE648020A (enrdf_load_stackoverflow) | 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 |