NO115758B - - Google Patents
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- NO115758B NO115758B NO16394666A NO16394666A NO115758B NO 115758 B NO115758 B NO 115758B NO 16394666 A NO16394666 A NO 16394666A NO 16394666 A NO16394666 A NO 16394666A NO 115758 B NO115758 B NO 115758B
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- parts
- piperidyl
- phenyl
- racemate
- antipodes
- Prior art date
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- 238000000034 method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 235000011118 potassium hydroxide Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- -1 methylenedioxy group Chemical group 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- GPOGKMPXBDGPJH-UHFFFAOYSA-N butan-2-yl acetate hydrochloride Chemical compound Cl.CCC(C)OC(C)=O GPOGKMPXBDGPJH-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- E—FIXED CONSTRUCTIONS
- E06—DOORS, WINDOWS, SHUTTERS, OR ROLLER BLINDS IN GENERAL; LADDERS
- E06B—FIXED OR MOVABLE CLOSURES FOR OPENINGS IN BUILDINGS, VEHICLES, FENCES OR LIKE ENCLOSURES IN GENERAL, e.g. DOORS, WINDOWS, BLINDS, GATES
- E06B7/00—Special arrangements or measures in connection with doors or windows
- E06B7/28—Other arrangements on doors or windows, e.g. door-plates, windows adapted to carry plants, hooks for window cleaners
- E06B7/30—Peep-holes; Devices for speaking through; Doors having windows
-
- E—FIXED CONSTRUCTIONS
- E06—DOORS, WINDOWS, SHUTTERS, OR ROLLER BLINDS IN GENERAL; LADDERS
- E06B—FIXED OR MOVABLE CLOSURES FOR OPENINGS IN BUILDINGS, VEHICLES, FENCES OR LIKE ENCLOSURES IN GENERAL, e.g. DOORS, WINDOWS, BLINDS, GATES
- E06B5/00—Doors, windows, or like closures for special purposes; Border constructions therefor
- E06B5/10—Doors, windows, or like closures for special purposes; Border constructions therefor for protection against air-raid or other war-like action; for other protective purposes
- E06B5/16—Fireproof doors or similar closures; Adaptations of fixed constructions therefor
- E06B5/162—Fireproof doors having windows or other openings, e.g. for permitting ventilation or escape
-
- E—FIXED CONSTRUCTIONS
- E06—DOORS, WINDOWS, SHUTTERS, OR ROLLER BLINDS IN GENERAL; LADDERS
- E06B—FIXED OR MOVABLE CLOSURES FOR OPENINGS IN BUILDINGS, VEHICLES, FENCES OR LIKE ENCLOSURES IN GENERAL, e.g. DOORS, WINDOWS, BLINDS, GATES
- E06B3/00—Window sashes, door leaves, or like elements for closing wall or like openings; Layout of fixed or moving closures, e.g. windows in wall or like openings; Features of rigidly-mounted outer frames relating to the mounting of wing frames
- E06B3/54—Fixing of glass panes or like plates
- E06B3/58—Fixing of glass panes or like plates by means of borders, cleats, or the like
- E06B3/5892—Fixing of window panes in openings in door leaves
Landscapes
- Engineering & Computer Science (AREA)
- Civil Engineering (AREA)
- Structural Engineering (AREA)
- Special Wing (AREA)
- Hydrogenated Pyridines (AREA)
Description
Fremgangsmåte til omdannelse av stereoisomere. Process for conversion of stereoisomers.
Framstillingen av a-fenyl-a-piperidyl-(2)-eddiksyrer og deres funksjonelle syrederivater, slik som estere og amider samt deres. funksjonelle avledning e;r kjent (sml. f. eks. fransk patent nr. 908.782). Estrene, særlig a-fenyl-a-piperidyl-(2)-ed-diksyremetylesteren med formelen The preparation of α-phenyl-α-piperidyl-(2)-acetic acids and their functional acid derivatives, such as esters and amides as well as their. functional derivations are known (cf. e.g. French patent no. 908,782). The esters, especially the α-phenyl-α-piperidyl-(2)-acetic acid methyl ester of the formula
utmerker seg ved en stimulerende virk-Det ble nu funnet at de ved deres distinguished by a stimulating effect-It was now found that they by their
ning. syntese erholdte a-fenyl-«-piperidyl-(2)-eddiksyrer eller deres funksjonelle syrederivater ved hjelp av fysikalske midler, særlig krystallisasjon, kan spaltes i 2 racemater. Derved viser det seg at ved ester-racematene tilkommer alltid bare et av de nothing. synthesis obtained α-phenyl-«-piperidyl-(2)-acetic acids or their functional acid derivatives by means of physical means, in particular crystallization, can be resolved into 2 racemates. Thereby it turns out that only one of them is always added to the ester racemates
ovenfor nevnte terapeutiske egenskaper mens det andre praktisk talt alltid er uvirksomt. Videre kunne også begge de optiske aktive antipoder av de farmalo-gisk virksomme racemater framstilles. Den ene av disse har en vesentlig større tera-peutisk virkning enn den andre. above mentioned therapeutic properties while the other is practically always inactive. Furthermore, both optically active antipodes of the pharmacologically active racemates could also be produced. One of these has a significantly greater therapeutic effect than the other.
I det følgende betegnes nå de farmakologisk virksomme esterracemater og In what follows, the pharmacologically active ester racemates are now designated as and
deres optisk aktive antipoder, samt de til disse tilsvarende racemater og antipoder av syrer og syrederivater med bokstavet their optically active antipodes, as well as those of these corresponding racemates and antipodes of acids and acid derivatives with the letter
b, idet b, kjennetegner den farmakologisk virksomme ester-antipode og b2 den mindre virksomme ester-antipode eller de tilsvarende syrer og syrederivater. De andre racemater skal nevnes som a-racemater og de til disse tilsvarende antipoder som a-antipoder og nærmere som a,- og a2-antipoder. b, where b characterizes the pharmacologically active ester antipode and b2 the less active ester antipode or the corresponding acids and acid derivatives. The other racemates are to be mentioned as a-racemates and those corresponding to these antipodes as a-antipodes and more precisely as a,- and a2-antipodes.
En videre gjenstand for oppfinnelsen består i en framgangsmåte til å omdanne a-racemater eller a-antipoder til de som legemiddel eller som utgangsstoffer til framstilling av disse verdifulle racemater henholdsvis antipoder fra b-rekken. Denne framgangsmåte består i at man behandler a-racemater eller a-antipoder av a-f enyl-a-piperidyl- (2) -eddiksyrer eller deres funksjonelle derivater med alkaliske midler, eventuelt av framgangsmåtepro-duktene isolerer b-racematene eller b-antipodene og, om ønskes før eller etter isoleringen omdanner den frie henholdsvis funksjonelt avledede karboksylgruppe.. A further object of the invention consists in a method for converting a-racemates or a-antipodes into those used as medicine or as starting materials for the production of these valuable racemates or antipodes from the b-series. This method consists in treating a-racemates or a-antipodes of a-phenyl-a-piperidyl-(2)-acetic acids or their functional derivatives with alkaline agents, possibly isolating the b-racemates or b-antipodes from the process products and, if desired before or after isolation, convert the free or functionally derived carboxyl group..
Som utgangsstoffer kan man anvende rene a-racemater, a-antipoder eller racemat-blandinger av a-fehyl-a-piperidyl-(2)-eddiksyrer eller deres funksjonelle syrederivater, slik som estere, særlig av lavere alkanoler, framfor alt av metanol eller amider. Fenylresten kan være substi-tuert med en metoksy- elier metylendiok-sygruppe. Fortrinsvis anvender man a-racemater eller a,-antipodene av usubsti-tuert a-f enyl-a-piperidyl-(2)eddiksyre eller deres funksjonelle derivater. Alkaliske midler er f. eks. alkali- eller jordal-kalihydroksyder eller -alkoholater eller sterke organiske baser, som f. eks. trime-tyl-bensyl-ammoniumhydroksyd, som fortrinsvis anvendes ved forhøyet temperatur. As starting materials, one can use pure α-racemates, α-antipodes or racemate mixtures of α-fehyl-α-piperidyl-(2)-acetic acids or their functional acid derivatives, such as esters, especially of lower alkanols, above all of methanol or amides. The phenyl radical can be substituted with a methoxy or methylenedioxy group. Preferably, α-racemates or the α,-antipodes of unsubstituted α-phenyl-α-piperidyl-(2)acetic acid or their functional derivatives are used. Alkaline agents are e.g. alkali or alkaline earth potassium hydroxides or alcoholates or strong organic bases, such as e.g. trimethyl-benzyl-ammonium hydroxide, which is preferably used at an elevated temperature.
Idet man går ut fra a-racemater eller racematblandinger får man blandinger av a- og b-racemater. Anvender man imidlertid a-antipoder, fåes på overraskende måte ikke racemater men optisk aktive framgangsmåteprodukter, idet det av a^ antipoder dannes b,-antipoder med motsatt dreining og av a2- på analog måte b2-antipoder. Derav framgår at motsatt det som skulle ventes, finner omleiringen ifølge framgangsmåten sted bare ved et av begge de asymmetriske kullstoffatomer. Starting from a-racemates or racemate mixtures, you get mixtures of a- and b-racemates. However, if a-antipodes are used, surprisingly not racemates are obtained but optically active process products, since a^ antipodes form b,-antipodes with opposite rotation and b2-antipodes are formed from a2- in an analogous manner. From this it appears that, contrary to what would be expected, the rearrangement according to the procedure only takes place at one of the two asymmetric carbon atoms.
De a-racemater som skal anvendes som untgangsstoffer lar seg f. eks. fram-stille ifølge den i det ovenfor nevnte franske patent nr. 908782 beskrevne framgangsmåte, a-antipodene kan framstilles ved hjelp av optisk aktiv vinsyre fra a-racematene ifølge vanlige framgangs-måter. The a-racemates that are to be used as precursors can e.g. produce according to the method described in the above-mentioned French patent no. 908782, the α-antipodes can be produced using optically active tartaric acid from the α-racemates according to usual methods.
Racematene som fåes ifølge framgangsmåten og antipodene av a-fenyl-a-piperidyl-(2)-eddiksyrer eller deres derivater, særlig b-racematet og b,-antipoden av a-f enyl-a-piperidyl-(2)-eddiksyremetyl-esteren kan anvendes som legemiddel eller som mellomprodukt. The racemates obtained according to the procedure and the antipodes of a-phenyl-a-piperidyl-(2)-acetic acids or their derivatives, in particular the b-racemate and the b,-antipode of the a-phenyl-a-piperidyl-(2)-acetic acid methyl ester can used as a medicine or as an intermediate.
Oppfinnelsen beskrives nærmere i de følgende eksempler. Mellom vektsdel og volumdel består det samme forhold som mellom gram og kubikcentimeter. Tempe-raturene er angitt i Celsiusgrader. The invention is described in more detail in the following examples. Between weight part and volume part there is the same relationship as between grams and cubic centimeters. The temperatures are indicated in degrees Celsius.
Eksempel 1: Example 1:
50 vektsdeler a-f enyl-a-piperidyl-(2)-eddiksyre-metylester-hydroklorid med et innhold av ca. 20 pst. b-racemat, framstilt ifølge det som er angitt i fransk patent nr. 908782, eksempel 1, oppløses i lite vann, oversj iktes med eter og tilsettes 1,5 ekvivalenter vandig 50 pst. kalilut. Etter ut-skilling av det eteriske sjikt ekstraherer man det vandige sjikt ennå to ganger med eter og inndamper deretter de forenede eteroppløsninger til tørrhet. Resten utgjør 43 vektsdeler. Det blandes med 50 vektsdeler kaliumhydroksyd oppløst i 100 volumdeler vann, og blandingen kokes 4 timer med tilbakeløpskjøler Ved avkjøling skil-ler reaksjonsoppløsriingen seg i to sjikt. Det øvre består av en blanding av kaliumsalter av begge de stereoisomere a-fenyl-a-piperidyl- (2) -eddiksyreracemater, som blir fast etter noen timers henstand ved 20°. Det fortynnes med 110 volumdeler 50 parts by weight of α-phenyl-α-piperidyl-(2)-acetic acid methyl ester hydrochloride with a content of approx. 20 per cent b-racemate, prepared according to what is stated in French patent no. 908782, example 1, is dissolved in a little water, covered with ether and 1.5 equivalents of aqueous 50 per cent potassium hydroxide are added. After separation of the ethereal layer, the aqueous layer is extracted twice more with ether and the combined ether solutions are then evaporated to dryness. The rest amounts to 43 parts by weight. It is mixed with 50 parts by weight of potassium hydroxide dissolved in 100 parts by volume of water, and the mixture is boiled for 4 hours with a reflux condenser. On cooling, the reaction solution separates into two layers. The upper one consists of a mixture of potassium salts of both stereoisomeric α-phenyl-α-piperidyl-(2)-acetic acid racemates, which become solid after standing for a few hours at 20°. It is diluted with 110 parts by volume
vann og innstilles med 137 volumdeler 2-n. svovelsyre til pH = 6,0. b-racematet av a-fenyl-a-piperidyl-(2)-eddiksyren faller ut, mens a-racematet forblir i oppløsning. Bunnfallet er kornet og lar seg godt suge fra. Det veier etter flere timers tørkning ved 100° 24,2 vektsdeler og består av rent b-racemat av a-fenyl-a-piperidyl-(2)-ed-dikksyre. water and set with 137 parts by volume 2-n. sulfuric acid to pH = 6.0. The b-racemate of the a-phenyl-a-piperidyl-(2)-acetic acid precipitates out, while the a-racemate remains in solution. The sediment is granular and can be easily sucked off. It weighs after several hours of drying at 100° 24.2 parts by weight and consists of pure b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid.
Gjenforestringen til b-racemater av a-f enyl-a-piperidyl- (2) - eddiksyreestere og dannelse av deres hydroklorider kan fore-gå på i og for seg kjent måte. The re-esterification to b-racemates of α-phenyl-α-piperidyl-(2)-acetic acid esters and formation of their hydrochlorides can take place in a manner known per se.
Metylester-hydrokloridet f. eks. får man ved oppslemming av 1 vektsdel b-racemat av a-fenyl-a-piperidyl-(2)-eddik-syre i 3,5 volumdeler metanol og to timers kokning med tilbakeløpskjøler under gjen-nomledning av tørr klorvannstoff. Etter avkjølingen av oppløsningen krystalliserer b-racematet av a-fenyl-a-piperidyl-(2)-eddiksyremetylesterhydrokloridet i fine prismer med smeltepunkt = 208—209°. The methyl ester hydrochloride e.g. is obtained by suspending 1 part by weight of the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid in 3.5 parts by volume of methanol and boiling for two hours with a reflux condenser while passing through dry hydrogen chloride. After cooling the solution, the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid methyl ester hydrochloride crystallizes in fine prisms with melting point = 208-209°.
b-racematet av butylester-hydrokloridet fåes på analog måte ved to timers om-røring av 1 vektsdel b-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre i 4 volumdeler n-butanol i klorvannstoff-strøm ved 80°. Det ved avkjøling krystalliserende b-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre-butylester-hydroklorid kan omkrystalliseres av aceton og smelter ved 165°. The b-racemate of the butyl ester hydrochloride is obtained in an analogous manner by stirring for two hours 1 part by weight of the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid in 4 parts by volume of n-butanol in a stream of hydrogen chloride at 80° . The b-racemate of α-phenyl-α-piperidyl-(2)-acetic acid butyl ester hydrochloride that crystallizes on cooling can be recrystallized from acetone and melts at 165°.
Eksempel 2: Example 2:
116 vektsdeler a-racemat av a^-fenyl-a-piperidyl- (2)-eddiksyre-hydroklorid kokes 116 parts by weight of a-racemate of a^-phenyl-a-piperidyl-(2)-acetic acid hydrochloride are boiled
med 2000 vektsdeler kaliumhydroksyd, opp-løst i 2000 volumdeler vann, i 5 timer og med tilbakeløpskjøler. Deretter nøytralise-rer man hele reaksjonsoppløsningen med with 2000 parts by weight of potassium hydroxide, dissolved in 2000 parts by volume of water, for 5 hours and with a reflux condenser. The entire reaction solution is then neutralized with
saltsyre til pH = 6,0 under samtidig fortynning med vann til 10 000 volumdeler. Det utfelles et kornet bunnfall som består av en blanding av kaliumklorid og b-racemat av a-f enyl-a-piperidyl-(2)-eddiksyre. Kaliumkloridet kan man fjerne ved ut-vasking med vann. Man får således 69 vektsdeler b-racemat av a-f enyl-a-piperidyl-(2)-eddiksyre, som lar seg forestre etter det som er angitt i eksempel 1. Til forestring kan man imidlertid også arbeide med en blanding av kaliumklorid og b-racemat. hydrochloric acid to pH = 6.0 while simultaneously diluting with water to 10,000 parts by volume. A granular precipitate is precipitated consisting of a mixture of potassium chloride and the b-racemate of α-phenyl-α-piperidyl-(2)-acetic acid. The potassium chloride can be removed by washing out with water. You thus get 69 parts by weight of the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid, which can be esterified according to what is stated in example 1. For esterification, however, you can also work with a mixture of potassium chloride and b- race food.
Det som utgangsmateriale anvendte a-racemat av a-fenyl-a-piperidyl-(2)-ed-diksyre-hydroklorid kan f. eks. fremstilles som følger: 50 vektsdeler a-fenyl-a-piperidyl-(2)- eddiksyre-hydroklorid med et innhold av ca. 20 pst. b-racemat behandles som angitt i eksempel 1 med kalilut. Den utskilte blanding av kaliumsalter av stereoisomere a-f enyl-a-piperidyl-(2)-eddiksyre-racemater fortynnes med 110 volumdeler vann og innstilles med 137 volumdeler 2-n. saltsyre på pH = 6. Det utfelte b-racemat suges fra, og moderluten inndampes til tørrhet. Resten omkrystalliseres av 6-n. saltsyre. Man får således rent a-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre-hydroklorid. The a-racemate of a-phenyl-a-piperidyl-(2)-acetic acid hydrochloride used as starting material can e.g. is prepared as follows: 50 parts by weight of a-phenyl-a-piperidyl-(2)- acetic acid hydrochloride with a content of approx. 20 percent of the b-racemate is treated as indicated in example 1 with potassium hydroxide. The separated mixture of potassium salts of stereoisomeric α-phenyl-α-piperidyl-(2)-acetic acid racemates is diluted with 110 parts by volume of water and adjusted with 137 parts by volume of 2-n. hydrochloric acid at pH = 6. The precipitated b-racemate is sucked off, and the mother liquor is evaporated to dryness. The remainder is recrystallized by 6-n. hydrochloric acid. Pure a-racemate of a-phenyl-a-piperidyl-(2)-acetic acid hydrochloride is thus obtained.
Eksempel 3: Example 3:
25 vektsdeler rå a-fenyl-a-piperidyl-(2)-acetamid, fremstilt ved katalytisk hy-drering av «-f enyl-a-piperidyl-(2)-acet-amid ifølge det som er angitt i eksempel 1 i fransk patent nr. 908 782, med et innhold av ca. 30 pst. b-racemat kokes med 25 vektsdeler kaliumhydroksyd, oppløst i 50 volumdeler vann, i 10 timer med tilbake-løpskjøler. Etter avkjøling utfelles 23,5 vektsdeler av en racematblanding av a-fenyl-a-piperidyl-(2)-acetamid med forhøyet innhold av b-racemat, som suges fra, vaskes med litt koldt vann og forsåpes ved 6 timers kokning med 47 volumdeler 40 pst. svovelsyre til a-f enyl-a-piperidyl-(2)-ed-diksyre. Forsåpningsoppløsningen innstilles med kalilut på pH = 6,0 under samtidig fortynning med vann til 400 volumdeler. Det faller ut 19 vektsdeler b-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre, som man kan forestre ifølge eksempel 1. 25 parts by weight of crude α-phenyl-α-piperidyl-(2)-acetamide, prepared by catalytic hydrogenation of α-phenyl-α-piperidyl-(2)-acetamide according to what is indicated in Example 1 in French patent no. 908 782, with a content of approx. 30 percent b-racemate is boiled with 25 parts by weight of potassium hydroxide, dissolved in 50 parts by volume of water, for 10 hours with a reflux condenser. After cooling, 23.5 parts by weight of a racemate mixture of a-phenyl-a-piperidyl-(2)-acetamide with an elevated content of b-racemate are precipitated, which are sucked off, washed with a little cold water and saponified by boiling for 6 hours with 47 parts by volume 40 per cent sulfuric acid to α-phenyl-α-piperidyl-(2)-acetic acid. The saponification solution is adjusted with caustic soda to pH = 6.0 while simultaneously diluting with water to 400 parts by volume. 19 parts by weight of the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid precipitates, which can be esterified according to example 1.
Eksempel 4: Example 4:
500 vektsdeler rå, ifølge eksempel 1 i fransk patent nr. 908 782 fremstilt a-fenyl-a-piperidyl-(2)-acetamid med et innhold av a-racemat på 68 pst. oppløses i 2000 volumdeler absolutt etylalkohol, oppløsningen mettes med tørr klorvannstoffgass og står i 2 timer ved 5—10°. Det krystalliserer 425 vektsdeler tilnærmet rent a-racemat av a-f enyl-a-piperidyl-(2)-acetamid-hydro-klorid. Det kokes med 425 vektsdeler kaliumhydroksyd, oppløst i 850 volumdeler vann, i 16 timer med tilbakeløpskjøler. Den ved avkjøling utfelte racematblanding av a-f enyl-a-piperidyl-(2)-acetamid forsåpes sammen med fordampningsresten fra den ovenfor erholdte alkoholiske moderluc av a-racematet, som består av praktisk talt rent b-racemat, ved 6 timers kokning med 1300 volumdeler 40 pst.'s svovelsyre. Ved fortynning og nøytralisasjon av forsåp-ningsoppløsningen til pH zn 6 får man en 500 parts by weight crude, according to example 1 in French patent no. 908 782 prepared a-phenyl-a-piperidyl-(2)-acetamide with a content of a-racemate of 68% are dissolved in 2000 parts by volume of absolute ethyl alcohol, the solution is saturated with dry hydrogen chloride gas and stand for 2 hours at 5—10°. It crystallizes 425 parts by weight of approximately pure a-racemate of a-phenyl-a-piperidyl-(2)-acetamide hydrochloride. It is boiled with 425 parts by weight of potassium hydroxide, dissolved in 850 parts by volume of water, for 16 hours with a reflux condenser. The racemate mixture of α-phenyl-α-piperidyl-(2)-acetamide precipitated on cooling is saponified together with the evaporation residue from the alcoholic mother liquor obtained above of the α-racemate, which consists of practically pure b-racemate, by boiling for 6 hours with 1300 parts by volume 40 percent sulfuric acid. By diluting and neutralizing the saponification solution to pH zn 6, one is obtained
felling av b-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre, som isoleres ifølge det som er angitt i eksempel 1. Utbyttet 382 vektsdeler. precipitation of b-racemate of α-phenyl-α-piperidyl-(2)-acetic acid, which is isolated according to what is indicated in Example 1. Yield 382 parts by weight.
Eksempel 5: Example 5:
40 vektsdeler av det i eksempel 4 anvendte rå a-fenyl-a-piperidyl-(2)-acetamid røres med 200 volumdeler av en 40 pst.'s oppløsning av trimetylbensylammonium-hydroksyd i vann i 2 timer ved 100°. Deretter innstilles under avkjøling med 6-n. saltsyre til pH = 9,9, og oppløsningen eks-traheres fullstendig med etylenklorid. Etylenkloridresten forsåpes analogt med eksempel 4 med 40 pst.'s svovelsyre, og for-såpningsoppløsningen opparbeides analogt. Man får således 19,9 vektsdeler b-racemat av a-fenyl-a-piperidyl-(2)-eddiksyre. 40 parts by weight of the crude α-phenyl-α-piperidyl-(2)-acetamide used in example 4 are stirred with 200 parts by volume of a 40% solution of trimethylbenzylammonium hydroxide in water for 2 hours at 100°. Then set during cooling with 6-n. hydrochloric acid to pH = 9.9, and the solution is extracted completely with ethylene chloride. The ethylene chloride residue is saponified analogously to example 4 with 40% sulfuric acid, and the saponification solution is worked up analogously. One thus obtains 19.9 parts by weight of the b-racemate of a-phenyl-a-piperidyl-(2)-acetic acid.
Eksempel 6: Example 6:
11 vektsdeler venstredreiende a-iso-mere av a-fenyl-a-piperidyl-(2)-acetamid — i beskrivelsen betegnet som a,-antipode 22 — med en spesifikk dreining på [a] D 11 parts by weight of levorotatory α-isomers of α-phenyl-α-piperidyl-(2)-acetamide — in the description designated as α,-antipode 22 — with a specific rotation of [a] D
= -68° (i 1 pst.'s oppløsning i 60 pst.'s etanol), kokes med 12 vektsdeler kaliumhydroksyd oppløst i 12 volumdeler vann, i 6 timer med tilbakeløpskjøler. Etter av-kjøling faller 10,5 vektsdeler av en blanding av a,-antipoder og b,-antipoder av a-fenyl-a-piperidyl-(2)-acetamidet igjen ut, som suges fra, vaskes med litt koldt vann og tørkes ved 70° i vakuum y2 time. = -68° (in a 1% solution in 60% ethanol), boil with 12 parts by weight of potassium hydroxide dissolved in 12 parts by volume of water, for 6 hours with a reflux condenser. After cooling, 10.5 parts by weight of a mixture of a,-antipodes and b,-antipodes of the a-phenyl-a-piperidyl-(2)-acetamide fall out again, which are sucked off, washed with a little cold water and dried at 70° in vacuum y2 hour.
22 Det har nå en spesifikk dreining på [a]D 22 It now has a specific turn of [a]D
= + 41° (i 1 pst.'s oppløsning i 60 pst.'s etanol). Ved omkrystallisasjon fra 350 volumdeler eddikester får man derav en første hovedfraksjon på 4,9 vektsdeler b,-antipoder, med en spesifikk dreining på = + 41° (in 1 percent solution in 60 percent ethanol). By recrystallization from 350 parts by volume of acetic acid, a first main fraction of 4.9 parts by weight of b,-antipodes is obtained, with a specific rotation of
[a] = -f- 65° (1 pst. i 60 pst.'s etanol). Fra moderlutene kan man ved systematisk fraksjonert krystallisasjon utvinne videre mengder b,-antipoder, samt 2,5 vektsdeler av den opprinnelig anvendte a,-antipode. Det er dog fordelaktig å underkaste mo-derlutproduktene fra den første b^anti-podekrystallisasjon sammen en videre alkalisk behandling, hvoretter man igjen i en eneste krystallisasjon fra eddikester kan utskille en hovedfraksjon av rent b,-antipoder. Denne prosess fortsetter man inntil praktisk talt den totale mengde a,-antipode er omdannet til b1-antipoder av a-f enyl-a-piperidyl- (2) -acetamidet. [a] = -f- 65° (1 percent in 60 percent ethanol). From the mother liquors, further quantities of b,-antipodes can be recovered by systematic fractional crystallization, as well as 2.5 parts by weight of the originally used a,-antipodes. It is, however, advantageous to subject the mother liquor products from the first β-antipode crystallization together to a further alkaline treatment, after which a main fraction of pure β-antipodes can again be isolated in a single crystallization from vinegar. This process is continued until practically the total amount of a,-antipode has been converted into b1-antipodes of the a-phenyl-a-piperidyl-(2)-acetamide.
Av 4,5 vektsdeler av denne b,-antipode av a-fenyl-a-piperidyl-(2)-acetamid får man ved 6 timers opphetning med tilbake-løpskjøler med 14,5 volumdeler 6-normal saltsyre og etterfølgende krystallisasjon ved 20° 5,0 vektsdeler av b,-antipoden av a-f enyl-a-piperidyl-(2)-eddiksyrehydro-klorid med en spesifikk dreining på [a] 22 From 4.5 parts by weight of this b,-antipode of a-phenyl-a-piperidyl-(2)-acetamide, heating with a reflux condenser for 6 hours with 14.5 parts by volume of 6-normal hydrochloric acid and subsequent crystallization at 20° 5.0 parts by weight of the b,-antipode of α-phenyl-α-piperidyl-(2)-acetic acid hydrochloride with a specific rotation of [a] 22
= -)- 63° (i 1 pst.'s oppløsning i vann. = -)- 63° (in 1 percent solution in water.
4,5 vektsdeler av dette oppløses i 12 volumdeler metanol, hvoretter man i 2 timer leder inn tørr klorvannstoffgass under kokning med tilbakeløpskjøler. Ved avkjø-ling krystalliserer 3,8 vektsdeler b-,-antipode av a-fenyl-a-piperidyl-(2)-eddiksyre-metylester-hydroklorid med en spesifikk 4.5 parts by weight of this are dissolved in 12 parts by volume of methanol, after which dry hydrogen chloride gas is fed in for 2 hours while boiling with a reflux condenser. On cooling, 3.8 parts by weight of b-,-antipode of α-phenyl-α-piperidyl-(2)-acetic acid methyl ester hydrochloride crystallize with a specific
22 22
dreining på [a]D = + 89° (i 1 pst.'s opp-løsning i metanol). rotation of [a]D = + 89° (in 1 percent solution in methanol).
De som utgangsmateriale anvendte a^ antipoder av a-fenyl-a-piperidyl-(2)-acet-amid får man på følgende måte: 109 vektsdeler a-racemat av a-fenyl-a-piperidyl-(2)-acetamid oppløses i 2500 volumdeler 96 pst.'s etanol, og den kokende oppløsning tilsettes en kokende oppløsning av 1-vinsyre i likeledes 2500 volumdeler 96 pst.'s etanol. Deretter lar man stå 15 timer ved 20°, i hvilken tid det utkrystalli-serer 112 vektsdeler sur, vinsur a-f enyl-a-piperidyl-(2)-acetamid, hvori a,-antipoden takket være sin høyere krystallisasjons-hastighet er anriket. Man løser det sure tartrat i 500 volumdeler vann, feller med 1,1 ekvivalenter 10-normal natronlut ut amidet og gjentar saltdannelses- og kry-, stallisasjonsprosessen med tilsvarende mindre vekt- og volumdeler 1-vinsyre og opp-løsningsmiddel ennå to ganger . Den da er holdte rå a,-antipode omkrystalliserer man ennå fra eddikester og får således 35 vektsdeler av den rene til omleiring anvendte a,-antipode av a-fenyl-a-piperidyl-(2)-acetamidet. The a^ antipodes of a-phenyl-a-piperidyl-(2)-acetamide used as starting material are obtained in the following way: 109 parts by weight of the a-racemate of a-phenyl-a-piperidyl-(2)-acetamide are dissolved in 2,500 parts by volume of 96 percent ethanol, and to the boiling solution is added a boiling solution of 1-tartaric acid in likewise 2,500 parts by volume of 96 percent ethanol. It is then allowed to stand for 15 hours at 20°, during which time 112 parts by weight of acidic, tartaric a-phenyl-a-piperidyl-(2)-acetamide crystallize, in which the a,-antipode is enriched thanks to its higher crystallization rate. The acidic tartrate is dissolved in 500 parts by volume of water, the amide is precipitated with 1.1 equivalents of 10-normal caustic soda and the salt formation and crystallisation process is repeated with correspondingly smaller parts by weight and volume of 1-tartaric acid and solvent two more times. That one is kept crude α,-antipode is further recrystallized from acetic ester and thus obtains 35 parts by weight of the pure α,-antipode used for rearrangement of the α-phenyl-α-piperidyl-(2)-acetamide.
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1041965A CH425164A (en) | 1965-07-21 | 1965-07-21 | Fire retardant door with window |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO115758B true NO115758B (en) | 1968-11-25 |
Family
ID=4363027
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO16394666A NO115758B (en) | 1965-07-21 | 1966-07-15 |
Country Status (10)
| Country | Link |
|---|---|
| AT (1) | AT264798B (en) |
| BE (1) | BE683959A (en) |
| CH (1) | CH425164A (en) |
| DE (1) | DE1683055A1 (en) |
| DK (1) | DK109355C (en) |
| FI (1) | FI42134B (en) |
| GB (1) | GB1101287A (en) |
| LU (1) | LU51549A1 (en) |
| NL (1) | NL146252B (en) |
| NO (1) | NO115758B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH606749A5 (en) * | 1976-12-20 | 1978-11-15 | Inventio Ag | |
| WO1985000196A1 (en) * | 1983-06-20 | 1985-01-17 | Fire Research Pty. Limited | Fire windows |
| AT387261B (en) * | 1984-09-21 | 1988-12-27 | Lindpointner Tore | DOOR OR GATE, IN PARTICULAR FIRE PROTECTION GATE |
| US5367770A (en) * | 1993-05-03 | 1994-11-29 | Masco Industries, Inc. | Method for embossing indented door light opening edge |
| DE102004039416A1 (en) | 2004-04-14 | 2005-11-10 | Hörmann KG Freisen | Glazed fire protection door leaf and system and method of making the same |
| DE202012104484U1 (en) * | 2012-11-20 | 2014-02-25 | Holzbau Schmid Gmbh & Co. Kg | Multi-layer glass pane with covered edge bond |
| CN114776190A (en) * | 2022-03-02 | 2022-07-22 | 安徽理工大学 | Thermal radiation prevention fire door |
-
1965
- 1965-07-21 CH CH1041965A patent/CH425164A/en unknown
-
1966
- 1966-06-29 FI FI173266A patent/FI42134B/fi active
- 1966-07-08 AT AT657366A patent/AT264798B/en active
- 1966-07-08 DE DE19661683055 patent/DE1683055A1/en active Pending
- 1966-07-11 BE BE683959D patent/BE683959A/xx not_active IP Right Cessation
- 1966-07-12 NL NL6609783A patent/NL146252B/en not_active IP Right Cessation
- 1966-07-13 LU LU51549D patent/LU51549A1/xx unknown
- 1966-07-15 NO NO16394666A patent/NO115758B/no unknown
- 1966-07-15 GB GB3185966A patent/GB1101287A/en not_active Expired
- 1966-07-20 DK DK378866A patent/DK109355C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| CH425164A (en) | 1966-11-30 |
| DK109355C (en) | 1968-04-16 |
| GB1101287A (en) | 1968-01-31 |
| LU51549A1 (en) | 1967-01-13 |
| NL6609783A (en) | 1967-01-23 |
| AT264798B (en) | 1968-09-10 |
| NL146252B (en) | 1975-06-16 |
| BE683959A (en) | 1967-01-11 |
| DE1683055A1 (en) | 1970-04-30 |
| FI42134B (en) | 1970-02-02 |
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