CH318326A - Process for preparing the levoisomers of 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol and 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol - Google Patents
Process for preparing the levoisomers of 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol and 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-olInfo
- Publication number
- CH318326A CH318326A CH318326DA CH318326A CH 318326 A CH318326 A CH 318326A CH 318326D A CH318326D A CH 318326DA CH 318326 A CH318326 A CH 318326A
- Authority
- CH
- Switzerland
- Prior art keywords
- cyclohexyl
- phenyl
- piperidinopropan
- pyrrolidinopropan
- levo
- Prior art date
Links
- WYDUSKDSKCASEF-UHFFFAOYSA-N procyclidine Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCC1 WYDUSKDSKCASEF-UHFFFAOYSA-N 0.000 title claims description 7
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 13
- 235000019441 ethanol Nutrition 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000001640 fractional crystallisation Methods 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 229960001270 d- tartaric acid Drugs 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 1-cyclohexyl Chemical group 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Description
Procédé de préparation des lévo-isomères du 1-cyclohexyl-1-phényl-3-pyrrolidinopropane-1-ol et du 1-cyclohexyl-1-phényl-3-pipéridinopropane-1-ol La présente invention a pour objet un pro cédé de préparation des lévo-isomères du 1- cyclohexyl -1-phényl-3-pyrrolidinopropane-1-ol et du 1-cyclohexyl-1-phényl-3-pipéridinopro- pane-1-ol,
dans lequel on forme les sels d'addi tion acides du 1-cyclohexyl-1-phényl-3-pyrro- lidinopropane-1-ol et du 1-cyclohexyl-1-phé- nyl-3-pipéridinopropane-1-ol avec l'acide d-tar- trique.
Les composés racémiques 1-cyclohexyl-1- phényl-3-pyrrolidinopropane-1-oI et 1-cyclo- hexyl-1-phényl-3-pipéridinopropane-1-oI et leurs sels quaternaires N-alcoyle inférieur, par exemple leurs sels quaternaires N-méthyle et N-éthyle, sont connus pour avoir des propriétés spasmolytiques, et les deux premiers composés mentionnés sont cliniquement employés pour le traitement symptomatique du parkinsonisme.
On a maintenant trouvé que les lévo-iso- mères de ces composés possèdent des proprié tés qui les rendent plus précieux comme agents thérapeutiques que leurs formes racémiques correspondantes. On a trouvé'que les propriétés semblables à celles de l'atropine sont limitées dans chacun des cas presque entièrement à ces lévo-isomères, les dextro-isomères étant pres que inactifs et, de plus, ce qui était inattendu, que le lévo isomère, dans chaque cas, n'est pas plus toxique, en injection intraveineuse chez la souris,
que la forme racémique ou la forme dextrogyre. Les lévo-isomères de ces composés présentent donc un avantage précieux et inat tendu sur leurs formes racémiques, pour l'em ploi comme agents d'action semblable à l'atro pine.
Les 1-cyclohexyl-1-phényl-3-pyrrolidino- propane-1-ol et 1-cyclohexyl 1-phényl43-pipé- ridinopropane-1-ol racémiques (préparés, par exemple, de la manière décrite par Adamson, Journal, of the Chemical Society, Londres, 1951, page 52) peuvent être dédoublés:
en leurs isomères optiques par toute méthode connue pouvant être employée pour le dédoublement d'une base organique ou d'un alcool, par exem ple en foimant le sel avec l'acide d-tartrique et séparant les deux sels par cristallisation frac tionnée dans l'alcool éthylique ou un mélange d'alcool éthylique et d'acétate d'éthyle. Le lévo- isomère peut être utilisé sous forme de chlor- hydrate ou de- sel de tout acide non toxique aux doses auxquelles il doit être administré.
Les sels quaternaires N-alcoyle peuvent être préparés à partir du lévo-isomère selon les méthodes ordinaires pour former les sels qua- ternaires à partir des amines tertiaires. Ainsi, le méthiodure ou l'éthiodure peuvent être pré parés en faisant réagir la base optiquement ac tive avec de l'iodure de méthyle ou die l'iodure d'éthyle, respectivement ; les composés quater naires peuvent avoir comme anion tout radical acide désiré.
Le procédé faisant l'objet de la présente invention est caractérisé en ce qu'on soumet le sel d'addition acide correspondant à un procédé de cristallisation fractionnée pour effectuer la séparation partielle des formes dextrogyre et lévogyre, on alcalinise les liqueurs mères com binées desdites cristallisations fractionnées qui contiennent la forme lévogyre,
on soumet ces liqueurs mères alcalinisées à _ un procédé de cristallisation fractionnée pour isoler la lévo- base et l'obtenir sous une forme pratiquement exempte de dextro-isomère.
Des exemples de mise en aeuvre du procédé selon l'invention sont donnés ci-après, dans les quels toutes les températures sont données en degrés centigrades.
<I>Exemple 1</I> <I>Dédoublement du</I> 1-cyclohexyl-1-phényl-3- pyrrolidinopropane-1-ol On a ajouté du 1-cyclohexyl-1-phényl-3- pyrrolidinopropane-1-ol (60 g) en solution dans de l'alcool éthylique chaud (120 cc) à une solution d'acide d-tartrique (30 g) dans de l'al cool éthylique (100 cc) et laissé cristalliser ; des enlèvements successifs du corps solide ont été faits jusqu'à ce qu'il ne se sépare plus qu'une substance huileuse.
On peut ajouter gra duellement de l'éther pour faciliter la cristalli- . sation. L'huile et la liqueur mère ont été com binées, basifiées avec de l'ammoniaque puis ex traites avec de l'éther, et la base a été cristalli sée d'ans de l'alcool éthylique. Les premières récoltes consistaient en lévo-base pure, les sui vantes en la forme racémique.
La base optique- ment active lévo-1-cyclohexyl-1-phényl-3-pyr- rolidinopropane-1-ol a un point de fusion de 105-106- ; [ a ]
EMI0002.0031
(C = 0,4 dans de l'alcool éthylique). Le chlorhydrate, obtenu par les méthodes usuelles, cristallise dans l'al cool éthylique-acétate d'éthyle et a un point de fusion de 2460 ; [ a ] (C = 0,4 dans du chloroforme).
EMI0002.0034
<I>Exemple 2</I> <I>Dédoublement du</I> 1-cyclohexyl-1-phényl-3- pipéridinopropane-1-ol Du 1-cyclohexyl-1-phényl-3 -pipéridino- propane-1-ol (20 g) a été dissous dans une so lution d'acide d-tartrique (10 g) dans de l'al cool éthylique (80 cc) et on a laissé cristalliser ; on a fait des enlèvements successifs du corps solide jusqu'à ce qu'il ne se sépare plus qu'une substance huileuse. On peut ajouter graduelle ment de l'éther pour faciliter la cristallisation.
L'huile et la liqueur mère ont été combinées, basifiées avec de l'ammoniaque, et la base a été cristallisée dans de l'alcool éthylique. La base lévo-1-cyclohexyl-1-phényl-3 -pipéridinopro- pane-1-ol, optiquement active, a un point de fusion de 112-113o ;
[a]
EMI0002.0050
(C = 0,4 dans de l'alcool éthylique). Son chlor- hydrate, obtenu par les méthodes usuelles, cris tallise dans l'alcool isopropylique et a un point de fusion de 2640 ;<B>[</B>a<B>]
EMI0002.0056
</B> (C = 0,4 dans du chloroforme).
Process for preparing the levo-isomers of 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol and of 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol The present invention relates to a process of preparation of the levo-isomers of 1-cyclohexyl -1-phenyl-3-pyrrolidinopropan-1-ol and 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol,
in which the acid addition salts of 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol and 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol are formed with d-tartaric acid.
The racemic compounds 1-cyclohexyl-1-phenyl-3-pyrrolidinopropane-1-oI and 1-cyclohexyl-1-phenyl-3-piperidinopropane-1-oI and their N-lower alkyl quaternary salts, for example their quaternary salts N-methyl and N-ethyl, are known to have spasmolytic properties, and the first two compounds mentioned are clinically used for the symptomatic treatment of parkinsonism.
It has now been found that the levo-isomers of these compounds possess properties which make them more valuable as therapeutic agents than their corresponding racemic forms. It was found that the atropine-like properties are in each case limited almost entirely to these levoisomers, the dextro-isomers being almost inactive and, moreover, unexpectedly, the levoisomer , in each case, is not more toxic, by intravenous injection in mice,
than the racemic form or the dextrorotatory form. The levoisomers of these compounds therefore exhibit a valuable and unexpected advantage over their racemic forms, for use as agents of atropine-like action.
Racemic 1-cyclohexyl-1-phenyl-3-pyrrolidino-propan-1-ol and 1-cyclohexyl 1-phenyl43-piperidinopropan-1-ol (prepared, for example, as described in Adamson, Journal, of the Chemical Society, London, 1951, page 52) can be split:
into their optical isomers by any known method which can be used for the resolution of an organic base or of an alcohol, for example by forming the salt with d-tartaric acid and separating the two salts by fractional crystallization in the ethyl alcohol or a mixture of ethyl alcohol and ethyl acetate. The levoisomer can be used as the hydrochloride or salt of any non-toxic acid at the doses at which it is to be administered.
The N-alkyl quaternary salts can be prepared from the levoisomer according to ordinary methods to form the quaternary salts from the tertiary amines. Thus, methiodide or ethiodide can be prepared by reacting the optically active base with methyl iodide or ethyl iodide, respectively; the quaternary compounds can have any desired acid radical as an anion.
The process forming the subject of the present invention is characterized in that subjecting the acid addition salt corresponding to a fractional crystallization process in order to effect the partial separation of the dextrorotatory and levorotatory forms, the combined mother liquors of said said liquors are basified. fractional crystallizations which contain the levorotatory form,
These alkalized mother liquors are subjected to a fractional crystallization process to isolate the levobase and obtain it in a form substantially free of dextro-isomer.
Examples of implementation of the process according to the invention are given below, in which all the temperatures are given in degrees centigrade.
<I> Example 1 </I> <I> Duplication of </I> 1-cyclohexyl-1-phenyl-3- pyrrolidinopropan-1-ol 1-cyclohexyl-1-phenyl-3- pyrrolidinopropane-1 was added -ol (60 g) dissolved in hot ethyl alcohol (120 cc) in a solution of d-tartaric acid (30 g) in ethyl alcohol (100 cc) and allowed to crystallize; successive removals of the solid body were made until only an oily substance separated.
Ether can be added gradually to facilitate crystallization. sation. The oil and the mother liquor were combined, basified with ammonia then extracted with ether, and the base was crystallized from ethyl alcohol. The first harvests consisted of pure levo-base, the following ones in the racemic form.
The optically active base levo-1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol has a melting point of 105-106-; [ at ]
EMI0002.0031
(C = 0.4 in ethyl alcohol). The hydrochloride, obtained by the usual methods, crystallizes from ethyl alcohol-ethyl acetate and has a melting point of 2460; [a] (C = 0.4 in chloroform).
EMI0002.0034
<I> Example 2 </I> <I> Depletion of </I> 1-cyclohexyl-1-phenyl-3- piperidinopropan-1-ol 1-cyclohexyl-1-phenyl-3 -piperidino-propane-1- ol (20 g) was dissolved in a solution of d-tartaric acid (10 g) in ethyl alcohol (80 cc) and allowed to crystallize; successive removals of the solid body were made until only an oily substance separated. Ether can be added gradually to facilitate crystallization.
The oil and mother liquor were combined, basified with ammonia, and the base was crystallized from ethyl alcohol. The optically active levo-1-cyclohexyl-1-phenyl-3 -piperidinopropan-1-ol base has a melting point of 112-113o;
[at]
EMI0002.0050
(C = 0.4 in ethyl alcohol). Its hydrochloride, obtained by the usual methods, crystallizes in isopropyl alcohol and has a melting point of 2640; <B> [</B> a <B>]
EMI0002.0056
</B> (C = 0.4 in chloroform).
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB318326X | 1953-03-23 | ||
| GB100853X | 1953-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH318326A true CH318326A (en) | 1956-12-31 |
Family
ID=26247251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH318326D CH318326A (en) | 1953-03-23 | 1954-03-23 | Process for preparing the levoisomers of 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol and 1-cyclohexyl-1-phenyl-3-piperidinopropan-1-ol |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH318326A (en) |
-
1954
- 1954-03-23 CH CH318326D patent/CH318326A/en unknown
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