CH475246A - Process for preparing a substituted naphthalene - Google Patents
Process for preparing a substituted naphthaleneInfo
- Publication number
- CH475246A CH475246A CH1865266A CH1865266A CH475246A CH 475246 A CH475246 A CH 475246A CH 1865266 A CH1865266 A CH 1865266A CH 1865266 A CH1865266 A CH 1865266A CH 475246 A CH475246 A CH 475246A
- Authority
- CH
- Switzerland
- Prior art keywords
- integer
- formula
- organic solvent
- methoxy
- pyridine derivative
- Prior art date
Links
- 150000002790 naphthalenes Chemical class 0.000 title claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- KNTDPNNXTUXQQV-UHFFFAOYSA-N [Na]CC1=CC=NC=C1 Chemical compound [Na]CC1=CC=NC=C1 KNTDPNNXTUXQQV-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- -1 6-methoxy-1- (4-pyridylmethylidene) -1,2,3,4-tetrahydro-naphthalene Chemical compound 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- VJXRKZJMGVSXPX-UHFFFAOYSA-N 4-ethylpyridine Chemical compound CCC1=CC=NC=C1 VJXRKZJMGVSXPX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- HFVTXZVMAVTOMU-UHFFFAOYSA-N 4-[3-(6-methoxy-3,4-dihydronaphthalen-1-yl)propyl]pyridine Chemical compound COC=1C=C2CCC=C(C2=CC1)CCCC1=CC=NC=C1 HFVTXZVMAVTOMU-UHFFFAOYSA-N 0.000 description 1
- JAWZAONCXMJLFT-UHFFFAOYSA-N 4-propylpyridine Chemical compound CCCC1=CC=NC=C1 JAWZAONCXMJLFT-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 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
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PURITTXNCHNYEP-UHFFFAOYSA-N mukoenine a Chemical compound N1C2=CC=CC=C2C2=C1C(CC=C(C)C)=C(O)C(C)=C2 PURITTXNCHNYEP-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 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)
- Pyridine Compounds (AREA)
Description
Procédé de préparation d'un naphtalène substitué La présente invention concerne un procédé de pré paration d'un naphtalène substitué dans les positions 1 et 6 qui exhibe des activités analogues à celles des sté roïdes.
Les composés obtenus par le procédé selon la pré sente invention sont des dérivés de naphtalène de for mule
EMI0001.0000
dans laquelle le noyau B dans la formule I a la struc ture partielle
EMI0001.0001
et dans laquelle R est H(CH2)n, n est un nombre entier de 1 à 4 et m est un nombre entier de 0 à 2 inclus, ainsi que les sels d'addition d'acide desdits composés. Ces dérivés de naphtalène présentent une activité biologique en tant qu'inhibiteurs de la croissance, réduisant l'acti vité métabolique des animaux à sang chaud.
Les nouveaux composés de formule I sont préparés par le procédé selon la présente invention par conden- sation d'une 6-alkoxy inférieur-1-tétralone avec une py- ridine de formule:
EMI0001.0005
dans laquelle m est un nombre entier de 0 à 2 et M est un métal alcalin, en présence d'un solvant organique inerte anhydre à une température comprise entre 0 et 1000 C dans des conditions anhydres pendant une pé riode de temps d'au moins 15 minutes. Le produit de condensation résultant peut ensuite être mélangé avec de l'eau et séparé de la matière minérale.
Le solvant sera ensuite chassé par distillation laissant un mélange de deux composés isomères, l'un portant une double liai son dans le système cyclique entre les positions 1 et 2 du noyau naphtalène, l'autre portant une double liai son entre le noyau naphtalène et l'atome de carbone exocyclique.
Le terme solvant organique inerte utilisé ci-dessus désigne un solvant qui ne réagit pas avec les réactifs, les intermédiaires ou le produit final présent dans le système, et qui dissout au moins 2 % de la matière or ganique de départ à la température ambiante. Parmi les solvants utiles on peut citer le méthanol, l'éthanol, le propanol, l'éther monométhylique du diéthylène glycol et leurs équivalents. L'expression solvant organique inerte anhydre veut dire que le milieu réactionnel doit être exempt d'eau et choisi de telle façon qu'il ne ré agisse pas avec la matière de départ ou avec le produit final.
Des exemples de solvants de ce type compren nent le toluène, le benzène ou un dérivé de pyridine de formule II illustrée ci-dessus dans laquelle M est un atome d'hydrogène.
On illustre la préparation des nouveaux composés par des exemples non limitatifs qui suivent. Exemple 1 6-méthoxy-1-(4-pyridylméthylidène)-1,2,3,4-tétrahydro- naphtalène et 6-méthoxy-1-(4-pyridylméthyl)-3,4-dihydro- naphtalène.
Pour la préparation du dérivé pyridylique sodé, on peut opérer ainsi A 250 ml d'ammoniaque liquide contenant un cris tal de nitrate ferrique on ajoute 10,05 g de sodium par petites portions sous agitation et refroidissement dans un bain de glace sèche-acétone. A la fin de l'addition du sodium, 42,5 ml (40,65 g) de g-picoline sont ajoutés goutte à goutte sous agitation sur une période de 10 minutes. Au bout de 15 minutes, le bain de refroidisse ment est enlevé et le condenseur à glace sèche initiale ment présent est remplacé par un condenseur à air. De l'éther sec (100 ml) est ajouté goutte à goutte pendant que l'ammoniaque s'évapore. Le récipient de réaction est ensuite placé dans un bain d'eau chaude pour chas ser l'ammoniaque résiduelle.
L'huile foncée résiduelle est refroidie dans un bain de glace et 25 g de 6-mé- thoxy-1-tétralone dans 85 ml de γ-picoline sont ajoutés rapidement. Le mélange est agité pendant une nuit à la température ambiante et versé ensuite dans de la glace. L'huile foncée obtenue est extraite à l'éther contenant une petite portion de chloroforme pour maintenir un solide blanc insoluble dans l'éther en solution. L'extrait éthéré est lavé à l'eau et séché sur du sulfate de magné sium anhydre. L'élimination du solvant sous pression réduite laisse 38 g d'une huile ambrée.
Les dernières traces de γ-picoline sont chassées par distillation sous une pression de 1,3 mm de Hg jusqu'à ce que la température de vapeur atteigne 1300 C. Le résidu est repris dans de l'acide chlorhydrique aqueux à 10 0/o et filtré avec aspi ration pour éliminer la tétralone n'ayant pas réagi.
Le filtrat acide est alcalinisé par addition d'une solu tion aqueuse de soude à 20 % et extraite à l'éther. L'ex trait éthéré est lavé à l'eau et séché sur du sulfate de magnésium anhydre. L'élimination du solvant sous pres sion réduite laisse 25,68 g d'un mélange de 6-méthoxy-1- (4-pyridylméthylidène)- 1,2,3,4-tétrahydronaphtalène et de 6-méthoxy-1-(4-pyridylméthyl)-3,4-dihydronaphtalène sous la forme d'une huile brun-jaune qui est dissoute dans l'éthanol absolu.
Après addition d'acide chlor hydrique éthéré, on obtient un solide jaune brut qui est identifié par l'analyse, les spectres infrarouge et de ré sonance magnétique nucléaire (RMN), comme étant un mélange à 50-50 de chlorhydrates de 6-méthoxy-1-(4- pyridylméthylidène)-1,2,3,4-tétrahydronaphtalène et de 6-méthoxy-1-4-pyridylméthyl)-3,4-dihydronaphtalène.
Si l'on répète ce procédé, en employant de l'amidure de sodium commercialement disponible, on obtient le même mélange de produit mais avec un rendement lé gèrement inférieur.
Exemple 2 6-méthoxy-1-(4-pyridyl-1-éthyl)-3,4-dihydronaphtalène. En remplaçant dans la proportion du dérivé pyridi- lique sodé, la γ-picoline, comme mentionné à l'exemple 1, par la 4-éthylpyridine, on obtient un produit brut dont le spectre RMN confirme la présence de sous-produits. Le mélange est placé sur une colonne de gel de silice et élué à l'éther. Les matières contaminantes demeurent sur la colonne et l'éluat à l'éther est traité pour donner des cristaux blancs de 6-méthoxy-1-(4-pyridyl-1-éthyl)- 3,4-dihydronaphtalène fondant à 73-75 C après recris- tallisation dans un mélange de benzène-hexane.
Les va leurs analytiques concordent avec celles calculées pour la formule empirique C18H19NO. Le chlorhydrate fond à 150-153 C. Le spectre RMN de la base libre montre un doublet correspondant au groupe méthyle à 88,5 cps (J = 7 cps), un quartet à 1 proton à 242,5 cps (J = 7 cps) et un triplet d'hydrogène vinylique à 356 cps (J = 4 cps).
De même, en remplaçant la 4-éthylpyridine dans le procédé ci-dessus par la 4-propylpyridine, on obtient le 6-méthoxy-1-(4-pyridyl-1-n-propyl)-3,4-dihydronaphta- lène.
Il est entendu que les composés décrits précédem ment forment facilement des sels d'addition d'acide avec des acides forts tels que les acides minéraux. Parmi les sels d'acides minéraux, ceux qui sont pharmaceuti- quement acceptables sont préférés, par exemple les sels chlorhydrate, sulfate et phosphate.
Les nouveaux composés, sous la forme de bases li bres ou de sels d'addition d'acide, peuvent être admi nistrés par voie orale, intramusculaire ou sous-cutanée sous la forme de suspension ou solution dans l'eau ou dans les huiles végétales contenant entre 0,5 et 2 n/o de matière active ; en particulier, ils inhibent la croissance des organes de reproduction lorsqu'ils sont administrés à des doses de 0,1 à 5 mg/kg par jour.
Process for the preparation of a substituted naphthalene The present invention relates to a process for the preparation of a naphthalene substituted in positions 1 and 6 which exhibits activities analogous to those of steroids.
The compounds obtained by the process according to the present invention are naphthalene derivatives of the formula
EMI0001.0000
in which the nucleus B in formula I has the partial structure
EMI0001.0001
and wherein R is H (CH2) n, n is an integer from 1 to 4 and m is an integer from 0 to 2 inclusive, as well as the acid addition salts of said compounds. These naphthalene derivatives exhibit biological activity as growth inhibitors, reducing the metabolic activity of warm-blooded animals.
The novel compounds of formula I are prepared by the process according to the present invention by condensing a 6-lower alkoxy-1-tetralone with a pyridine of the formula:
EMI0001.0005
wherein m is an integer of 0 to 2 and M is an alkali metal, in the presence of an inert anhydrous organic solvent at a temperature between 0 and 1000 C under anhydrous conditions for a period of time of at least 15 minutes. The resulting condensation product can then be mixed with water and separated from the mineral material.
The solvent will then be removed by distillation leaving a mixture of two isomeric compounds, one bearing a double bond in the ring system between positions 1 and 2 of the naphthalene ring, the other bearing a double bond between the naphthalene ring and the exocyclic carbon atom.
The term inert organic solvent used above denotes a solvent which does not react with the reagents, intermediates or the final product present in the system, and which dissolves at least 2% of the starting organic material at room temperature. Among the useful solvents, mention may be made of methanol, ethanol, propanol, diethylene glycol monomethyl ether and their equivalents. The expression anhydrous inert organic solvent means that the reaction medium must be free from water and chosen such that it does not react with the starting material or with the final product.
Examples of such solvents include toluene, benzene or a pyridine derivative of formula II illustrated above in which M is a hydrogen atom.
The preparation of the new compounds is illustrated by the following non-limiting examples. Example 1 6-methoxy-1- (4-pyridylmethylidene) -1,2,3,4-tetrahydro-naphthalene and 6-methoxy-1- (4-pyridylmethyl) -3,4-dihydro-naphthalene.
For the preparation of the sodium pyridyl derivative, it is thus possible to operate. To 250 ml of liquid ammonia containing a salt of ferric nitrate, 10.05 g of sodium are added in small portions with stirring and cooling in a dry ice-acetone bath. At the end of the sodium addition, 42.5 ml (40.65 g) of g-picoline is added dropwise with stirring over a period of 10 minutes. After 15 minutes, the cooling bath is removed and the dry ice condenser initially present is replaced by an air condenser. Dry ether (100 ml) is added dropwise as the ammonia evaporates. The reaction vessel is then placed in a hot water bath to remove residual ammonia.
The residual dark oil is cooled in an ice bath and 25 g of 6-metoxy-1-tetralone in 85 ml of γ -picoline are added rapidly. The mixture is stirred overnight at room temperature and then poured into ice. The dark oil obtained is extracted with ether containing a small portion of chloroform to maintain a white solid insoluble in ether in solution. The ethereal extract is washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure leaves 38 g of an amber oil.
The last traces of γ -picoline are removed by distillation under a pressure of 1.3 mm Hg until the vapor temperature reaches 1300 C. The residue is taken up in aqueous hydrochloric acid at 10 0 / o and filtered with suction to remove unreacted tetralone.
The acidic filtrate is basified by adding a 20% aqueous sodium hydroxide solution and extracted with ether. The ethereal extract is washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure leaves 25.68 g of a mixture of 6-methoxy-1- (4-pyridylmethylidene) - 1,2,3,4-tetrahydronaphthalene and 6-methoxy-1- (4 -pyridylmethyl) -3,4-dihydronaphthalene in the form of a yellow-brown oil which is dissolved in absolute ethanol.
After addition of ethereal hydrochloric acid, a crude yellow solid is obtained which is identified by analysis, infrared and nuclear magnetic resonance (NMR) spectra, as being a 50-50 mixture of 6-methoxy hydrochlorides. -1- (4-pyridylmethylidene) -1,2,3,4-tetrahydronaphthalene and 6-methoxy-1-4-pyridylmethyl) -3,4-dihydronaphthalene.
If this process is repeated, employing commercially available sodium amide, the same product mixture is obtained but in slightly lower yield.
Example 2 6-methoxy-1- (4-pyridyl-1-ethyl) -3,4-dihydronaphthalene. By replacing, in the proportion of the sodium pyridyl derivative, β -picoline, as mentioned in Example 1, by 4-ethylpyridine, a crude product is obtained, the NMR spectrum of which confirms the presence of by-products. The mixture is placed on a column of silica gel and eluted with ether. Contaminants remain on the column and the ether eluate is treated to give white crystals of 6-methoxy-1- (4-pyridyl-1-ethyl) - 3,4-dihydronaphthalene, melting at 73-75 C after recrystallization from a mixture of benzene-hexane.
The analytical values agree with those calculated for the empirical formula C18H19NO. The hydrochloride melts at 150-153 C. The NMR spectrum of the free base shows a doublet corresponding to the methyl group at 88.5 cps (J = 7 cps), a quartet with 1 proton at 242.5 cps (J = 7 cps ) and a vinyl hydrogen triplet at 356 cps (J = 4 cps).
Likewise, by replacing 4-ethylpyridine in the above process with 4-propylpyridine, 6-methoxy-1- (4-pyridyl-1-n-propyl) -3,4-dihydronaphthalene is obtained.
It is understood that the compounds described above easily form acid addition salts with strong acids such as mineral acids. Among the salts of mineral acids, those which are pharmaceutically acceptable are preferred, for example the hydrochloride, sulfate and phosphate salts.
The new compounds, in the form of free bases or acid addition salts, can be administered orally, intramuscularly or subcutaneously as a suspension or solution in water or in vegetable oils. containing between 0.5 and 2 n / o of active ingredient; in particular, they inhibit the growth of reproductive organs when administered in doses of 0.1 to 5 mg / kg per day.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51754965A | 1965-12-30 | 1965-12-30 | |
| US517818A US3386996A (en) | 1965-12-30 | 1965-12-30 | Process for producing certain 8-hydroxy or lower-alkoxy-(4-pyridyl lower-alkylidene)-, 2, 3, 4-tetrahydro-naphthalenes; 8-hydroxy or lower-alkoxy-(4-pyridyl lower-alkyl)-3, 4-dihydro-naphthalenes and derivatives thereof |
| US517849A US3453283A (en) | 1965-12-30 | 1965-12-30 | Novel 6-substituted-1-(piperidyl-alkyl)-1,2,3,4-tetrahydronaphthalenes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH475246A true CH475246A (en) | 1969-07-15 |
Family
ID=27414668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1865266A CH475246A (en) | 1965-12-30 | 1966-12-28 | Process for preparing a substituted naphthalene |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH475246A (en) |
-
1966
- 1966-12-28 CH CH1865266A patent/CH475246A/en not_active IP Right Cessation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0012643B1 (en) | 1-phenyl-3-(4-piperidyl)-propan-1-one derivatives, processes for their preparation, and medicaments containing them | |
| EP0110755B1 (en) | Piperidine dione derivatives with a myocardium protecting and antiarrhytmic activity, process for their preparation and medicines containing them | |
| EP0360685B1 (en) | 1-[(Diaryl methoxy)alkyl] pyrrolidines and piperidines, process for their preparation and pharmaceutical compounds containing them | |
| FR2663328A1 (en) | HEXAHYDROAZEPINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. | |
| EP0418933A1 (en) | Derivatives of alcadienes, their preparations and medicinal compositions containing them and intermediates | |
| EP0376850B1 (en) | Benzene derivates, their preparation and pharmaceutical compositions containing them | |
| EP0002978B1 (en) | Thiazolidinedione-2,4 derivatives, their preparation and pharmaceutical applications | |
| EP0042322B1 (en) | Indene derivatives, their preparation and medicines containing them | |
| EP0275742B1 (en) | 5-hydroxymethyl derivatives of 2-oxazolidinones, their preparation and their therapeutical use | |
| EP0327455A1 (en) | Alkyl or benzyl ethers of phenol, processes for their preparation and their therapeutical use | |
| EP0173585B1 (en) | Medicines based on piperidine derivatives, piperidine derivatives and process for their preparation | |
| CH475246A (en) | Process for preparing a substituted naphthalene | |
| EP0656884A1 (en) | Novel poly-iodated compounds, method of preparation and contrast product containing same | |
| EP0294258A1 (en) | Hydrazine derivatives, process for obtaining them and pharmaceutical composition containing them | |
| FR2506769A2 (en) | Cyano:pentyl:phenyl-methoxymethyl-oxazolidinone - useful as antidepressant | |
| EP0100257B1 (en) | Aminoalkyl naphthalene derivatives, their salts, process for their preparation and the therapeutical use of these derivatives and salts | |
| EP0005385A1 (en) | Piperazine methane imine derivatives, methods for their preparation and their therapeutical use | |
| FR2508032A1 (en) | 3-Amino-2-aryloxy-methyl-1-propanol derivs. - are used to treat cardiovascular troubles, esp. angina esp 3-tri:methoxy-cinnamoyl-piperazino- 2-1,4-benzodioxan-5-yl-oxy-methyl cpds. | |
| EP0082059A1 (en) | Alpha-Beta-unsaturated oxime ethers, process for their preparation and their use as medicines | |
| EP0259228A1 (en) | 5-Aminomethyl-2-oxazolidinone derivatives, their preparation and their therapeutical use | |
| FR2692894A1 (en) | Aryl-1- (o-alkoxy-phenyl-4-piperazinyl-1) -2,3-or 4-alkanols, process for their preparation and their use in the preparation of medicaments. | |
| CH420107A (en) | Process for the preparation of new substituted aralkylaminoalkylcyclohexane derivatives | |
| EP0226475A1 (en) | Diphenoxyethyl amine derivatives, process for their preparation and pharmaceutical compositions containing them | |
| EP0113600B1 (en) | Gamma-butyrolactone derivatives with myocardium protecting and antiarrhytmic activity, process for their preparation and medicines containing them | |
| FR2461497A1 (en) | NOVEL THERAPEUTIC COMPOSITIONS BASED ON CERTAIN ISOQUINOLINE DERIVATIVES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |