DE914973C - Process for the preparation of substituted threo-configured ª ‡ -halogen-ª ‰ -oxy-acylamino-ethanes - Google Patents
Process for the preparation of substituted threo-configured ª ‡ -halogen-ª ‰ -oxy-acylamino-ethanesInfo
- Publication number
- DE914973C DE914973C DEP4575A DE0004575A DE914973C DE 914973 C DE914973 C DE 914973C DE P4575 A DEP4575 A DE P4575A DE 0004575 A DE0004575 A DE 0004575A DE 914973 C DE914973 C DE 914973C
- Authority
- DE
- Germany
- Prior art keywords
- group
- denotes
- threo
- oxy
- halogen
- 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
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000002253 acid Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XODAOBAZOQSFDS-JXMROGBWSA-N (e)-2-acetamido-3-phenylprop-2-enoic acid Chemical compound CC(=O)N\C(C(O)=O)=C\C1=CC=CC=C1 XODAOBAZOQSFDS-JXMROGBWSA-N 0.000 description 2
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- -1 3-methoxy-4-acetoxyphenyl Chemical group 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011491 glass wool Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von substituierten threo-konfigurierten a-Halogen-@-oxy-acylamino-äthanen Verschiedene der in a-Stellung halogenierten ß-Oxyacylamino-äthane der allgemeinen Formel in welcher R1 einen gegebenenfalls substituierten Arylrest, R2 eine gegebenenfalls veresterte Carboxylgruppe und schließlich R3 Wasserstoff oder einen gegebenenfalls substituierten Alkyl-, Aralkyl- oder Arylrest bedeutet, besitzen, wie auf Grund längerer Versuchsreihen gefunden wurde, eine erhebliche antimikrobielle Wirksamkeit oder stellen Vorstufen zur Gewinnung von therapeutisch wertvollen Produkten vor. Allerdings sind erfahrungsgemäß Stoffe der angegebenen Zusammensetzung, welche in der Literatur noch nicht beschrieben sind, nur dann wirksam, wenn sie hinsichtlich der relativen Stellung der Hydroxyl- und der Acylaminogruppe threo-Konfiguration aufweisen, während die gleichen Vertreter der erythro-Reihe unwirksam bzw. bedeutend weniger wirksam sind.Process for the preparation of substituted threo-configured α-halogen - @ - oxy-acylaminoethanes Various of the α-halogenated β-oxyacylaminoethanes of the general formula in which R1 denotes an optionally substituted aryl group, R2 denotes an optionally esterified carboxyl group and finally R3 denotes hydrogen or an optionally substituted alkyl, aralkyl or aryl group, have, as has been found on the basis of lengthy series of tests, considerable antimicrobial activity or are precursors for the production of therapeutically valuable products. However, experience has shown that substances of the specified composition, which have not yet been described in the literature, are only effective if they have a threo configuration with regard to the relative position of the hydroxyl and acylamino groups, while the same representatives of the erythro series are ineffective or significant are less effective.
Es wurde nun gefunden, daß die Verfahrensprodukte mit threo-Konfiguration sich dadurch herstellen lassen, daß man Acylamino-äthylene der allgemeinen Formel in welcher R1 und R2 die oben angegebene Bedeutung haben und X eine gegebenenfalls durch R3 (s. oben) substituierte acylierte Aminogruppe bzw. eine in eine solche umwandelbare Gruppe bedeutet, wobei hier X und R, auch Bestandteile eines gemeinsamen Oxazolinringes sein können, mit unterhalogenigen Säuren oder diese liefernden Mitteln behandelt. Hierbei findet an den gekennzeichneten Ausgangsstoffen unter Dirigierung des Hydroxyls in die ß-Stellung zur Acylaminogruppe stets Addition unter Ausbildung der threo-Konfiguration statt. Dieser Befund muß als außerordentlich überraschend bezeichnet werden und steht in einem gewissen Widerspruch zu den bisherigen Erfahrungen bezüglich der Anlagerung von u. a. Halogen an mehrfache Bindungen, nach denen nämlich fast immer cis- (erythro-) und Irans- (threo-) Addition nebeneinander herlaufen (vgl. Hückel »Theoretische Grundlagen der organischen Chemie«, Bd. I, S. 429, 194q.).It has now been found that the products of the process with a threo configuration can be prepared by using acylaminoethylenes of the general formula in which R1 and R2 have the meaning given above and X is an acylated amino group optionally substituted by R3 (see above) or a group convertible into such a group, where X and R here can also be components of a common oxazoline ring, with hypohalogenous Acids or agents that supply them. In this case, addition always takes place on the marked starting materials, with the hydroxyl being directed into the β-position to the acylamino group, with the formation of the threo configuration. This finding must be described as extraordinarily surprising and stands in a certain contradiction to previous experience with the addition of halogen, among others, to multiple bonds, according to which cis (erythro) and iran (threo) addition almost always run side by side ( See Hückel "Theoretical Foundations of Organic Chemistry", Vol. I, pp. 429, 194q.).
Da die Ausgangsmaterialien größtenteils leicht zugänglich sind, kommt dem vorliegenden Verfahren eine erhebliche technische Bedeutung zu. Beispiele 1. 38 g des Azlactons der a-Acetylamino-zimtsäure (vgl. Organic Syntheses, Coll. Vol. II, i) und 9 g N atriumhydroxyd werden in Zoo ccm Wasser gelöst, und die Lösung wird bei 4° zu einer Auflösung von 32 g Brom und 57 g kristallisierter Soda in 3oo ccm Wasser gegeben. Nach i Stunde wird das Reaktionsgemisch über Glaswolle filtriert und mit 50 ccm konzentrierter Salzsäure angesäuert. Es scheidet sich etwas unveränderte a-Acetylamino-zimtsäure ab, die abfiltriert wird. Das Filtrat wird mit 8oo ccm Äther ausgeschüttelt und der ätherische Extrakt über Natriumsulfat getrocknet. Nach dem Abdampfen des Äthers kristallisiert das Produkt, nämlich threoa-Acetylamino-a-brom-ß-oxy-ß-phenyl-propionsäure, in derben Kristallen vom Schmelzpunkt 176°. Durch Aufarbeitung des wäßrigen Rückstandes kann eine weitere Menge desselben gewonnen werden. Ausbeute insgesamt 8o °/o der Theorie.Since most of the starting materials are easily accessible, the present process is of considerable technical importance. EXAMPLES 1. 38 g of the azlactone of α-acetylamino-cinnamic acid (cf. Organic Syntheses, Coll. Vol. II, i) and 9 g of sodium hydroxide are dissolved in zoo cc of water, and the solution is dissolved at 4 ° 32 g of bromine and 57 g of crystallized soda were added to 300 cc of water. After 1 hour, the reaction mixture is filtered through glass wool and acidified with 50 cc of concentrated hydrochloric acid. Somewhat unchanged α-acetylamino-cinnamic acid separates out and is filtered off. The filtrate is extracted with 800 cc of ether and the ethereal extract is dried over sodium sulfate. After evaporation of the ether, the product, namely threoa-acetylamino-a-bromo-ß-oxy-ß-phenyl-propionic acid, crystallizes in coarse crystals with a melting point of 176 °. A further amount of the same can be obtained by working up the aqueous residue. Total yield 80% of theory.
Der Methylester dieses Produktes läßt sich leicht auf folgende Weise gewinnen: 3o,2 g dieser Säure werden in 150 ccm Methanol gelöst. Die Lösung wird unter Kühlung bei r5° mit trockenem Salzsäuregas gesättigt. Man läßt etwa 3 Stunden stehen und leitet nochmals Salzsäuregas ein. Das Reaktionsgemisch wird im Vakuum eingeengt, wobei der Ester sich zunächst als Öl abscheidet, das durch Verreiben mit Petroläther durchkristallisiert; Schmelzpunkt 1q.6°. Die Ausbeute ist praktisch quantitativ.The methyl ester of this product can be easily prepared in the following way win: 3o.2 g of this acid are dissolved in 150 cc of methanol. The solution will be saturated with dry hydrochloric acid gas while cooling at r5 °. It is left for about 3 hours stand and introduce hydrochloric acid gas again. The reaction mixture is in vacuo concentrated, the ester initially separating out as an oil, which is caused by trituration crystallized with petroleum ether; Melting point 1q.6 °. The yield is practical quantitatively.
2. 11 g des in Befolgung der Arbeitsweise der in Beispiel 1 genannten Literaturstelle aus Vanillin hergestellten Azlactons der ß-(3-Methoxy-4-acetoxyphenyl)-a-acetylamino-acrylsäure (F. 163°) und 4 g Natriumhydroxyd werden in 50 ccm Wasser gelöst. Das Gemisch wird zu einer Lösung von 2,8 g Chlor und 11,6 g Soda in 50 ccm Wasser bei 4° im Laufe von fo Minuten eingetropft. Man läßt über Nacht stehen und säuert mit konzentrierter H Cl an, trennt von geringen Spuren unveränderten Ausgangsmaterials ab und äthert aus. Der Ätherextrakt wird in üblicher Weise zur threo-ß-(3-Methoxy-4-oxy-phenyl)-ß-oxy-a-chlor-a-acetamino-propionsäure aufgearbeitet, die einen Schmelzpunkt von 187° besitzt.2. 11 g of the azlactone prepared in following the procedure mentioned in Example 1 from vanillin reference of the SS (3-methoxy-4-acetoxyphenyl) -a-acetylamino-acrylic acid (163 ° F.) and 4 g of sodium hydroxide in 50 ccm of water dissolved. The mixture is added dropwise to a solution of 2.8 g of chlorine and 11.6 g of soda in 50 cc of water at 4 ° in the course of fo minutes. It is left to stand overnight and acidified with concentrated HCl, small traces of unchanged starting material are separated off and etherified. The ether extract is worked up in the usual way to threo-ß- (3-methoxy-4-oxy-phenyl) -ß-oxy-a-chloro-a-acetaminopropionic acid, which has a melting point of 187 °.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4575A DE914973C (en) | 1950-11-15 | 1950-11-15 | Process for the preparation of substituted threo-configured ª ‡ -halogen-ª ‰ -oxy-acylamino-ethanes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4575A DE914973C (en) | 1950-11-15 | 1950-11-15 | Process for the preparation of substituted threo-configured ª ‡ -halogen-ª ‰ -oxy-acylamino-ethanes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE914973C true DE914973C (en) | 1954-07-12 |
Family
ID=5648103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEP4575A Expired DE914973C (en) | 1950-11-15 | 1950-11-15 | Process for the preparation of substituted threo-configured ª ‡ -halogen-ª ‰ -oxy-acylamino-ethanes |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE914973C (en) |
-
1950
- 1950-11-15 DE DEP4575A patent/DE914973C/en not_active Expired
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