CH331057A - Process for the preparation of basic benzilic acid esters - Google Patents
Process for the preparation of basic benzilic acid estersInfo
- Publication number
- CH331057A CH331057A CH331057DA CH331057A CH 331057 A CH331057 A CH 331057A CH 331057D A CH331057D A CH 331057DA CH 331057 A CH331057 A CH 331057A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- benzilic acid
- basic
- preparation
- acid esters
- Prior art date
Links
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical class C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 2
- 229940087675 benzilic acid Drugs 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229930003347 Atropine Natural products 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- AIPVNQQMYPWQSX-UHFFFAOYSA-N ethyl 2-hydroxy-2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC)C1=CC=CC=C1 AIPVNQQMYPWQSX-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 108010030727 lens intermediate filament proteins Proteins 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 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
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Description
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Verfahren zur Herstellung von basischen Benzilsäureestern Es ist bereits bekannt, dass Dialkylamino- alkylester der Benzilsäure pharmazeutisch wertvolle Eigensehaften besitzen (AP 2399736, AP 2401219 und AP 2570181).
Es wurde gefunden, dass man durch Umsetzung von Benzilsäure oder deren funktionellen Derivaten mit N-Alkyl-4-oxy-piperidi- nen, deren Alkylgruppe bis zu 4 Kohlenstoffatome enthält und deren Piperidinkern keine weiteren Substituenten trägt, pharmazeutisch wertvolle Benzilsäure-N-alkyl-piperidyl-(4)- ester herstellen kann.
Die neuen Verbindungen zeichnen sich insbesondere durch gute spasmolytische Wirksamkeit bei geringer Toxizität aus. Beispielsweise entspricht die spasmolytische Wirksamkeit des Benzilsäure-N-methyl-piperidyl-(4)- esters, wie am isolierten Meerschweinchen- Diekdarm nach Tontraktion mit Lentin festgestellt wurde, etwa der dreifachen Wirkung des Atropins; dabei besitzt die Verbindung nur 1/3 der Toxizität des Atropins.
Die erhaltenen Verbindungen lassen sich mit Hilfe von anorganischen oder organischen Säuren in die entsprechenden Salze überführen. Als anorganische Säuren kommen beispielsweise Halogenwasserstoffsäuren, Phosphorsäure, Schwefelsäure und Amidosulfon- säure in Betracht. Als organische Säuren können beispielsweise Oxalsäure, Essigsäure, Milchsäure,. Bernsteinsäure, .Maleirisäüre, Apfelsäüre, Weinsäure, Salicylsäure, Zitro- nensäure, Oxyäthansulfonsäure, Acetursäure und Äthylendiamintetraessigsäure verwendet werden.
Beispiel 1 25,6 g Benzilsäureäthylester, 12 g N- 1@Iethyl-4-oxypiperidin und eine Lösung von 0,5g Natrium in 10 em3 absolutem Alkohol werden gemischt und die Mischung 2i/2 Stunden unter 80 mm Druck auf 110-120 C erhitzt. Nach dem Abkühlen wird in verdünnter Salzsäure gelöst und die klare Lösung mit Soda alkalisch gemacht, wobei der Benzil- säure-N-methyl-piperidyl-(4)-ester ausfällt. Ausbeute 22 g, F. = 164 C. F des Chlor- hydrates = 209-210 C.
Beispiel 2 Zu einer Lösung von 1,5g Natrium in 60 em3 absolutem Äthanol werden 73 g Benzil- ; säuremethylester und 39 g N-Äthyl-4-oxy- piperidin hinzugegeben. Das Reaktionsgemisch wird 5 Stunden unter 80 mm Druck auf 110-120 C erhitzt und nach dem Abkühlen in verdünnter Salzsäure gelöst. Anschliessend wird ausgeäthert und die wässrige Lösung mit Pottasche alkalisch gemacht, wobei der Benzil- säure-N-äthyl-piperidyl-(4)-ester ausfällt. Ausbeute 50 g, Schmelzpunkt 93 C (nach Um- kristallisieren aus Diisopr opyläther) .
Das
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Chlorhydrat schmilzt bei 1$2 C (nach Um- kristallisieren aus Acetonitril).
<Desc / Clms Page number 1>
Process for the preparation of basic benzilic acid esters It is already known that dialkylaminoalkyl esters of benzilic acid have pharmaceutically valuable properties (AP 2399736, AP 2401219 and AP 2570181).
It has been found that reacting benzilic acid or its functional derivatives with N-alkyl-4-oxy-piperidines whose alkyl group contains up to 4 carbon atoms and whose piperidine nucleus carries no further substituents, pharmaceutically valuable benzilic acid-N-alkyl piperidyl (4) - ester can produce.
The new compounds are distinguished in particular by good spasmolytic effectiveness with low toxicity. For example, the spasmolytic activity of benzilic acid-N-methyl-piperidyl- (4) - ester, as was found on the isolated guinea pig bowel after traction with lentin, is approximately three times as effective as atropine; the compound has only 1/3 the toxicity of atropine.
The compounds obtained can be converted into the corresponding salts with the aid of inorganic or organic acids. Inorganic acids that can be used are, for example, hydrohalic acids, phosphoric acid, sulfuric acid and amidosulfonic acid. As organic acids, for example, oxalic acid, acetic acid, lactic acid,. Succinic acid, maleic acid, malic acid, tartaric acid, salicylic acid, citric acid, oxyethane sulfonic acid, aceturic acid and ethylenediaminetetraacetic acid can be used.
EXAMPLE 1 25.6 g of ethyl benzilate, 12 g of N-1 @ methyl-4-oxypiperidine and a solution of 0.5 g of sodium in 10 cubic meters of absolute alcohol are mixed and the mixture is heated to 110-120 ° C. for 2½ hours under 80 mm pressure heated. After cooling, it is dissolved in dilute hydrochloric acid and the clear solution is made alkaline with soda, whereupon the benzilic acid N-methyl-piperidyl (4) ester precipitates. Yield 22 g, F. = 164 C. F. of the chlorohydrate = 209-210 C.
Example 2 To a solution of 1.5 g of sodium in 60 cubic meters of absolute ethanol, 73 g of benzil; acid methyl ester and 39 g of N-ethyl-4-oxypiperidine are added. The reaction mixture is heated to 110-120 ° C. under 80 mm pressure for 5 hours and, after cooling, dissolved in dilute hydrochloric acid. It is then extracted with ether and the aqueous solution is made alkaline with potash, the benzilic acid N-ethyl-piperidyl (4) ester precipitating out. Yield 50 g, melting point 93 ° C. (after recrystallization from diisopropyl ether).
The
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Chlorohydrate melts at 12 ° C (after recrystallization from acetonitrile).
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH331057T | 1954-11-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH331057A true CH331057A (en) | 1958-06-30 |
Family
ID=4501925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH331057D CH331057A (en) | 1954-11-25 | 1954-11-25 | Process for the preparation of basic benzilic acid esters |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH331057A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4697703A (en) * | 1986-07-02 | 1987-10-06 | Malcolm Will | Joint prosthesis package |
-
1954
- 1954-11-25 CH CH331057D patent/CH331057A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4697703A (en) * | 1986-07-02 | 1987-10-06 | Malcolm Will | Joint prosthesis package |
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