SE186327C1 - - Google Patents

Description

Uppfinnare: I Kollonitsch och A Hajos Prioritet begard fra'n den 31 mars 1955 (Ungern) Estrar av det racemiska /3-(p-nitrofeny1)-serinet har redan separerats i de optiska antipoderna. Sasom framgar av det indiska patentet 48 135 har etylestern av racemiskt erytro-p-nitrofenylserin och etylestern av racemiskt treo-p-nitrofenylserin spjalkats i sina optiska antipoder med dibensoy1-(+)--vinsyra. I. Elphinoff-Felkin, H. Felkin och Z. Welvart redogora vidare (Bulletin de In Soc. Chim. France, rgang 1955, hafte 1, sid. 145) utan narmare uppgifter for spjalkningen av etylestern av racemiskt treo-p-nitrofenylserin med optiskt aktiv mjolksyra. Det fir anmarkningsvart, att etylestern av racemiskt treo-p-nitrofenylserin icke kan spjfilkas i sina optiska antipoder med d-vinsyra. Inventor: In Kollonitsch and A Hajos Priority requested from March 31, 1955 (Hungary) Esters of the racemic / 3- (p-nitrophenyl) serine have already been separated in the optical antipodes. As is apparent from Indian Patent 48,135, the ethyl ester of racemic erythro-p-nitrophenylserine and the ethyl ester of racemic threo-p-nitrophenylserine have been cleaved in their optical antipodes with dibenzoyl - (+) - tartaric acid. I. Elphinoff-Felkin, H. Felkin and Z. Welvart further report (Bulletin de In Soc. Chim. France, vol 1955, hafte 1, p. 145) without further information on the cleavage of the ethyl ester of racemic threo-p-nitrophenylserine with optically active lactic acid. It is noteworthy that the ethyl ester of racemic threo-p-nitrophenylserine cannot be diluted in its optical antipodes with d-tartaric acid.

Det har visat sig att man med utinfirkt utbyte kan spjalka metylestern av det racemiska treo/3-(p-nitrofeny1)-serinet i dess optiska isomerer, om man underkastar d-vinsyresaltet av den racemiska treo - p- (p - nitrofeny1)- serin- metylestern fraktionerad kristallisation och ur de erhallna diastereoisomera salterna utvinner de fria metylestrarna av de optiskt aktiva treo-fi-(pnitrofeny1)-serinerna. It has been found that the methyl ester of the racemic threo-3- (p-nitrophenyl) serine can be cleaved in its optical isomers by inert exchange, if the d-tartaric acid salt of the racemic threo - p- (p - nitrophenyl) is subjected to fractional crystallization of the serine methyl ester and from the resulting diastereoisomeric salts the free methyl esters recover from the optically active threo-fi (pnitrophenyl) serines.

FOr den fraktionerade kristalliseringen al-Milder man som lOsningsmedel lampligen alkoholer. Om man exempelvis som losningsmedel anvander metanol, kristalliserar d-vinsyresaltet av D(—)- treo-i3-(p-nitrofeny1)-serinmetylestern i nastan kvantitativt utbyte ur lOsningen, medan man ur moderlOsningen med kvantitativt utbyte erhaller d-vinsyresaltet av L(+)-treo-kp-nitrofenyI)-seiin-metylestern. For the fractional crystallization al-Milder, alcohols are suitably solvents. For example, if methanol is used as solvent, the d-tartaric acid salt of the D (-) - threo-β- (p-nitrophenyl) -serine methyl ester crystallizes in almost quantitative yield from the solution, while from the parent solution with quantitative yield the d-tartaric acid salt of L ( +) - threo-kp-nitrophenyl) -sezin-methyl ester.

Ur de genom fraktionerad kristallisering separerade diastereoisomera salterna kunna de optiskt aktiva metylestrarna exempelvis utvinnas pa sa satt, att man behandlar salterna med ammoniak i vattenlosning eller med utspadda vattenlosningar av alkalier och dfirigenom frig& den basiska estern. Man kan emellertid aven forfara sd, att man behandlar salterna med i alkohol lost saltsyra och sa forst erhaller hydrokloriden av aminosyraestern och om sa onskas ur hydrokloriden frigor den basiska estern genom alkalisk behandling eller med en jonbytare. From the diastereoisomeric salts separated by fractional crystallization, the optically active methyl esters can be recovered, for example, by treating the salts with ammonia in aqueous solution or with dilute aqueous solutions of alkalis and thereby liberating the basic ester. However, it is also possible to treat the salts with hydrochloric acid dissolved in alcohol and then first obtain the hydrochloride of the amino acid ester and, if desired, release from the hydrochloride the basic ester by alkaline treatment or with an ion exchanger.

Den enligt foreliggande fOrfarande behandlade metylestern av det racemiska treo-fl-(p-nitrofeny1)-serinet har tidigare joke beskrivits. Metylestern kan erhallas ur serin pa vanligt satt genom forestring med metanol. For framstfillning av den nya estern kan man exempelvis fOrfara pa foljande satt. g treo-fl(p-nitrofenyl)serin forsattes med 150 ml med saltsyregas mattad absolut metanol. Dfirefter halles det hela under inledande av saltsyregas och under aterflodeskylning vid kokning i 2 timmar. Lbsningen indunstas darefter till torrhet och den kristalliniska Aterstoden avfiltreras med eter. Man erhaller hydrokloriden av treo -f3-(p-nitrofenyl)serinmetylestern,vilken smfilter vid 193-195° C under sonderdelning. Utbyte omkring 95 %. The methyl ester of the racemic threo-fl- (p-nitrophenyl) serine treated according to the present process has been jokingly described previously. The methyl ester can be obtained from serine in the usual way by esterification with methanol. For the preparation of the new ester, one can, for example, proceed in the following manner. g of threo-fl (p-nitrophenyl) serine was added to 150 ml of hydrochloric acid gas saturated absolute methanol. Then the whole thing is kept under the introduction of hydrochloric acid gas and under reflux when boiling for 2 hours. The solution is then evaporated to dryness and the crystalline residue is filtered off with ether. The hydrochloride of the threo -f3- (p-nitrophenyl) serine methyl ester is obtained, which is filtered at 193-195 ° C with probing. Yield about 95%.

Den sá erhallna hydrokloriden av estern loses i 80 ml vatten och den filtrerade losningen forsattes under iskylning med 100 ml 10 %-ig natriumbikarbonatlosning. Ur den iskylda losningen utskiljer sig i ett omkring 80 %-igt utbyte treo-p-(p-nitrofeny1)-serin-metylestern, vilken under sonderdelning smfilter vid 137-138° C. The resulting hydrochloride of the ester is dissolved in 80 ml of water and the filtered solution is continued under ice-cooling with 100 ml of 10% sodium bicarbonate solution. The threo-p- (p-nitrophenyl) -serine methyl ester differs from the ice-cold solution in an approximately 80% yield, which is filtered at 137-138 ° C during probe division.

De med forfarandet erhallna produkterna firo vardefulla mellanprodukter for framstallning av kloramfenikol. The products obtained by the process were valuable intermediates for the production of chloramphenicol.

Exempel I. 2,40 g treo-fl(p-nitrofenylyserin-metylester och 1,50 g d-vinsyra loses under uppvarmning i 50 ml 2— — metanol. Darefter later man losningen sta over natten vid rumstemperatur. De utskilda vita kristallerna avfiltreras, tvattas med metanol och torkas. Man erhaller i omkring 75 %-igt utbyte d-vinsyresaltet av D(—)-treo.fr(p-nitrofeny1)-serin-metylestern, som smatter vid 169-170° C och i 2 %-ig vattenlosning uppvisar en vridningsformaga av (a)D: —5°. Moderlasningen indunstas till torrhet och aterstoden omkristalliseras ur 3 ml metanol. Man erhaller ytterligare omkring 15 % av namnda salt. Genom indunstning av den har erhallna moderlaisningen erhaller man d-vinsyresaltet av L(—)-treo-(p-nitrofeny1)-serin-metylestern, vilken i rent tillstand smaller vid 149-150° C. Example I. 2.40 g of threo-fl (p-nitrophenylycerin methyl ester and 1.50 g of d-tartaric acid are dissolved under heating in 50 ml of 2-methanol. The solution is then allowed to stand overnight at room temperature. The separated white crystals are filtered off. , washed with methanol and dried to give in about 75% yield the d-tartaric acid salt of the D (-) - threo.fr (p-nitrophenyl) -serine methyl ester, which melts at 169-170 ° C and in 2% The aqueous solution has a torsional shape of (a) D: -5 °. The mother solution is evaporated to dryness and the residue is recrystallized from 3 ml of methanol. An additional 15% of the said salt is obtained. of the L (-) - threo- (p-nitrophenyl) -serine methyl ester, which in its pure state narrows at 149-150 ° C.

Ur det vid hogre temperatur smaltande saltet kan aminosyraestern exempelvis utvinnas pa ftiliande Ott. 0,60 g av saltet blandas med en blandning av 3 ml vatten och 4 ml 10 %-ig natriumbikarbonatlosning. Darefter avfiltreras den utskilda aminosyraestern, tvattas med vatten och torkas. Man erhaller ett omkring 90 %-igt utbyte av D(—)-treo-(p-nitrofeny1)-serin-metylestern, vilken under sonderdelning smaller vid 150 —151° C och i 2 %-ig losning i normal klorvatesyra uppvisar en vridningsformaga av —27°. Utbyte omkring 90 %. From the salt melting at a higher temperature, the amino acid ester can be extracted, for example, on liquid Ott. 0.60 g of the salt is mixed with a mixture of 3 ml of water and 4 ml of 10% sodium bicarbonate solution. The separated amino acid ester is then filtered off, washed with water and dried. An approximately 90% yield of the D (-) - threo- (p-nitrophenyl) -serine methyl ester is obtained, which, during probe division, narrows at 150-151 ° C and in 2% solution in normal chloroacetic acid shows a torsional shape. of —27 °. Yield about 90%.

Det pa liknande satt behandlade vid lagre temperatur smaltande saltet lamnar L(—)-treoA-(p-nitrofeny1)-serin-metylestern, vars smallpunkt ar densamma som den foregaende produktens smaltpunkt. The similarly treated lower melting salt leaves the L (-) - threoA- (p-nitrophenyl) serine methyl ester, the melting point of which is the same as the melting point of the preceding product.

Exempel II. 28,9 g d-vinsyra Aires i 200 ml metanol tills en klar losning erhalles. Man tillsatter 46,1 g treo-13-(p-nitrofeny1)-serin-metylester och cum.& under en timme vid rumstemperatur. Slutligen upphettar man under aterflodeskylning och under omroring under 10 min till kokning. Efter avkylning till rumstemperatur avfiltreras de utskilda kristallerna, tvattas med en liten mangd metanol och torkas vid 60° C i vakuum. Man erhailer 36,85 g (utbyte 98,5 %) av d-vinsyresaltet D(—)-treo-(p-nitrofeny1)-serin-metylestern. Example II. 28.9 g of d-tartaric acid Aires in 200 ml of methanol until a clear solution is obtained. 46.1 g of threo-13- (p-nitrophenyl) -serine methyl ester and cum. Are added over one hour at room temperature. Finally, heat under reflux and stir for 10 minutes until boiling. After cooling to room temperature, the separated crystals are filtered off, washed with a small amount of methanol and dried at 60 ° C in vacuo. 36.85 g (yield 98.5%) of the d-tartaric acid salt D (-) - threo- (p-nitrophenyl) -serine methyl ester are obtained.

Ur indunstningsaterstoden av moderlosningen erhaller man genom omkristallisering i vatten d-vinsyresaltet av L(+)-treo-p-(p-nitrofeny1)-serin-metylestern. From the evaporation residue of the mother solution, the d-tartaric acid salt of the L (+) - threo-p- (p-nitrophenyl) -serine methyl ester is obtained by recrystallization from water.

I det foregaende har de optiskt aktiva isomererna av treo-(p-nitrofenyl)serin-metylestern alltefter konfigurationen hos den intill fenylresten belagna kolatomen betecknats som D- eller L-isomer. De angivna konfigurationerna ha bekraftats genom reduktion av D(—)-p-nitrofenylserin-metylestern med kalciumborhydrid till D(—)-treo- 1- (p- nitrof eny1)- 2- amino-1,3-dihydroxipropan. In the foregoing, the optically active isomers of the threo- (p-nitrophenyl) serine methyl ester have been referred to as the D- or L-isomer according to the configuration of the carbon atom located adjacent to the phenyl residue. The indicated configurations have been confirmed by reduction of the D (-) - p-nitrophenylserine methyl ester with calcium borohydride to D (-) - threo-1- (p-nitrophenyl) -2-amino-1,3-dihydroxypropane.

Claims (3)

Patentansprak:Patent claim: 1. Ftirfarande for utvinning av de optiska isomererna av metylestern av racemiskt treo-fl(p-nitrofeny1)-serin, kannetecknat darav, att man underkastar d-vinsyrasaltet av racemisk treo-19(p-nitrofeny1)-serin-metylester fraktionerad kristallisation och ur de erhallna diastereoisomera salterna pa i och for sig kant satt utvinner de fria metylestrarna av de optiskt aktiva treo-fl(p-nitrofeny1)-serinerna.A process for recovering the optical isomers of the methyl ester of racemic threo-β (p-nitrophenyl) -serine, characterized in that the d-tartaric acid salt of racemic threo-19 (p-nitrophenyl) -serine methyl ester is subjected to fractional crystallization and from the resulting diastereoisomeric salts per se, the free methyl esters recover from the optically active threo-fl (p-nitrophenyl) serines. 2. Forfarande enligt patentanspraket 1, kannetecknat darav, att den fraktionerade kristallisationen genomfores i alkoholer, foretradesvis i metanol.Process according to Claim 1, characterized in that the fractional crystallization is carried out in alcohols, preferably in methanol. 3. Forfarande enligt patentanspraket 1 eller 2, kannetecknat darav, att man ur de vid den fraktionerade kristallisationen separerade diastereoisomera salterna utvinner de motsvarande, optiskt aktiva, basiska aminosyraestrarna genom behandling med en vattenlosning av ammoniak eller med utspadda vattenlosningar av alkalier. Anforda publikationer: Patentskrifter Iron Storbritannien 674 015, 715 876; USA 2 514 377.Process according to Claim 1 or 2, characterized in that the corresponding, optically active, basic amino acid esters are recovered from the diastereoisomeric salts separated in the fractional crystallization by treatment with an aqueous solution of ammonia or with dilute aqueous solutions of alkalis. Request Publications: U.S. Patent Nos. 674,015, 715,876; USA 2,514,377.