CH301435A - Process for the preparation of threo-B-p-nitrophenyl-serine ethyl ester. - Google Patents
Process for the preparation of threo-B-p-nitrophenyl-serine ethyl ester.Info
- Publication number
- CH301435A CH301435A CH301435DA CH301435A CH 301435 A CH301435 A CH 301435A CH 301435D A CH301435D A CH 301435DA CH 301435 A CH301435 A CH 301435A
- Authority
- CH
- Switzerland
- Prior art keywords
- threo
- nitrophenyl
- ethyl ester
- hydrolysis
- oxazolidine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group 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 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims 4
- 238000006460 hydrolysis reaction Methods 0.000 claims 4
- -1 2-p-nitrophenyl -4-carbethoxy-5-p-nitrophenyl oxazolidine Chemical compound 0.000 claims 2
- 230000001419 dependent effect Effects 0.000 claims 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 229960005091 chloramphenicol Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Verfahren zur Herstellung von threo-ss-p-Nitrophenyl-serinäthylester. Die vorliegende Erfindung betrifft die Herstellung von threo-ss-p-Nitrophenyl-serin- estern der allgemeinen Formel
EMI0001.0006
in welcher R einen Alkyl- oder Aralkylrest bedeutet. Diese Verbindungen sind wertvolle Zwisehenprodukte für die Gewinnung von Chloramphenicol.
Vorliegendes Patent hat ein Verfahren zur Herstellung eines :dieser Serinester zum Ge genstand, nämlich des threo-ss-p-Nitrophenyl- szerinäthylesters. Dieses Verfahren ist dadurch gekennzeichnet, dass man Glykokolläthylester mit der doppeltmolaren Menge p-Nitrobenzal- dehyd kondensiert, wobei man ein Gemisch der stereoisomeren threo- und erythro-Formen des 2-p-Nitrophenyl-4-carbäthoxy-5-p-nitro- phenyl-oxazolidins erhält,
dass man aus diesem Isomerengemisch die erythro-Form abtrennt, das verbleibende threo-Isomere in saurem Milieu hydrolysiert und das so gebildete Salz des threo-ss-p-Nitrophenyl-serinäthylesters mit einem alkalischen Mittel umsetzt, um die freie Esterbase zu erhalten.
Der so gebildete threo-ss-p-Nitrophenyl- serinäthylester ist eine schon bekannte Sub stanz, welche als Racemat vorliegt und deren sämtliche optische Isomeren (D, L und DL) als Zwischenprodukte für die Gewinnung von Chloramphenicol dienen.
Der erfindungsgemässe Verfahren ist durch folgendes Formelschema veranschaulicht
EMI0002.0001
Die Kondensation des p-Nitrobenzaldehyds mit Glykokolläthylester wird vorzugsweise in einem hydroxylgruppenhaltigen Lösungsmit tel, wie Äthanol oder Methanol, ausgeführt, zweckmässig bei einer Temperatur von liöeli- stens 40 C.
Nach Beendigung der Reaktion lässt man, nach Abtrennung des in fester Form ausgeschiedenen DL-erytliro-2-p-Nitro- phenyl--l-carbäthoxy -5-p-nitropheny1-oxazoli- dins, auf das in der Mutterlauge verbliebene threo-Isoniere ein vorzugsweise wasserfreies, saures Lösungsmittel, wie Eisessig oder halo genwasserstoffhaltigen Alkohol, einwirken, z. B. indem man für kurze Zeit erwärmt. Das Reaktionsgemisch, welches nun ein Salz des threo-''-p-Nitrophenyl-serinäthylesters enthält, wird z.
B. durch vollständiges Eindampfen im Vakuum und Extraktion des Rückstandes mit Nasser aufgearbeitet, worauf die wässe rige Phase (Salz), gewöhnlich nach Entfär- bung und Filtration, mit einem alkalischen Mittel, z. B. Ammoniak, umgesetzt wird, wo bei der threo-ss-p-Nitrophenyl-serinäthylester in fester Form ausfällt und durch L?mkristal- lisieren in einem geeigneten Lösungsmittel wie Alkohol gereinigt werden kann.
Wenn man -ünscht, kann man < las so erhaltene Raeeniat, z. B. über das Bromeanipliersttlfosäui-e-@alz und fraktionierte Kristallisation desselben, in die optisch aktiven D- und L-Forinen aufspal- t en.
Das bei der Kondensation als Nebenprodukt. erhaltene DL-erythro-2-p-Nitrophen y1--l-carb- ätlioxy-5-p-nitrophenyl-oxazolidin kann eben- fatls sauer verseift und das;
-ebildete DL- ery thro-#)-p-Nitroplienyl -serinätliyl ester-.salz isoliert und durch Isomerisation in die tlireo- Verbindung umgelagert werden, so dass es für die Synthese des Endproduktes nicht verlo ren geht.
Das erfindun,sgeinässe Verfahren sei an Hand folgenden Beispiels näher erläutert <I>Beispiel:</I> 62 Gewichtsteile p-Nitrobenzaldehyd wer den in 800 Raumteilen Alkohol heiss gelöst, dann auf Raumtemperatur abgekühlt und mit 21,5 Gewichtsteilen Glykol@oll.-äthylester ver setzt.
Nach etwa 1 Stunde beginnt eine Kri- stallabseheidung. Nach weiteren 1:1 Stunden saugt man das DL-erythro-2-p-Nitrophenyl- 4-carbäthoxy-5-p-nitrophenyl-oxazolidin ab und wäscht es mit. kaltem Äther (Ausbeute = 20,5 (ewiehtsteile). Durch Einengen der Mut können noch weitere 16,5 Gewichts- leilc eryt.lrr-o-Oxazoliclin erhalten werden. Aus :1lkohol umgelöst, schmilzt es bei 152-154 C.
Die das threo-Isomere enthaltende Mutter- lauge wird im Vakuum der Wasserstrahl- punrpe bei 30--10 C vollständig eingedampft. Naeli Zugabe von 50 Raumteilen 30oloiger alkolioliseher Salzsäure erwärmt man 5 1Vlinu- teri auf dem Wasserbad, versetzt das Reak- lioris@,-eiriiselr dann,
eventuell naelr Eindamp- fen irn Vakuum, mit<B>100</B> Raumteilen Wasser und zieht. das Gemisch mit 10 Raumteilen Essigester aus. Die wässrige Phase wird nach Zugabe von Tierkohle filtriert, gekühlt und mit konzentriertem Ammoniak bis zur stark alkalischen Reaktion versetzt, worauf sich der unreine DL-threo-ss-p-Nitrophenyl-serinäthyl- ester allmählich abscheidet.
Durch Umlösen aus Alkohol erhält man den reinen Ester vom Schmelzpunkt 137-139 C.
Ausbeute: 7,$ Gewichtsteile.
Process for the preparation of threo-ss-p-nitrophenyl-serine ethyl ester. The present invention relates to the preparation of threo-ss-p-nitrophenyl-serine esters of the general formula
EMI0001.0006
in which R denotes an alkyl or aralkyl radical. These compounds are valuable intermediate products for the production of chloramphenicol.
The subject of the present patent is a process for the production of one of these serine esters, namely the threo-ss-p-nitrophenyl serine ethyl ester. This process is characterized in that glycocollethyl ester is condensed with twice the molar amount of p-nitrobenzaldehyde, a mixture of the stereoisomeric threo and erythro forms of 2-p-nitrophenyl-4-carbethoxy-5-p-nitro-phenyl -oxazolidins receives,
that the erythro form is separated from this isomer mixture, the remaining threo isomer is hydrolyzed in an acidic medium and the salt of threo-ss-p-nitrophenyl-serine ethyl ester thus formed is reacted with an alkaline agent in order to obtain the free ester base.
The threo-ss-p-nitrophenyl serine ethyl ester formed in this way is an already known substance which is present as a racemate and all of the optical isomers (D, L and DL) of which serve as intermediates for the production of chloramphenicol.
The method according to the invention is illustrated by the following equation
EMI0002.0001
The condensation of p-nitrobenzaldehyde with glycocollethyl ester is preferably carried out in a hydroxyl-containing solvent, such as ethanol or methanol, expediently at a temperature of at least 40 ° C.
After the reaction has ended, after the DL-erytliro-2-p-nitrophenyl-1-carbethoxy -5-p-nitropheny1-oxazolidine has separated off in solid form, the threo-isonate remaining in the mother liquor is allowed to react a preferably anhydrous, acidic solvent, such as glacial acetic acid or halogenated hydrogen-containing alcohol, act, for. B. by heating for a short time. The reaction mixture, which now contains a salt of threo -''- p-nitrophenyl-serine ethyl ester, is z.
B. worked up by complete evaporation in vacuo and extraction of the residue with water, whereupon the aqueous phase (salt), usually after decolorization and filtration, with an alkaline agent, eg. B. ammonia, where the threo-ss-p-nitrophenyl-serine ethyl ester precipitates in solid form and can be purified by crystallizing it in a suitable solvent such as alcohol.
If you wish, you can read the Raeeniat thus obtained, e.g. B. via the Bromeanipliersttlfosäui-e- @ alz and fractional crystallization of the same, split into the optically active D and L forins.
The by-product of condensation. DL-erythro-2-p-nitrophen y1-l-carb-ätlioxy-5-p-nitrophenyl-oxazolidine can also be acid hydrolyzed fatls and that;
-formed DL ery thro - #) - p-nitroplienyl -serinätliyl ester-.salz are isolated and rearranged by isomerization into the tlireo compound, so that it is not lost for the synthesis of the end product.
The process according to the invention will be explained in more detail using the following example <I> Example: </I> 62 parts by weight of p-nitrobenzaldehyde are dissolved in 800 parts by volume of hot alcohol, then cooled to room temperature and treated with 21.5 parts by weight of Glykol@oll.- ethyl ester ver sets.
After about 1 hour, crystals begin to separate out. After a further 1: 1 hours, the DL-erythro-2-p-nitrophenyl-4-carbethoxy-5-p-nitrophenyl-oxazolidine is filtered off and washed with it. cold ether (yield = 20.5 parts by weight). By reducing courage, a further 16.5 parts by weight of eryt.lrr-o-oxazoliclin can be obtained. From: 1l alcohol, it melts at 152-154 C.
The mother liquor containing the threo isomer is completely evaporated in the vacuum of the water jet pump at 30-10 ° C. Add 50 parts by volume of 30-vol. Alcoholic hydrochloric acid, heat 5 1 vlinuters on the water bath, then add the reac- lioris @, - eiriiselr,
possibly after evaporation in a vacuum, with <B> 100 </B> spatial parts water and draws. the mixture with 10 parts by volume of ethyl acetate. After the addition of animal charcoal, the aqueous phase is filtered, cooled and concentrated ammonia is added until a strongly alkaline reaction occurs, whereupon the impure DL-threo-ss-p-nitrophenyl-serine ethyl ester gradually separates out.
The pure ester with a melting point of 137-139 C.
Yield: $ 7 parts by weight.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH301435T | 1951-11-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH301435A true CH301435A (en) | 1954-09-15 |
Family
ID=4491033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH301435D CH301435A (en) | 1951-11-09 | 1951-07-31 | Process for the preparation of threo-B-p-nitrophenyl-serine ethyl ester. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH301435A (en) |
-
1951
- 1951-07-31 CH CH301435D patent/CH301435A/en unknown
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