CH501595A - 2-phenoxy-2-phenylacetamides - Google Patents
2-phenoxy-2-phenylacetamidesInfo
- Publication number
- CH501595A CH501595A CH131068A CH131068A CH501595A CH 501595 A CH501595 A CH 501595A CH 131068 A CH131068 A CH 131068A CH 131068 A CH131068 A CH 131068A CH 501595 A CH501595 A CH 501595A
- Authority
- CH
- Switzerland
- Prior art keywords
- carbon atoms
- dimethylpiperidino
- phenoxy
- formula
- atoms
- Prior art date
Links
- QEBZGDYGMMSNRY-UHFFFAOYSA-N 2-phenoxy-2-phenylacetamide Chemical class C=1C=CC=CC=1C(C(=O)N)OC1=CC=CC=C1 QEBZGDYGMMSNRY-UHFFFAOYSA-N 0.000 title abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical group 0.000 claims 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 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 12
- SUKGAHDFSLAYEI-UHFFFAOYSA-N 5-(2,6-dimethylpiperidin-1-yl)pentan-1-amine Chemical compound CC1CCCC(C)N1CCCCCN SUKGAHDFSLAYEI-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 2
- 239000000284 extract Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- ABUKMOCUMIPDHV-UHFFFAOYSA-N 2-phenoxy-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)OC1=CC=CC=C1 ABUKMOCUMIPDHV-UHFFFAOYSA-N 0.000 abstract 1
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- -1 pyrrolidino, pyrrolidino Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 description 2
- UDEJUBDPPQVWEX-UHFFFAOYSA-N 2-bromo-2-phenylacetyl chloride Chemical compound ClC(=O)C(Br)C1=CC=CC=C1 UDEJUBDPPQVWEX-UHFFFAOYSA-N 0.000 description 2
- CLHNVBRCQXWHLZ-UHFFFAOYSA-N 4-(2,6-dimethylpiperidin-1-yl)butan-1-amine Chemical compound CC1CCCC(C)N1CCCCN CLHNVBRCQXWHLZ-UHFFFAOYSA-N 0.000 description 2
- DWGYWTUZNOPSLU-UHFFFAOYSA-N 4-(2,6-dimethylpiperidin-1-yl)butanenitrile Chemical compound CC1CCCC(C)N1CCCC#N DWGYWTUZNOPSLU-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- CIBGXJVJPZCMFX-UHFFFAOYSA-N 2-bromobutanenitrile Chemical compound CCC(Br)C#N CIBGXJVJPZCMFX-UHFFFAOYSA-N 0.000 description 1
- ORGQCHRBCWEDEW-UHFFFAOYSA-N 5-(2,6-dimethylpiperidin-1-yl)pentanenitrile Chemical compound CC1CCCC(C)N1CCCCC#N ORGQCHRBCWEDEW-UHFFFAOYSA-N 0.000 description 1
- KPJYGUUXENZNQM-UHFFFAOYSA-N CC1CCCC(C)N1CCCCCNC(=O)C(OC1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CC1CCCC(C)N1CCCCCNC(=O)C(OC1=CC=CC=C1)C1=CC=CC=C1 KPJYGUUXENZNQM-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 239000008096 xylene Substances 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
- C07D295/12—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 or doubly bound nitrogen atoms
- C07D295/125—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
(A) 2-Phenoxy-2-phenylacetamides (I) A= (2-7C) alkylene, with at least 2 consecutive C atoms separating the N atoms. R1 & R2 = (1-6C) alkyl or (is not >6C) cycloalkyl, or together = (4-9C) alkylene, with 4 or 5 atoms forming a ring together with N. (B) Acid addn. salts of (I) a) Anti-arrhythmics b) Intermediates 2-phenoxy-2-phenylacetic acid ethyl esster (25.6g) and 5-(2,6-dimethylpiperidino) pentylamine (19.8g) were heated 22hr. at 150-160 deg., cooled, dissolved in PhMe, and extd. with d.HCl. Extract basified (NaOH), extd. with PhMe, dried, filtered, evapd. in vac., and recryst from Ph-Me/Petrol, giving I, m.p. 100-2 deg.
Description
Procédé de préparation d'amides organiques
La présente invention a pour objet un procédé de préparation de nouveaux 2phénoxy-2-phénylacétamides de formule:
EMI1.1
Dans la formule ci-dessus A est un groupe alcoylène ayant de 2 à 7 atomes de carbone inclus, et séparant les atomes d'azote auxquels il est relié par au moins deux atomes de carbone; Rj et R. sont un radical alcoyle ou cycloalcoyle contenant au plus 6 atomes de carbone, ou Rt et R sont réunis et représentent ensemble un groupe alcoylène ayant de 4 à 9 atomes de carbone inclus, 4 ou 5 atomes de carbone formant un cycle avec l'atome d'azote auquel ils sont fixés.
Lorsque R1 et R sont réunis et forment un groupe alcoylène, la combinaison -NR1R2 représente un groupe pyrrolidino, pyrrolidino(alcoyle infé rieur)-substitué, pipéridino ou pipéridino(alcoyle inférieur)-substitué.
Conformément à l'invention, les composés précédents sont préparés en faisant réagir un ce-haloamide de formule:
EMI1.2
avec un phénoxyde de formule:
EMI1.3
dans ces formules A, R1 et R sont comme définis plus haut; X est un atome d'halogène, de préférence de brome; et M est un métal alcalin. On utilise normalement des quantités équimoléculaires des réactifs ou jus qu'à un excès modéré du phénoxyde. Si on le désire, on peut former l'a-haloamide in situ par la réaction d'un sel d'addition d'acide avec une base forte. De même on peut former le phénoxyde in situ par la réaction du phénol avec une base forte. Une base forte appropriée à ce but est un alcoxyde de métal alcalin.
Des solvants appropriés pour la réaction sont les alcanols inférieurs anhydres comme le méthanol, L'méthanol et l'alcool isopropylique; des éthers comme le diéthyléther, le diisopropyléther et le dibutyléther; et des hydrocarbures comme le benzène, le toluène et le xylène. Un solvant que l'on préfère est l'éthanol anhydre. La durée et la température de la réaction ne sont pas critiques et d'habitude on effectue la réaction à une température de 50 à 1500 C ou à la température de reflux du solvant, pendant une période de 4 à 48 heures. A la température de reflux de l'éthanol, un temps de réaction de 12 à 20 heures suffit.
On isole le produit soit comme base libre, soit comme sel d'addition d'acide en ajustant le pH selon les besoins.
Les a-haloamides requis comme matières de départ dans ce procédé peuvent être préparés de diverses manières. Par exemple. on fait réagir un halogénure dX-ha- lophénylacétyle avec une diamine de formule: HaN-A-NRtR.
dans un solvant non hydroxylique à une température inférieure à 00 C afin d'obtenir un sel d'hydracide de l'u.- haloamine; A, R1 et R, sont comme définis précédemment. On utilise ce produit tel quel dans le procédé selon l'invention ou après sa conversion en base libre. Les bases libres obtenues par le procédé selon Invention forment des sels d'addition d'acides avec toute une variété d'acides inorganiques et organiques.
Des sels d'addition pharmaceutiquement acceptables sont formés par la réac tion avec des acides tels que l'acide chlorhydrique, bromhydrique, sulfurique, phosphorique, acétique, succinique, citnque, maléique et pamoique. Les sels d'addition d'acides sont convertis en bases libres par la réaction avec une base telle que l'hydroxyde de sodium, le carbonate de potassium ou le bicarbonate de potassium. Les bases libres et leurs sels d'addition d'acides ont des propriétés de solubilité différentes mais autrement sont généralement équivalents pour les buts de l'invention.
Les composés préparés conformément à Invention sont utiles en tant qu'agents pharmacologiques et comme produits chimiques intermédiaires. Ils sont d'une valeur particulière comme agents antiarythmiques capables de rétablir un rythme cardiaque normal. On peut mesurer quantitativement leur activité par un essai standard de laboratoire. Dans cet essai standard, des chiens dont on a ligaturé la branche descendante antérieure de l'artère coronaire gauche manifestent de la tachycardie ventriculaire. On administre un composé de l'invention par voie intraveineuse et l'on mesure le pourcentage du rétablissement d'un rythme cardiaque normal. Un rétablissement complet ou presque complet du rythme cardiaque normal indique une activité élevée.
Certains des composés préférés de l'invention sont ceux dans lesquels le groupe
= NR1R2 représente le radical 2,6- diméthylpipéridino.
Exemple
En agitant, on ajoute 41,8 g de chlorhydrate de N-[4- (2,6-diméthylpipéridin.o)butyl] - 2 - bromo -2- phénylacétamide à une solution de 10,8 g de méthoxyde de sodium et de 9,4 g de phénol dans 500 ml d'éthanol absolu. On chauffe à reflux le mélange de la réaction pendant 18 heures puis on refroidit et on filtre. On évapore le filtrat sous pression réduite et l'on obtient un résidu de N-[4
(2,6-diméthylpipéridino)butyl]-2-phénoxy -2- phénylacétamide. Pour la purification, on extrait le résidu à l'éther.
On lave l'extrait éthéré avec de l'eau, le sèche puis on évapore et on cristallise le résidu dans du benzène/éther de pétrole: il fond de 81 à 830 C.
Selon le procédé précédent, en remplaçant le chlorhydrate de N-[4-(2,6-diméthylpipéridinobutyl]-2-bromo-2- phénylacétamide par 43,2 g de chlorhydrate de N-[5-(2,6 diméthylpipéridino)pentyl]-2-bromo -2 - phénylacétamide.
on obtient le N-[5- (2,6-diméthylpipéridino)pentyl] -2-phé- noxy-2-phénylacétamide qui fond de 100 à 1020 C.
On chauffe à reflux pendant 5 heures une solution de 148 g de 2-bromo-butyronitrile et de 226 g de 2,6diméthylpipéridine dans 400 ml de toluène. On refroidit le mélange de la réaction et le rend légèrement acide avec de l'acide chlorhydrique dilué. On sépare la couche aqueuse, la rend basique avec une solution d'hydroxyde de sodium, puis l'extrait à l'éther. On sèche et on évapore l'extrait d'éther pour obtenir un résidu de 4-(2,6-diméthylpipéridino)butyronitrile qui bout de 140 à 1500 C sous 14 mu. Selon la même méthode, on obtient encore le 5-(2,6-diméthylpipéridino)valéronitrile; p éb. 164-1660 C sous 20 mm.
En agitant on ajoute goutte à goutte 121 g de 4-(2,6 diméthylpipéridino)butyronitrile à 25,5 g d'hydrure de lithium-aluminium dans 2000 ml d'éther. On chauffe alors à reflux le mélange de la réaction pendant 2 heures et on le dilue avec 27 ml d'eau, 20 ml d'hydroxyde de sodium aqueux à 20 oxo et 90 ml d'eau ajoutés dans l'ordre indiqué. On sépare la matière insoluble par filtration et l'on évapore le filtrat sous pression réduite et l'on obtient un résidu de 4- (2,6-diméthylpipéridino)butylamine qui bout de 130 à 1340 C sous 16 mm.
En agitant et en refroidissant extérieurement jusqu'à - 100 C, on ajoute 18,4 g de 4-(2,6-diméthylpipéridino)butylamine à une solution de 23,4 g de chlorure de 2bromo-2-phénylacétyle dans 200ml de tétrachlorure de carbone. On laisse le mélange se réchauffer à la température ordinaire puis on l'évapore sous pression réduite et l'on obtient un résidu de chlorhydrate de N-[4-(2,6diméthylpipéridino)butyl] -2- bromo -2 - phénylacétamide, qui peut être utilisé sans autre purification. Selon le même procédé, on fait réagir de la 5-(2,6-diméthylpipéridino)pentylamine et du chlorure de 2-bromo-2-phénylacétyle pour obtenir du chlorhydrate de N-[5-(2,6-diméthylpipéridino)pentyl] -2-bromo-2-phénylacétamide.
De manière similaire on prépare encore la 5-(2,6 diméthylpipéridino)pentylamine; p. éb. 86-880 C sous 0,25 mm.
Process for preparing organic amides
The subject of the present invention is a process for preparing novel 2phenoxy-2-phenylacetamides of formula:
EMI1.1
In the above formula A is an alkylene group having from 2 to 7 carbon atoms inclusive, and separating the nitrogen atoms to which it is attached by at least two carbon atoms; Rj and R. are an alkyl or cycloalkyl radical containing at most 6 carbon atoms, or Rt and R are united and together represent an alkylene group having from 4 to 9 carbon atoms inclusive, 4 or 5 carbon atoms forming a ring with the nitrogen atom to which they are attached.
When R1 and R are united and form an alkylene group, the combination -NR1R2 represents a pyrrolidino, pyrrolidino (lower alkyl) -substituted, piperidino or piperidino (lower alkyl) -substituted group.
In accordance with the invention, the preceding compounds are prepared by reacting a ce-haloamide of formula:
EMI1.2
with a phenoxide of formula:
EMI1.3
in these formulas A, R1 and R are as defined above; X is a halogen atom, preferably bromine; and M is an alkali metal. Normally, equimolecular amounts of the reactants or up to a moderate excess of the phenoxide are used. If desired, the α-haloamide can be formed in situ by reacting an acid addition salt with a strong base. Likewise, the phenoxide can be formed in situ by the reaction of the phenol with a strong base. A strong base suitable for this purpose is an alkali metal alkoxide.
Suitable solvents for the reaction are anhydrous lower alkanols such as methanol, methanol and isopropyl alcohol; ethers such as diethyl ether, diisopropyl ether and dibutyl ether; and hydrocarbons such as benzene, toluene and xylene. A preferred solvent is anhydrous ethanol. The time and temperature of the reaction are not critical and the reaction is usually carried out at a temperature of 50 to 1500 C or at the reflux temperature of the solvent, for a period of 4 to 48 hours. At the ethanol reflux temperature, a reaction time of 12 to 20 hours is sufficient.
The product is isolated either as a free base or as an acid addition salt by adjusting the pH as needed.
The α-haloamides required as starting materials in this process can be prepared in various ways. For example. an dX-halophenylacetyl halide is reacted with a diamine of the formula: HaN-A-NRtR.
in a non-hydroxylic solvent at a temperature below 00 C to obtain a hydracid salt of u-haloamine; A, R1 and R, are as defined above. This product is used as it is in the process according to the invention or after its conversion into free base. The free bases obtained by the process according to the invention form acid addition salts with a variety of inorganic and organic acids.
Pharmaceutically acceptable addition salts are formed by reaction with acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, succinic, citric, maleic and pamic acid. Acid addition salts are converted to free bases by reaction with a base such as sodium hydroxide, potassium carbonate or potassium bicarbonate. Free bases and their acid addition salts have different solubility properties but otherwise are generally equivalent for the purposes of the invention.
The compounds prepared according to the invention are useful as pharmacological agents and as chemical intermediates. They are of particular value as antiarrhythmic agents capable of restoring a normal heart rhythm. Their activity can be quantitatively measured by a standard laboratory test. In this standard trial, dogs whose anterior descending branch of the left coronary artery has been ligated exhibit ventricular tachycardia. A compound of the invention is administered intravenously and the percentage of restoration of normal heart rhythm is measured. A complete or almost complete recovery of the normal heart rhythm indicates high activity.
Some of the preferred compounds of the invention are those in which the group
= NR1R2 represents the 2,6-dimethylpiperidino radical.
Example
With stirring, 41.8 g of N- [4- (2,6-dimethylpiperidin.o) butyl] - 2 - bromo -2-phenylacetamide hydrochloride is added to a solution of 10.8 g of sodium methoxide and 9.4 g of phenol in 500 ml of absolute ethanol. The reaction mixture is refluxed for 18 hours then cooled and filtered. The filtrate is evaporated under reduced pressure and a residue of N- [4 is obtained.
(2,6-Dimethylpiperidino) butyl] -2-phenoxy -2-phenylacetamide. For purification, the residue is extracted with ether.
The ethereal extract is washed with water, dried and then evaporated and the residue crystallized from benzene / petroleum ether: it melts at 81 to 830 C.
According to the preceding process, by replacing the hydrochloride of N- [4- (2,6-dimethylpiperidinobutyl] -2-bromo-2-phenylacetamide with 43.2 g of N- [5- (2,6 dimethylpiperidino) pentyl hydrochloride ] -2-bromo -2 - phenylacetamide.
N- [5- (2,6-dimethylpiperidino) pentyl] -2-phenoxy-2-phenylacetamide is obtained which melts at 100 to 1020 C.
A solution of 148 g of 2-bromo-butyronitrile and 226 g of 2,6dimethylpiperidine in 400 ml of toluene is refluxed for 5 hours. The reaction mixture is cooled and made slightly acidic with dilute hydrochloric acid. The aqueous layer is separated, made basic with sodium hydroxide solution, then extracted with ether. The ether extract is dried and evaporated to give a residue of 4- (2,6-dimethylpiperidino) butyronitrile which boils at 140 to 1500 C under 14 mu. By the same method, 5- (2,6-dimethylpiperidino) valeronitrile is also obtained; p eb. 164-1660 C under 20 mm.
With stirring, 121 g of 4- (2,6 dimethylpiperidino) butyronitrile are added dropwise to 25.5 g of lithium aluminum hydride in 2000 ml of ether. The reaction mixture was then heated to reflux for 2 hours and diluted with 27 ml of water, 20 ml of 20 oxo aqueous sodium hydroxide and 90 ml of water added in the order listed. The insoluble material is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue of 4- (2,6-dimethylpiperidino) butylamine which boils at 130 to 1340 C under 16 mm.
While stirring and cooling externally to - 100 C, 18.4 g of 4- (2,6-dimethylpiperidino) butylamine are added to a solution of 23.4 g of 2bromo-2-phenylacetyl chloride in 200ml of tetrachloride of carbon. The mixture is allowed to warm to room temperature and then evaporated under reduced pressure to give a residue of N- [4- (2,6dimethylpiperidino) butyl] -2-bromo -2-phenylacetamide, which can be used without further purification. According to the same process, 5- (2,6-dimethylpiperidino) pentylamine and 2-bromo-2-phenylacetyl chloride are reacted to obtain N- [5- (2,6-dimethylpiperidino) pentyl] hydrochloride. -2-bromo-2-phenylacetamide.
In a similar manner, 5- (2,6 dimethylpiperidino) pentylamine is also prepared; p. eb. 86-880 C at 0.25 mm.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45051065A | 1965-04-23 | 1965-04-23 | |
| CH585666A CH451907A (en) | 1965-04-23 | 1966-04-22 | Process for preparing organic amides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH501595A true CH501595A (en) | 1971-01-15 |
Family
ID=25698522
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH131068A CH501595A (en) | 1965-04-23 | 1966-04-22 | 2-phenoxy-2-phenylacetamides |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH501595A (en) |
-
1966
- 1966-04-22 CH CH131068A patent/CH501595A/en not_active IP Right Cessation
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| PL | Patent ceased |