BE566659A - - Google Patents
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- Publication number
- BE566659A BE566659A BE566659DA BE566659A BE 566659 A BE566659 A BE 566659A BE 566659D A BE566659D A BE 566659DA BE 566659 A BE566659 A BE 566659A
- Authority
- BE
- Belgium
- Prior art keywords
- general formula
- reduction
- hydrogen
- radicals
- atom
- Prior art date
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 150000002148 esters Chemical class 0.000 claims description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 6
- -1 diphenyl (2-piperidyl) acetate Chemical compound 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000004429 atoms Chemical group 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000004305 biphenyl Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000005936 piperidyl group Chemical group 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 235000011044 succinic acid Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- 210000001513 Elbow Anatomy 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
<Desc/Clms Page number 1>
La présente invention concerne de nouveaux dérivés de la pipéridine et leurs sels, ainsi que leur préparation.
Ces nouveaux dérivés de-la pipéridine comprennent les alcools de formule générale:
EMI1.1
et leurs esters avec des acides minéraux ou organiques.
Dans cette formule R1 représente un atome d'hydrogène ou un radical alcoyle inférieur et Ar1 et Ar2, identiques ou différents, représentent des radicaux phényle éventuellement substi,
<Desc/Clms Page number 2>
tués en particulier par des atomes d'halogène ou des radicaux alcoyles ou alcoxyles.
Les esters avec les acides minéraux comprennent en particulier le dérivé chloré, l'ester nitriaue. Parmi les esters avec les acides organiques il faut citer plus spécialement les esters acétique, propionique, butyrique, benzoïque éventuellement substitué, phénylacétique etc...
L'invention comprend également les sels obtenus par réaction de ces alcools et esters avec les acides thérapeutique- ment utilisables, comme les acides chlorhydrique, sulfurique, maléique, succinique.
Selon l'invention les nouveaux alcools dérivés de la pipéridine peuvent être obtenus par réduction d'un diphényl (pipéridyl-2) acétate de formule générale:
EMI2.1
dans laquelle R1, Ar1 et Ar2, sont définis comme ci-dessus et R3 représente un radical hydrocarboné monovalent.
Cette réduction peut être effectuée par toute méthode connue pour réduire un ester en alcool. Dans le cas où R1 repré- sente un radical alcoyle la réduction peut être effectuée direc- tement sur l'ester de formule (II) pour lequel R1 = alcoyle, ou l'alcoylation de l'atome d'azote de la pipéridine peut être réalisée après réduction de l'ester. Les nouveaux alcools peuvent être préparés également par réduction d'un diphényl-2,2 (pyridy1-2')¯ 2 éthanol de formule générale :
EMI2.2
'ou d'un dérivé à ammonium quaternaire correspondant
<Desc/Clms Page number 3>
EMI3.1
selon que dans le dérivé de formule I désiré R1 désigne un atome d'hydrogène ou un radical alcoyle. Dans la formule IV ci-dessus X désigne un atome d'halogène ou un reste d'ester sulfurique et R2 un radical alcoyle inférieur.
Les symboles Ar1 et Ar2 des formules III et IV ont la même signification que pour la formule I.
La réduction des dérivés de formules III et IV s'effectue -par les moyens habituellement utilisés pour la transformation du noyau pyridinique en noyau pipéridinique- Dans le cas des composés de formule III on effectue toutefois cette réduction de préférence par l'hydrogène en présence de platine d'Adams et en milieu acide acétique. Dans le cas des composés de formule IV on procède égale- ment de préférence à une réduction par l'hydrogène en présence de platine d'Adams mais en utilisant un milieu alcoolique ou hydro- alcoolique comme milieu réactionnel.
Les esters sont préparés à. partir des alcools pa.r les méthodes classiques d'estérification.
Les produits obtenus selon l'invention possèdent des propriétés pharmacodynamiques précieuses, ce sont en particulier des diurétiques puissants. Certains peuvent en outre être utilisés comme intermédiaires pour d'autres synthèses.
Les exemples suivants, à titre non limitatif, montrent comment l'invention peut être mise en pratique. Les points de fusion, sauf indication contraire, ont été déterminés au banc Kofler.
EXEMPLE 1. -
A une suspension de 10,7 g d'hydrure de lithium-aluminium dans 400 cm3 d'éther anhydre on ajoute en 1 h 30 en refroidissant par un bain d'eau glacée, 48 g de diphényl (pipéridyl-2) acétate d'éthyle dans 250 cm3 d'éther anhydre. Après 2 heures d'agitation
<Desc/Clms Page number 4>
à la température ordinaire on ajoute successivement 10 cm3 d'eau distillée, 10 cm3 deoude à 15% et 20 cm3 d'eau distillée. La sus pension est filtrée et la solution éthérée séchée sur sulfate de sodium anhydre. L'éther est chassé au bain-marie. On obtient
39 g de diphényl-2,2 (pipéridyl-2')-2 éthanol sous forme d'une huile jaune pâle.
A 11,2 g de la base précédente en solution dans 70 cm3 de méthanol on ajoute 4,7 g d'acide succinique et chauffe jusqu'à dissolution. Par refroidissement le sel cristallise : est essoré, lavé à. l'alcool éthylique et séché sous un vide de 0,2 mm de mer- cure à 60 . On obtient 10 g de succinate de diphényl-2,2 (pipéri- 'dyl-2')-2 éthanol, fondant à 214-215 .
EXEMPLE 2 . -
On agite jusqu'à dissolution une suspension de 25 g de chlorhydrate de diphényl-2,2 (pipéridyl-2')-2 éthanol dans 50 cm3 d'anhydride acétique et 175 cm3 de chlorure d'acétyle. Après 4 heures de repos à la température du laboratoire, on filtre le précipité formé que l'on lave avec 2 fois 25 cm3 d'acétone et sèche sous vide de 0,2 mm de mercure à la température ordinaire. On obtient 16,5 g de chlorhydrate de diphényl-2,2 (pipéridyl-2')-2 acétoxy-1 éthane fondant à 257-259' .
EXEMPLE 3. -
On chauffe à reflux pendant 24 heures un mélange de
28,2 g de diphényl-2,2 (pipéridyl-2')-2 éthanol, 16 cm de formoll à 30%, 9,2 g d'acide formique (98-99%)f et 64 cm3 d'eau distillées
Après refroidissement on ajoute 300 cm3 d'éther et alcalinise avec une solution de soude (d : 1,33). L'extrait éthéré est séché sur sulfate de sodium anhydre et on chasse l'éther. On orient 29 g de diphényl-2,2 (méthyl-1' pipéridy1-2')-2 éthanol fondant à 124-125 .
A 29 g de la base précédente on ajoute 17 cm3 d'une solution;6"N d'acide chlorhydrique dans l'alcool puis à la solu- tion obtenue 200 cm3 d'acétone jsqu'à apparition de trouble. On laisse alors à la glacière pendit 24 heures. On filtre, lave à
<Desc/Clms Page number 5>
l'acétone et sèche sous vide de 0,2 mm de mercure à. 60 : on ob- tient 21 g de chlorhydrate de diphényl-2,2 (méthyl-l' pipéridyl-2')
2 éthanol fondant à. 259-261 (bloc Maquenne).
EXEMPLE 4.-
On hydrogène à 70 et sous 80 kg/cm2 de pression un mélange de 74 g de bis (méthoxy-4' phényl)-2,2 (pyridyl-2")-2 éthanol, 25J cm3 d'acide acétique cristallisable et 3 g de platine
Adams. En 20 minutes la quantité théorique d'hydrogène a été absorbée. On filtre le catalyseur, et on chasse l'acide acétique sous une pression absolue de 10 mm de mercure au bain-marie.
Le résidu huileux est repris par 400 cm3 d'eau distillée et 25 cm3 d'acide chlorhydrique 10 N. On extrait par 2 fois
200 cm3 d'éther. La solution aqueuse décantée est alcalinisée par
50 cm3 de soude 10 N. Une huile précipite que l'on extrait par
2 fois 300 cm3 d'éther. Les extraits éthérés réunis, sont séchés .sur sulfate de sodium anhydre, On filtre et chasse l'éther au bain-marie.
On obtient ainsi 68 g d'une huile jaune pâle que l'on reprend par 250 cm3 d'eau distillée. On ajoute 23,5 g d'acide succinique puis porte au bain-marie jusqu'à dissolution totale.
On ajoute 2 g de noir et filtre. Le filtrat est abandonné pendant une nuit à la glacière.
On essore le précipité formé que l'on lave ensuite avec
2 fois 20 cm3 d'eau glacée puis sèche à 60 sous un vide de 0,2 mm de mercure.
On obtient ainsi 33 g de succinate de bis (méthoxy-4' phényl)-2,2 (pipéridyl-2")-2 éthanol fondant à 207-208 (bloc Maquenne).
EMI5.1
Le bis (méthoxry-4' phényly-2,2 (pyriùyl-2u)-2 éthanol qui sert de matière première peut être préparé par réduction au moyen d'hydrure de lithium-aluminium du bis (méthoxy-4' phényl) pyridyl-2 acétate d'éthyle. Ce dernier est préparé par condensa- .tion du chloroformiate d'éthyle sur le dérivé potassique du (méthoxy-4' phényl) pyridyl-2 méthane.
<Desc / Clms Page number 1>
The present invention relates to novel piperidine derivatives and their salts, as well as their preparation.
These new piperidine derivatives include alcohols of general formula:
EMI1.1
and their esters with mineral or organic acids.
In this formula R1 represents a hydrogen atom or a lower alkyl radical and Ar1 and Ar2, identical or different, represent optionally substituted phenyl radicals,
<Desc / Clms Page number 2>
killed in particular by halogen atoms or alkyl or alkoxyl radicals.
Esters with mineral acids include in particular the chlorinated derivative, the nitric ester. Among the esters with organic acids, mention should be made more especially of acetic, propionic, butyric, optionally substituted benzoic, phenylacetic, etc.
The invention also comprises the salts obtained by reaction of these alcohols and esters with therapeutically usable acids, such as hydrochloric, sulfuric, maleic or succinic acids.
According to the invention, the new alcohols derived from piperidine can be obtained by reduction of a diphenyl (2-piperidyl) acetate of general formula:
EMI2.1
in which R1, Ar1 and Ar2 are defined as above and R3 represents a monovalent hydrocarbon radical.
This reduction can be carried out by any known method for reducing an ester to alcohol. In the case where R1 represents an alkyl radical, the reduction can be carried out directly on the ester of formula (II) for which R1 = alkyl, or the alkylation of the nitrogen atom of piperidine can be carried out. carried out after reduction of the ester. The new alcohols can also be prepared by reduction of a 2,2-diphenyl (pyridy1-2 ') ¯ 2 ethanol of general formula:
EMI2.2
'or a corresponding quaternary ammonium derivative
<Desc / Clms Page number 3>
EMI3.1
depending on whether in the desired derivative of formula I R1 denotes a hydrogen atom or an alkyl radical. In formula IV above, X denotes a halogen atom or a residue of sulfuric ester and R2 a lower alkyl radical.
The symbols Ar1 and Ar2 of formulas III and IV have the same meaning as for formula I.
The reduction of the derivatives of formulas III and IV is carried out -by the means usually used for the transformation of the pyridine ring into a piperidine ring- In the case of the compounds of formula III, however, this reduction is preferably carried out with hydrogen in the presence of Adams platinum and in acetic acid medium. In the case of the compounds of formula IV, a reduction with hydrogen is also preferably carried out in the presence of Adams platinum, but using an alcoholic or aqueous-alcoholic medium as reaction medium.
Esters are prepared at. from alcohols by conventional esterification methods.
The products obtained according to the invention have valuable pharmacodynamic properties, in particular they are powerful diuretics. Some can also be used as intermediates for other syntheses.
The following examples, without limitation, show how the invention can be put into practice. Melting points, unless otherwise indicated, were determined on the Kofler bench.
EXAMPLE 1. -
To a suspension of 10.7 g of lithium aluminum hydride in 400 cm3 of anhydrous ether is added over 1 hour 30 minutes while cooling with an ice-water bath, 48 g of diphenyl (2-piperidyl) acetate. ethyl in 250 cm3 of anhydrous ether. After 2 hours of stirring
<Desc / Clms Page number 4>
at room temperature are added successively 10 cm3 of distilled water, 10 cm3 of 15% elbow and 20 cm3 of distilled water. The suspension is filtered and the ethereal solution dried over anhydrous sodium sulfate. The ether is driven off in a water bath. We obtain
39 g of 2,2-diphenyl (2 'piperidyl) - 2 ethanol in the form of a pale yellow oil.
4.7 g of succinic acid are added to 11.2 g of the previous base dissolved in 70 cm3 of methanol and heated until dissolved. By cooling the salt crystallizes: is drained, washed with. ethyl alcohol and dried under a vacuum of 0.2 mm mercury to 60. 10 g of 2,2-diphenyl (2-piperidyl) -ethanol succinate are obtained, melting point 214-215.
EXAMPLE 2. -
A suspension of 25 g of 2,2-diphenyl (2 'piperidyl) - 2 ethanol hydrochloride in 50 cm3 of acetic anhydride and 175 cm3 of acetyl chloride is stirred until dissolved. After standing for 4 hours at laboratory temperature, the precipitate formed is filtered, washed with 2 times 25 cm3 of acetone and dried under vacuum with 0.2 mm of mercury at room temperature. 16.5 g of 2,2-diphenyl (2 'piperidyl) - 2 acetoxyethane hydrochloride is obtained, melting at 257-259'.
EXAMPLE 3. -
A mixture of
28.2 g of 2,2-diphenyl (2 'piperidyl) - 2 ethanol, 16 cm of 30% formalin, 9.2 g of formic acid (98-99%) f and 64 cm3 of distilled water
After cooling 300 cm3 of ether are added and basified with a sodium hydroxide solution (d: 1.33). The ethereal extract is dried over anhydrous sodium sulfate and the ether is removed. 29 g of 2,2-diphenyl (methyl-1 'piperidy1-2') - 2 ethanol, melting point 124-125, are orientated.
17 cm 3 of a 6 "N hydrochloric acid in alcohol solution are added to 29 g of the above base, followed by 200 cm 3 of acetone to the solution obtained until cloudiness appears. the cooler hung for 24 hours.
<Desc / Clms Page number 5>
acetone and dry under vacuum from 0.2 mm Hg to. 60: 21 g of 2,2-diphenyl hydrochloride (methyl-l 'piperidyl-2') are obtained
2 ethanol melting at. 259-261 (Maquenne block).
EXAMPLE 4.-
A mixture of 74 g of bis (4 'methoxy-phenyl) -2.2 (pyridyl-2 ") - 2 ethanol, 25J cm3 of crystallizable acetic acid and 3 g is hydrogenated at 70 and under 80 kg / cm2 of pressure. platinum
Adams. In 20 minutes the theoretical quantity of hydrogen was absorbed. The catalyst is filtered off, and the acetic acid is removed under an absolute pressure of 10 mm of mercury in a water bath.
The oily residue is taken up in 400 cm3 of distilled water and 25 cm3 of 10N hydrochloric acid. Extraction is carried out twice.
200 cm3 of ether. The decanted aqueous solution is made alkaline by
50 cm3 of 10 N soda. An oil precipitates which is extracted by
2 times 300 cm3 of ether. The combined ethereal extracts are dried over anhydrous sodium sulphate, filtered and the ether removed in a water bath.
68 g of a pale yellow oil are thus obtained, which is taken up in 250 cm3 of distilled water. 23.5 g of succinic acid are added and then taken to a water bath until complete dissolution.
2 g of charcoal are added and filtered. The filtrate is left overnight in the cooler.
The precipitate formed is filtered off which is then washed with
2 times 20 cm3 of ice-cold water then dried at 60 under a vacuum of 0.2 mm of mercury.
33 g of succinate of bis (4 'methoxy-phenyl) -2.2 (piperidyl-2 ") - 2 ethanol melting at 207-208 (Maquenne block) are thus obtained.
EMI5.1
The bis (methoxy-4 'phenyly-2,2 (pyriùyl-2u) -2 ethanol which serves as a raw material can be prepared by reduction with lithium aluminum hydride of bis (methoxy-4' phenyl) pyridyl- Ethyl acetate 2. The latter is prepared by condensing ethyl chloroformate with the potassium derivative of (4 'methoxy phenyl) pyridyl-2 methane.
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