CS271971B1 - Method of 4-phenyl-4-piperidine carboxylic acid's ethyl ester hydrochloride preparation - Google Patents
Method of 4-phenyl-4-piperidine carboxylic acid's ethyl ester hydrochloride preparation Download PDFInfo
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- CS271971B1 CS271971B1 CS742088A CS742088A CS271971B1 CS 271971 B1 CS271971 B1 CS 271971B1 CS 742088 A CS742088 A CS 742088A CS 742088 A CS742088 A CS 742088A CS 271971 B1 CS271971 B1 CS 271971B1
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Abstract
RieSenie ea týká apoeobu pripravy hydrochloridu etyleeteru kyeeliny 4-fenyl-4-piparidinkarboxylovej katalytickou hydrogenačnou N-debenzyláclou hydrochloridu etyleeteru kyseliny l-benzyl-4-fenyl-4-plperidlnkarboxylovaj e cielom odstranit použivanls drahého paládicvého katalyzátora. Podetata spočívá v tom, žs N-debsnzyláela sa prevádza tlakovou hydrogenáciou za katalýzy Raney-niklu v polárných organických rozpúStadlách. Připravená zlúčenina Je medziproduktom pri priamyealnej farmaceutickaj výrobě analgetlka psthidinu.Solutions and concerns about preparation kyeelina ethyl ether hydrochloride 4-phenyl-4-piparidinecarboxylic acid catalytic by hydrogenating N-debenzylate hydrochloride 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether aim using expensive palladic catalyst. The reason is that The N-debsnzylaela is subjected to pressure by hydrogenation under Raney-nickel catalysis in polar organic solvents. The compound prepared is an intermediate for direct real pharmaceutical production analgesic psthidin.
Description
Vynález sa týká sposobu přípravy hydrochloridu etylesteru kyseliny 4-fenyl-4-piperidinkarboxylovej z hydrochloridu etylesteru kyseliny l-benzyl-4-fenyl-4-piperidinkarboxylovej katalytickou hydrogenačnou N-debenzyláciou za použitia Raney-niklu ako katalyzátora. Btylester kyseliny 4-fenyl-4-piperidinkarboxylovej je medziprodukt při priemyselnej farmaceutickéj výrobě analgetika pethidinu.The present invention relates to a process for the preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride from 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride by catalytic hydrogenation N-debenzylation using Raney nickel as a catalyst. 4-Phenyl-4-piperidinecarboxylic acid butyl ester is an intermediate in the industrial pharmaceutical production of the analgesic pethidine.
Hydrochlorid etylesteru kyseliny 4-fenyl-4-piperidinkarboxylovej sa připravuje beztlakovou katalytickou hydrogenačnou N-debenzyláciou hydrochloridu etylesteru kyseliny l-benzyl~4-fenyl-4-piperidinkarboxylovej, za použitia paládiového katalyzátora při teplote 50 až 60 °C a přetlaku vodíka 20 kPa počas 40 hodin (Eisleb 0.: US patent 2 167 351, US pat. 2 486 792). Nevýhodou tohto postupu je vysoká cena paládia a dlhý reakčný čas.4-Phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride is prepared by pressureless catalytic hydrogenation N-debenzylation of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride using a palladium catalyst at 50-60 ° C and a hydrogen overpressure of 20 kPa for 40 hours (Eisleb 0 .: U.S. Pat. No. 2,167,351, U.S. Pat. No. 2,486,792). The disadvantage of this process is the high cost of palladium and the long reaction time.
Uvedené nedostatky odstraňuje sposob přípravy hydrochloridu etylesteru kyseliny 4-fenyl-4-piperidinkarboxylovej katalytickou hydrogenačnou N-debenzyláciou hydrochloridu etylesteru kyseliny l-benzyl-4-fenyl-4-piperidinka.rboxylove j podl'a tohoto vynálezu, ktorého podstata spočívá v tom, že N-debenzylécia sa prevádza tlakovou hydrogenáciou za tlaku 0,2 až 5 MPa, za katalýzy 2 až 20 % hmot. Raney-niklu, vztiahnuté na hmotnost východiskovej látky, v polárných organických rozpúšttadlách ako např. etylalkohol, metyláfcohol alebo ich zmesi s vodou, při teplote 70 až 150 °C. Reakcia prebieha prakticky kvantitativné bez vedlajších produktov a při teplote 90 °C a tlaku 2 MPa trvá 1,5 hodiny.The process for the preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride by catalytic hydrogenation of N-debenzylation of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride according to the invention eliminates these drawbacks. N-debenzylation is carried out by pressure hydrogenation at a pressure of 0.2 to 5 MPa, catalyzed by 2 to 20% by weight. Raney nickel, based on the weight of the starting material, in polar organic solvents such as e.g. ethyl alcohol, methyl alcohol or mixtures thereof with water, at a temperature of 70 to 150 ° C. The reaction proceeds practically quantitatively without by-products and takes 1.5 hours at a temperature of 90 ° C and a pressure of 2 MPa.
V ňalšom je. postup podl'a vynálezu i lustrovaný príkladmi , bez toho že by bol nimi obmedzený. ,It's in the next one. the process according to the invention is illustrated by the examples without being limited thereto. ,
Příklad 1Example 1
Do 250 ml autoklávu s miešadlom sa dá 20 g (0,055 mol) hydrochloridu etylesteru kyseliny l-benzyl-4-fenyl-4-piperidinkarboxylovej, 75 ml etylalkoholu, 25 ml destilovanej vody a 1 g Raney-niklu (5 % hmot.vztiahnuté na hmotnost východiskovej látky). Autokláv sa uzavřie, prepláchne sa dvakrát dusíkem a třikrát vodíkom a za miešania sa obsah autoklávu zohreje na 90 °C. Při tejto teplote sa hydrogenuje vodíkom pri tlaku 1,5 MPa počas 2 hodin za intenzívneho miešania. Potom sa autokláv ochladí na 20 °C, vypustí sa vodík, autokláv sa prepláchne dvakrát dusíkom. Raney-nikel sa odfiltruje, filtrát aa zahustí na vákuovej odparke. Získá sa 14,7 g (98 %) hydrochloridu etylesteru kyseliny 4-fenyl-4-pi'peridinkarboxylovej. Obsah (HPLO) je 98 % hmot.20 g (0.055 mol) of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, 75 ml of ethyl alcohol, 25 ml of distilled water and 1 g of Raney nickel (5% by weight) are placed in a 250 ml stirred autoclave. weight of starting material). The autoclave is sealed, purged twice with nitrogen and three times with hydrogen, and the contents of the autoclave are heated to 90 ° C with stirring. At this temperature, it is hydrogenated with hydrogen at a pressure of 1.5 MPa for 2 hours with vigorous stirring. The autoclave is then cooled to 20 ° C, hydrogen is vented, the autoclave is purged twice with nitrogen. The Raney nickel is filtered off, the filtrate and concentrated on a vacuum evaporator. 14.7 g (98%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained. The content (HPLO) is 98% by weight.
Příklad 2Example 2
Do 250 ml autoklávu a miešadlom sa dá 20 g (0,055 mol) hydrochloridu etylesteru kyseliny 1 -benzyl-4-fenyl-4-piperidinkarboxylovej, 130 ml etylalkoholu a 4 g Raney-niklu (20 % hmot, vztiahnuté na hmotnost východiskovej látky). Autokláv sa uzavrie, prepláchne sa dvakrát dusikom a třikrát vodíkom a za miešania sa obsah autoklávu zohreje na 70 °C. Pri. tejto teplote sa hydrogenuje vodíkom při tlaku 0,2 MPa počas 10 hodin za intenzívneho miešania. Potom sa autokláv ochladí na 20 °C, vypustí sa vodík, autokláv sa prepláchne dvakrát dusíkom. Raney-nikel sa odfiltruje, filtrát sa zahustí na vákuovej odparke. Získá sa 14,85 g (99 %) hydrochloridu etylesteru kyseliny 4-fenyl-4-piperidinkarboxylovej. Obsah (HPLO) je 96,9 % hmot.20 g (0.055 mol) of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, 130 ml of ethyl alcohol and 4 g of Raney nickel (20% by weight, based on the weight of the starting material) are added to a 250 ml autoclave and stirrer. The autoclave is sealed, purged twice with nitrogen and three times with hydrogen, and the contents of the autoclave are heated to 70 ° C with stirring. At. at this temperature it is hydrogenated with hydrogen at a pressure of 0.2 MPa for 10 hours with vigorous stirring. The autoclave is then cooled to 20 ° C, hydrogen is vented, the autoclave is purged twice with nitrogen. The Raney nickel is filtered off and the filtrate is concentrated on a vacuum evaporator. 14.85 g (99%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained. The content (HPLO) is 96.9% by weight.
Příklad 3Example 3
Postupuje sa ako v příklade 2e tým rozdielom, že na miesto etylalkoholu sa použije metylalkohol, použije sa 0,4 g Raney-niklu (2 % hmot, vztiahnuté na hmotnost východiskovej látky) a hydrogenuje sa 1,5 hodiny za tlaku 5 MPa a při teplote 150 °C. Získá sa 14,75 g (98,4 %) hydrochloridu etylesteru kyseliny 4-fenyl-4-piperidinkarboxylovej. Obsah (HPLO) 97,5 %hmot.The procedure is as in Example 2e, except that methyl alcohol is used instead of ethyl alcohol, 0.4 g of Raney nickel (2% by weight, based on the weight of the starting material) is used and hydrogenated for 1.5 hours at 5 MPa and at temperature of 150 ° C. 14.75 g (98.4%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained. Content (HPLO) 97.5 wt.
CS 271 971 BlCS 271 971 Bl
Příklad 4Example 4
Postupuje sa ako v příklade 1, s tým rozdielom, že namiesto etylalkoholu sa použije metylalkohol, použije sa 2 g Raney-niklu (10 % hmot, vztiahnuté na hmotnost východiskovej látky) a hydrogenuje sa 1,5 hodiny za tlaku 3,5 MPa a pri. teplote 110 °C. Získá sa 14,8 g (98,7 %) hydrochlořidu etylestenu kyseliny 4-fenyl-4-piperidinkarboxylovej. Obsah (HPLC) je 97,8 % hmot.The procedure is as in Example 1, except that methyl alcohol is used instead of ethyl alcohol, 2 g of Raney nickel (10% by weight, based on the weight of the starting material) are used and hydrogenated for 1.5 hours at a pressure of 3.5 MPa and at. temperature 110 ° C. 14.8 g (98.7%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained. The content (HPLC) is 97.8% by weight.
Příklad 5Example 5
Postupuje sa ako v příklade 1, s tým plote 100 °C a za tlaku 2,5 MPa. Získá sa ny 4-fenyl-4-piperidinkarboxylovej. Obsah rozdielom, že sa hydrogenuje 1,5 hodiny pri. te14,85 g (99 %) hydrochlořidu etylesteru kyseli(HPLC) je 98,1 % hmot.The procedure is as in Example 1, with a fence of 100 DEG C. and a pressure of 2.5 MPa. 4-Phenyl-4-piperidinecarboxylic acid is obtained. The contents, except that they are hydrogenated for 1.5 hours at. 14.85 g (99%) of ethyl acid hydrochloride hydrochloride (HPLC) is 98.1% by weight.
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CS742088A CS271971B1 (en) | 1989-05-29 | 1989-05-29 | Method of 4-phenyl-4-piperidine carboxylic acid's ethyl ester hydrochloride preparation |
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