CS270532B1 - Method of 1-methyl-4-phenyl-4-piperidine carboxyl acid's ethyl ester preparation - Google Patents
Method of 1-methyl-4-phenyl-4-piperidine carboxyl acid's ethyl ester preparation Download PDFInfo
- Publication number
- CS270532B1 CS270532B1 CS887421A CS742188A CS270532B1 CS 270532 B1 CS270532 B1 CS 270532B1 CS 887421 A CS887421 A CS 887421A CS 742188 A CS742188 A CS 742188A CS 270532 B1 CS270532 B1 CS 270532B1
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- CS
- Czechoslovakia
- Prior art keywords
- phenyl
- methyl
- piperidinecarboxylic acid
- ethyl ether
- ethyl ester
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 9
- 239000002253 acid Substances 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title abstract description 4
- ZTVIKZXZYLEVOL-DGKWVBSXSA-N 2-hydroxy-2-phenylacetic acid [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] ester Chemical group C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-DGKWVBSXSA-N 0.000 title 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000019253 formic acid Nutrition 0.000 claims abstract description 6
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- DZZGGKPKWGPNJA-UHFFFAOYSA-N Normeperidinicacid Chemical compound C=1C=CC=CC=1C1(C(=O)O)CCNCC1 DZZGGKPKWGPNJA-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000007069 methylation reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 2
- 229920013624 Tylac Polymers 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 18
- KHUPPYUUMRDAAX-UHFFFAOYSA-N pethidinic acid Chemical compound C1CN(C)CCC1(C(O)=O)C1=CC=CC=C1 KHUPPYUUMRDAAX-UHFFFAOYSA-N 0.000 abstract description 9
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
RieSenie aa týká sposobu pripravy etyleateru kyeeliny l-metyi-4-fenyl-4- -piperidinkarboxylovej N-mstyláciou etvlestsru kyeeliny 4-fenyl-4-piperidinkerboxylovsj formaldehydom a kyselinou mravčou v polárných organických rozpúStadlách. Hydrochlorld etyleateru kyseliny 1-metyl- -4-fsnyl-4-piperidinkarboxylovej ea vyrába vo farmaceutickom priemysle a používá ea v terapeuticksj praxi ako analgetlkum (psthidin)The solution and concerns the method of preparation etyleater kyeeliny 1-methyl-4-phenyl-4- -piperidinecarboxylic acid by N-esterification of the ester 4-phenyl-4-piperidinecerboxylate kyeelins formaldehyde and formic acid in polar organic solvents. Hydrochloride of ethyl ether of 1-methyl- -4-Phenyl-4-piperidinecarboxylic acid and produced in the pharmaceutical industry and uses and in therapeutical practice as an analgesic (psthidin)
Description
Vynález ea týká spoaobu přípravy etyleeteru kyeeliny l-metyl-4-fenyl-4-piperidinkarboxylovaj z etyleeteru kyeeliny 4-fsnyl-4-piperidinkarboxylovej N-metyláciou a formaldehydom a kyselinou mravčou. Hydrochlorid etyleeteru kyeeliny l-metyl-4-fenyl-4-piperidinkarboxylovej sa vyrába vo farmaceuticko·» priemysle a používá ea v terapeut lekej praxi ako analgetikum (pethidin).The present invention relates to a process for the preparation of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether from 4-phenyl-4-piperidinecarboxylic acid ethyl ether by N-methylation and formaldehyde and formic acid. 1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride is manufactured in the pharmaceutical industry and is used in therapeutic practice as an analgesic (pethidine).
Etyleeter kyseliny l-metyl-4-fenyl-4-piperidinkarboxylovej sa připravuje ž hydrochlor ridu etyleeteru kyseliny 4-fenyl-4-piperidinkarboxylovej a formaIdshydu redukčnou metyláciou za podmlanok beztlakovej katalytickéj hydrogenácla na paládiovom katalyzátore, pri teplete 50 až 60 °C a přetlaku vodíka 20 kPa počas 40 hodin (Eieleb O.: U.S. patent 2 167 351). Nevýhodou tohto postupu js vysoká cena paládia a dlhý reakčný čas. Sálej sa etylsstsr kyseliny l-metyl-4-fenýl-4-piperidinkarboxylovej připravuje N-metyláciou etyleeteru kyseliny 4-fenyl-4-pipsridlnkarboxylovej mstyljodidom (Brit, patent 592 016),. Nevýhodou tohto poetupu je tiež poměrně vysoká cena metyljodidu a jeho toxicita.1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether was prepared from 4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride and formaldehyde by reductive methylation under pressurized catalytic hydrogenation on a palladium catalyst at 50-60 ° C and water overpressure. 20 kPa for 40 hours (Eieleb O .: U.S. Patent 2,167,351). The disadvantages of this process are the high cost of palladium and the long reaction time. The salt of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester is prepared by N-methylation of 4-phenyl-4-piperidinecarboxylic acid ethyl ether with methyl iodide (Brit, patent 592 016). The disadvantage of this procedure is also the relatively high cost of methyl iodide and its toxicity.
Uvedená nedostatky odstraňuje sposob přípravy etyleeteru kyseliny l-mstyl-4-fenyl-4-piperidinkarboxylovaj N-metyláciou etyleeteru kyseliny 4-fenyl-4-piperidinkarboxylovej podlá tohto vynálezu, ktoráho podstata apočívav tom, že N-metyláoia ea prevádza formaldehydom a kyselinou mravčou v polárných organických rozpúšťadléch ako napr. metylalkohol, etylalkohol alebo ich zmeei s vodou, pri teploto 60 °C až teploto varu použitého rozpúštadla.These disadvantages are overcome by the process for the preparation of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether by N-methylation of 4-phenyl-4-piperidinecarboxylic acid ethyl ether according to the invention, which consists in converting N-methylaea ea with formaldehyde and formic acid in polar organic solvents such as e.g. methyl alcohol, ethyl alcohol or a mixture thereof with water, at a temperature of 60 ° C to the boiling point of the solvent used.
Reakcia prebieha prakticky kvantitativné bez vedlejších produktov a v atylalkohols pri teploto varu rozpúštadla trvá 4 hodiny.The reaction proceeds practically quantitatively without by-products and takes 4 hours in ethyl alcohol at the boiling point of the solvent.
V SalŠom je postup podlá vynálezu ilustrovaný príkladmi, bez toho, Že by bol nimi obmedzený.In SalŠ, the process according to the invention is illustrated by way of examples, without being limited thereto.
Příklad 1Example 1
250 ml banky, opatrenej miešadlom, spatným chladičom, sa předloží 233 g (0,1 mol) etyleeteru kyeeliny 4-fenyl-4-piperidinkarboxylovej a 120 ml etanolu.233 g (0.1 mol) of 4-phenyl-4-piperidinecarboxylic acid ethyl ether and 120 ml of ethanol are introduced into a 250 ml flask equipped with a stirred condenser.
Přidá ea 14,5 ml (0,1 mol) 37 % formaldehydu a 9 ml (0,2 mol) 85 % kyseliny mravčej. Reakčná zmes sa vyhřeje za mlešania do varu a pri teplote varu sa mieša 4 hodiny. Počas reakcia uniká oxid uhličitý. Reakčná zmes ea ochladí na 20 až 30 °C a přidá sa 20 % vodný roztok hydroxidu sodného do pH-9.14.5 ml (0.1 mol) of 37% formaldehyde and 9 ml (0.2 mol) of 85% formic acid are added. The reaction mixture was heated to reflux with stirring and stirred at reflux for 4 hours. Carbon dioxide escapes during the reaction. The reaction mixture is cooled to 20-30 ° C and 20% aqueous sodium hydroxide solution is added to pH-9.
Potom se oddestiluje etanol. Přidá sa 120 ml benzínu a 50 ml deetilovanej vody. Organické vrstva sa oddslí a premyje 50 ml dsstílovansj vody. Benzín sa oddestiluje a získá sa 24 g (97 %) etyleeteru kyseliny l-mstyl-4-fenyl-4-piperidinkarboxylovej.Ethanol is then distilled off. 120 ml of petrol and 50 ml of deethylated water are added. The organic layer was slurried and washed with 50 mL of distilling water. Gasoline was distilled off to give 24 g (97%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether.
Obsah (HPLC) je 97 % hmot.The content (HPLC) is 97% by weight.
Příklad 2Example 2
Do 250 ml banky opatrenej miešadlom a spatným chladičom aa předloží 23,3 g (0,1 mol) etyleeteru kyeeliny 4-fenyl-4-plperidinkarboxylovej, 100 ml etylalkoholu a 20 ml vody.23.3 g (0.1 mol) of 4-phenyl-4-piperidinecarboxylic acid ethyl ether, 100 ml of ethyl alcohol and 20 ml of water are introduced into a 250 ml flask equipped with a stirrer and a reflux condenser.
Přidá aa 14,5 ml (0,1 mol) 37 % formaldehydu a 9 ml (0,2 mol) 85 % kyeeliny mravčaj. Reakčná zmes sa vyhraje za mlešania do varu a pri teplote varu ea mieša 4,5 hodiny. PoSaa reakcia uniká oxid uhličitý. Potom aa z reakčnej zmeei oddestiluje etylalkohol a k destilačnému zvyšku sa přidá 25 ml 50 %-ného vodného roztoku hydroxidu sodného. Po krátkom zmlešaní a oddálení vretiev sa organická vrstva oddělí a premyje a 20 ml vody. Takto získaný surový produkt sa vákuovo destiluje (160 až 165 °C pri tlaku 0,4 až 0,6 kPa).14.5 ml (0.1 mol) of 37% formaldehyde and 9 ml (0.2 mol) of 85% formic acid are added. The reaction mixture was heated to reflux with stirring and stirred at reflux for 4.5 hours. After the reaction, carbon dioxide escapes. Then, ethyl alcohol was distilled off from the reaction mixture, and 25 ml of 50% aqueous sodium hydroxide solution was added to the distillation residue. After brief stirring and stirring, the organic layer is separated and washed with 20 ml of water. The crude product thus obtained is distilled under vacuum (160 to 165 ° C at a pressure of 0.4 to 0.6 kPa).
Získá es 21,7 g (87,7 %) etyleeteru kyeeliny l-metyl-4-fenyl-4-piperidinkarboxylovej.21.7 g (87.7%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether are obtained.
Ohaeh (HPL6) je 09,8 % hmot.Ohaeh (HPL6) is 09.8% by weight.
CS 270 532 BlCS 270 532 Bl
Příklad 3Example 3
Postupuje ea ako v přiklade 1, e tým rozdielom, že ako rozpúétadlo ea namissto etylalkoholu použije metylelkohol.The procedure is as in Example 1, except that methyl alcohol is used as the solvent instead of ethyl alcohol.
Získá ea 23,8 g (96 %) etyleeteru kyseliny l-metyl-4-fenyl-4~plperidinkarboxylovej.23.8 g (96%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether are obtained.
Obsah (HPLC) je 97 % hmot.The content (HPLC) is 97% by weight.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS887421A CS270532B1 (en) | 1988-11-11 | 1988-11-11 | Method of 1-methyl-4-phenyl-4-piperidine carboxyl acid's ethyl ester preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS887421A CS270532B1 (en) | 1988-11-11 | 1988-11-11 | Method of 1-methyl-4-phenyl-4-piperidine carboxyl acid's ethyl ester preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS742188A1 CS742188A1 (en) | 1989-11-14 |
| CS270532B1 true CS270532B1 (en) | 1990-07-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS887421A CS270532B1 (en) | 1988-11-11 | 1988-11-11 | Method of 1-methyl-4-phenyl-4-piperidine carboxyl acid's ethyl ester preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS270532B1 (en) |
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1988
- 1988-11-11 CS CS887421A patent/CS270532B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS742188A1 (en) | 1989-11-14 |
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