DE1199779B - Process for the preparation of N-benzyl-alpha, alpha-dimethyl-beta- (p-fluorophenyl) -aeth and its salts - Google Patents
Process for the preparation of N-benzyl-alpha, alpha-dimethyl-beta- (p-fluorophenyl) -aeth and its saltsInfo
- Publication number
- DE1199779B DE1199779B DET24221A DET0024221A DE1199779B DE 1199779 B DE1199779 B DE 1199779B DE T24221 A DET24221 A DE T24221A DE T0024221 A DET0024221 A DE T0024221A DE 1199779 B DE1199779 B DE 1199779B
- Authority
- DE
- Germany
- Prior art keywords
- fluorophenyl
- dimethyl
- benzyl
- salts
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 title 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 239000002262 Schiff base Substances 0.000 claims description 2
- 150000004753 Schiff bases Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- -1 benzyl halide Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 150000002739 metals Chemical class 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 claims description 2
- 230000000737 periodic effect Effects 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- 230000004899 motility Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000005574 benzylation reaction Methods 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
AUSLEGESCHRIFTEDITORIAL
Int. α.:Int. α .:
C07cC07c
Deutsche Kl.: 12 q-1/02 German class: 12 q- 1/02
Nummer: 1199 779Number: 1199 779
Aktenzeichen: T 24221IV b/12 qFile number: T 24221IV b / 12 q
Anmeldetag: 2. Juli 1963 Filing date: July 2, 1963
Auslegetag: 2. September 1965Opening day: September 2, 1965
Als Psychotonika und zentralstimulierende Mittel werden eine erhebliche Anzahl von chemischen Verbindungen verwendet, unter denen das Coffein und seine Strukturanaloga, das l-Phenyl-2-aminopropan und l-Phenyl-2-methylaminopropan wohl die häufigste Anwendung gefunden haben. Diese zentralstimulierend gut wirksamen Verbindungen weisen jedoch neben einer verhältnismäßig hohen Toxizität gemeinsam als häufig unerwünschte Nebenwirkung eine starke Kreislauf wirkung auf, die ihre Anwendung bei einem unter Kreislaufbelastung stehenden Personenkreis, z. B. Hypertonikern oder älteren Patienten, erschwert.As psychotonics and central stimulants, a significant number of chemical are used Compounds used, among which the caffeine and its structural analogues, the l-phenyl-2-aminopropane and l-phenyl-2-methylaminopropane probably the most common application. These compounds have a good central stimulating effect however, in addition to a relatively high toxicity, they have one common side effect, which is often undesirable strong circulatory effect, which makes its use in a group of people who are under circulatory stress, z. B. hypertensive or elderly patients.
Es ergab sich daher die Aufgabenstellung, Substanzen von guter zentralstimulierender Wirksamkeit und geringer Toxizität zu finden, die keine Kreislaufwirkung besitzen.The task was therefore to find substances with a good central stimulating effect and low toxicity that have no circulatory effect.
Ausgehend von dem wegen seiner geringen Kreislaufwirkung und geringen Toxizität, aber auch wegen seiner fehlenden zentralen Stimulation bereits bekannten ao l-(p-Chlorphenyl)-2-methyl-2-aminopropan (im weiteren Verlauf als I bezeichnet) wurde festgestellt, daß durch Benzylierung von I zum N-Benzylderivat (Hydrochlorid F. = 224 bis 225°C) eine Verbindung erhalten wird, bei der trotz geringer Toxizität und fehlender Kreislaufwirkung eine zentralstimulierende Wirkung vorhanden ist. Das ebenfalls hergestellte N-(p-Chlorbenzyl)-derivat von I (Hydrochlorid F. = 259 bis 2600C) und das N-Benzyl-N-methylderivat von I (F. = 63,5 bis 64,3° C) führten zunächst zuVerbindungen mit ungünstigeren pharmakologischen Eigenschaften. Durch Benzylierung des schwach zentralerregend wirkenden «,«-Dimethyl-/3-(p-fluorphenyl)-äthylamins (Hydrochlorid F. = 185 bis 186° C) wurde jedoch überraschend in dem N-Benzyl-«,a-dimethyl-/3-(p-fluorphenyl)-äthylamin eine Verbindung von starker zentralstimulierender Wirkung und geringer Toxizität gefunden. Ihr stimulierender Effekt ist nur l,5mal geringer als der von D,L-1-Phenyl-2-aminopropan; sie ist jedoch 15mal weniger toxisch und weist damit einen lOmal größeren therapeutischen Index auf. Darüber hinaus zeigt die Verbindung keine pharmakologisch nachweisbaren Kreislaufwirkungen.Starting from the ao l- (p-chlorophenyl) -2-methyl-2-aminopropane (referred to below as I), which is already known because of its low circulatory effect and low toxicity, but also because of its lack of central stimulation, it was found that by benzylation from I to the N-benzyl derivative (hydrochloride temperature = 224 to 225 ° C) a compound is obtained in which, despite low toxicity and lack of circulatory effects, a central stimulating effect is present. The likewise produced N- (p-chlorobenzyl) derivative of I (hydrochloride F. = 259 to 260 0 C) and the N-benzyl-N-methyl derivative of I (F. = 63.5 to 64.3 ° C) initially led to compounds with less favorable pharmacological properties. However, by benzylation of the weak central excitatory "," - dimethyl- / 3- (p-fluorophenyl) -ethylamine (hydrochloride mp = 185 to 186 ° C) surprisingly in the N-benzyl - ", a-dimethyl- / 3 - (p-fluorophenyl) ethylamine found a compound with a strong central stimulating effect and low toxicity. Their stimulating effect is only 1.5 times less than that of D, L-1-phenyl-2-aminopropane; however, it is 15 times less toxic and thus has a 10 times greater therapeutic index. In addition, the compound shows no pharmacologically detectable circulatory effects.
Das Maß der erregenden Wirkung von N-Benzyl- «,a-dimethyl-(S-(p-fluorphenyl)-äthylamin (die sögenannte
Spontanmotilität) wurde an Ratten von 60 bis 100 g Gewicht nach oraler Applikation nach
der modifizierten Methode von Druckrey und Köhler (Naunyn-Schmiedebergs Archiv für experimentelle
Pathologie und Pharmakologie, Bd. 183 [1936] S. 106) geprüft, bei der die Bewegung der
Versuchstiere mittels eines am Ohr befestigten Hebels Verfahren zur Herstellung von N-Benzyla,a-dimethyl-ß-(p-fluorphenyl)-äthylaminund
dessen SalzenThe degree of the excitatory effect of N-benzyl- «, a-dimethyl- (S- (p-fluorophenyl) ethylamine (the so-called spontaneous motility) was determined in rats weighing 60 to 100 g after oral administration according to the modified method of Druckrey and Köhler (Naunyn-Schmiedebergs Archiv für experimental Pathologie und Pharmakologie, Vol. 183 [1936] p. 106) examined, in which the movement of the test animals by means of a lever attached to the ear process for the production of N-benzyla, a-dimethyl-ß- (p-fluorophenyl) ethylamine and
its salts
Anmelder:Applicant:
Troponwerke Dinklage & Co.,Troponwerke Dinklage & Co.,
Köln-Mülheim, Berliner Str. 220-232Cologne-Mülheim, Berliner Str. 220-232
Als Erfinder benannt:Named as inventor:
Dr. Dietrich Lorenz,Dr. Dietrich Lorenz,
Kleinhurden, Post Immekeppel-Bensberg;Kleinhurden, Post Immekeppel-Bensberg;
Dipl.-Chem. Dr. Karl-Heinz Boltze,Dipl.-Chem. Dr. Karl-Heinz Boltze,
Bensberg bei KölnBensberg near Cologne
über eine Kontaktleiste auf einen Telefonzähler übertragen wird (vgl. auch R. Kopf und D. Lorenz, Archiv für experimentelle Pathologie und Pharmakologie, Bd. 241 [1961] S. 185). 30 Minuten nach Applikation werden 30 Minuten lang die Impulse gezählt. Als Maß der motilitätssteigernden Wirkung wurde aus Dosiswirkungskurven die Dosis ermittelt, die die Motilität auf durchschnittlich 2000 Impulse, etwa dem doppelten Wert der Spontanmotilität, erhöht (De// 2000)· Die Werte betragen für die erfindungsgemäße Verbindung: Bei einer Dosis von 3 mg/kg 1296 Impulse/30 Minuten, bei 6,25 mg 2041, bei 12,5 mg 1833, bei 25 mg 2300 und bei 50 mg 3159 (Durchschnittswerte von je zwölf Tieren). Mittlere ZV/2000 ist 10 mg/kg. Die De// 2000 von D,L-l-Phenyl-2-aminopropan und Coffein belaufen sich auf etwa 6 bis 7 mg/kg. Demnach ist die erfindungsgemäße Verbindung I1I2OHaI schwächer erregend wirksam als die beiden Vergleichssubstanzen. 20 mg/kg D,L-1-Phenyl-2-aminopropan bewirken eine gleichbleibende Motilitätssteigerung von über 7V2 Stunden, bei äquimolarer Dosis von 32 mg der erfindungsgemäßen Verbindung ist die Wirkung nach 4 Stunden abgeklungen; eine unerwünscht langanhaltende stimulierende Wirkung tritt demnach bei normaler Dosierung nicht ein. Die DL50 der erfindungsgemäßen Verbindung beträgt oral 500 mg/kg (5-Tage-Versuch), bei D,L-1-Phenyl-2-aminopropan 33,5 mg/kg. Der »therapeutiche Index« (Abstand zwischen den motilitätssteigernd wirksamen Dosen und DL50-Werten) beträgt für die erfindungsgemäße Verbindung 50, bei D,L-l-Phenyl-2-aminopropan hingegen nur 5. Die mydriatische Wirkung ist bei der erfindungsgemäßen Verbindung 2- bis 3mal schwächer als bei D,L-l-Phenyl-2-aminopropan. Dieis transmitted via a contact strip to a telephone counter (see also R. Kopf and D. Lorenz, Archive for experimental pathology and pharmacology, vol. 241 [1961] p. 185). 30 minutes after application, the impulses are counted for 30 minutes. As a measure of the motility-increasing effect, the dose was determined from dose-effect curves, which increases the motility to an average of 2000 impulses, about twice the value of spontaneous motility (De // 2000) The values for the compound according to the invention are: At a dose of 3 mg / kg 1296 impulses / 30 minutes, at 6.25 mg 2041, at 12.5 mg 1833, at 25 mg 2300 and at 50 mg 3159 (average values of twelve animals each). Mean ZV / 2000 is 10 mg / kg. The D e // 2000 of D, Ll-phenyl-2-aminopropane and caffeine amount to about 6 to 7 mg / kg. Accordingly, the compound I 1 I 2 OHaI according to the invention is less exciting than the two comparison substances. 20 mg / kg of D, L-1-phenyl-2-aminopropane cause a constant increase in motility of over 7V 2 hours, with an equimolar dose of 32 mg of the compound according to the invention the effect has subsided after 4 hours; an undesirably long-lasting stimulating effect therefore does not occur with normal dosage. The DL 50 of the compound according to the invention is 500 mg / kg orally (5-day test), and 33.5 mg / kg for D, L-1-phenyl-2-aminopropane. The "therapeutic index" (distance between the motility-increasing effective doses and DL 50 values) is 50 for the compound according to the invention, whereas it is only 5 for D, Ll-phenyl-2-aminopropane. The mydriatic effect of the compound according to the invention is 2- to 3 times weaker than with D, Ll-phenyl-2-aminopropane. the
509 659/461509 659/461
Untersuchung der Kreislaufwirkung bei intravenöser Verabreichung an der narkotisierten Katze ergab bis zur Verträglichkeitsgrenze bei Dosen von 1 bis 5 mg keine spezifischen Blutdruckänderungen. Versuche am Menschen bei einer Dosierung von 10 mg oral zeigten einen etwa 2stündigen Wachhalteeffekt, ohne daß Kreislaufsensationen oder euphorisierende Effekte wie bei D,L-l-Phenyl-2-aminopropan festgestellt wurden. Investigation of the circulatory effects when administered intravenously to the anesthetized cat showed up to No specific changes in blood pressure compared to the tolerance limit at doses of 1 to 5 mg. Attempts on Humans at a dose of 10 mg orally showed an approximately 2 hour wakefulness effect without this Circulatory sensations or euphoric effects such as those found with D, L-l-phenyl-2-aminopropane.
Gegenstand der Erfindung ist daher ein Verfahren zur Herstellung von N-Benzyl-*,<x-dimethyl-^-(p-fluorphenyl)-äthylamin und dessen Salzen, welches dadurch gekennzeichnet ist, daß in an sich bekannter Weise «,«-Dimethyl-^ip-fluorphenyrj-äthylammThe invention therefore relates to a process for the preparation of N-benzyl - *, <x-dimethyl - ^ - (p-fluorophenyl) ethylamine and its salts, which is characterized in that in a manner known per se "," - Dimethyl- ^ ip-fluorophenyrj-ethylamm
a) mit Benzaldehyd umgesetzt und die entstehende 1S Schiffsche Base anschließend mit einem gemischten Metallhydrid der Metalle der I. und III. Gruppe des Periodischen Systems, z. B. LiAlH4 oder NaBH4, oder auch katalytisch an Nickel- oder Edelmetallkatalysatoren hydriert odera) reacted with benzaldehyde and the resulting 1 S Schiff base then with a mixed metal hydride of the metals of the I. and III. Group of the Periodic Table, e.g. B. LiAlH 4 or NaBH 4 , or catalytically hydrogenated over nickel or noble metal catalysts or
b) mit einem Benzylhalogenid oder einem Ester von Benzylalkohol und einer Sulfonsäure, z. B. p-Toluolsulfonsäure, umgesetzt und die so erhaltene freie Base gegebenenfalls in die Salze übergeführt wird bzw. die erhaltenen Salze der Base a5 in die freie Base übergeführt werden.b) with a benzyl halide or an ester of benzyl alcohol and a sulfonic acid, e.g. B. p-toluenesulfonic acid, reacted and the free base thus obtained is optionally converted into the salts or the obtained salts of the base a5 are converted into the free base.
Das als Ausgangssubstanz verwendete «,«-Dimethyl-j8-(p-fluorphenyl)-äthylamin kann durch Reaktion von Λ,«-Dimethyl-/S-fp-rluorphenyl)-bzw.|β,|ö-Dimethyl-«-(p-fluorphenyl)-äthanol mit einem AJkalicyanid oder mit Blausäure in Gegenwart einer starken organischen oder anorganischen Säure, wie Schwefelsäure, hergestellt werden. Für die Herstellung der Ausgangsverbindung wird Schutz im Rahmen der Erfindung nicht begehrt.The "," - dimethyl-18- (p-fluorophenyl) -ethylamine used as the starting substance can be obtained by the reaction of Λ, "- dimethyl- / S-fp-fluorophenyl) or | β, | ö-dimethyl-" - (p-fluorophenyl) -ethanol with an alkali cyanide or with hydrogen cyanide in the presence of a strong one organic or inorganic acid such as sulfuric acid. For making the Starting compound, protection is not sought in the context of the invention.
a) 14,5 g NaCN werden unter Eis-Kochsalz-Kühlung in 34 ml Eisessig gelöst, anschließend wird ein Gemisch aus 68 g konzentrierter Schwefelsäure und 34 ml Eisessig zugetropft und sodann 4,4 g α,α-Dimethyl-jÖ-(p-fluorphenyl)-äthanol zugefügt. Nach langsamen Erwärmen auf 50 bis 55 0C werden weitere 37,7 g des vorstehenden Alkoholderivats zugetropft, die Lösung 1 Stunde auf 7O0C erwärmt, abgekühlt und 2 Stunden bei Raumtemperatur stehengelassen. Beim Zufügen von Wasser tritt eine Trennung in zwei Schichten ein; die organische Phase wird ausgeäthert, mit Alkalilösung, Natriumhypochloridlösung und Wasser gewaschen, abgedampft und durch einstündiges Kochen mit konzentrierter Salzsäure verseift. Anschließend wird die Lösung alkalisiert, ausgeäthert, die ätherische Lösung mit Wasser neutralgewaschen, getrocknet, abgedampft und fraktioniert destilliert. Das gebildete a,«-Dimethyl-/5-(p-fluorphenyl)-äthylamin besitzt einen Siedepunkt von Kp.4 = 67°C; «B 20·5 = 1,4942. Das durch Einleiten von Chlorwasserstoff in die ätherische Lösung hergestellte Hydrochlorid zeigt einen Schmelzpunkt von 185 bis 186°C.a) 14.5 g of NaCN are dissolved in 34 ml of glacial acetic acid while cooling with ice and salt, then a mixture of 68 g of concentrated sulfuric acid and 34 ml of glacial acetic acid is added dropwise and then 4.4 g of α, α-dimethyl-jÖ- (p -fluorophenyl) ethanol added. After slowly heating to 50 to 55 0 C for an additional 37.7 g of the above alcohol derivative are added dropwise, the solution was heated for 1 hour at 7O 0 C, cooled and allowed to stand for 2 hours at room temperature. When water is added, a separation into two layers occurs; the organic phase is extracted with ether, washed with alkali solution, sodium hypochlorite solution and water, evaporated and saponified by boiling for one hour with concentrated hydrochloric acid. The solution is then made alkaline, extracted with ether, the ethereal solution washed neutral with water, dried, evaporated and fractionally distilled. The α, «- dimethyl / 5- (p-fluorophenyl) ethylamine formed has a boiling point of bp 4 = 67 ° C; « B 20 x 5 = 1.4942. The hydrochloride produced by introducing hydrogen chloride into the ethereal solution has a melting point of 185 to 186 ° C.
b) 0,1 Mol a,(x-Dimethyl-^-(p-fiuorphenyl)-äthylamin
werden in 50 ml absolutem Toluol aufgenommen, mit 0,05 Mol Benzylchlorid versetzt und unter Feuchtigkeitsausschluß
15 Stunden unter Rückfluß erhitzt. Nach dem Abkühlen der Lösung wird von ausgefallenem
Ä,«-Dimethyl-/9-(p-fluorphenyl)-äthylaminhydrochlorid
abfiltriert, der Filterinhalt mehrfach mit wenig Toluol gewaschen, die vereinigten Filtrate
im Vakuum abgedampft, der Eindampfrückstand in Äther aufgenommen und die so erhaltene Lösung
mit gasförmigem Chlorwasserstoff bis zur Beendigung der Fällung behandelt. Das hierbei ausgefallene
kristalline N-Benzyl-«,«-dimethyl-^-(p-fluorphenyl)-äthylamin-hydrochlorid
zeigt nach der mehrmaligen Rekristallisation aus Isopropanol einen Schmelzpunkt von 220 bis 2210C (unkorrigiert).
Analyse: C17H21ClFNb) 0.1 mol of a, (x-dimethyl - ^ - (p-fluorophenyl) ethylamine are taken up in 50 ml of absolute toluene, 0.05 mol of benzyl chloride is added and the mixture is refluxed for 15 hours with exclusion of moisture The solution is filtered off from the precipitated dimethyl- / 9- (p-fluorophenyl) -ethylamine hydrochloride, the filter contents are washed several times with a little toluene, the combined filtrates are evaporated in vacuo, the evaporation residue is taken up in ether and the resulting solution with gaseous hydrogen chloride treated until completion of the precipitation and the precipitated crystalline N-benzyl -. ',' - dimethyl - ^ - (p-fluorophenyl) ethylamine hydrochloride shows after repeated recrystallization from isopropanol, melting point 220-221 0 C (uncorrected) .
Analysis: C 17 H 21 ClFN
Berechnet... C 69,5, H 7,21, Cl 12,07, N 4,77; gefunden ... C 69,56, H 7,36, Cl 12,00, N 4,69.Calculated ... C 69.5, H 7.21, Cl 12.07, N 4.77; Found ... C 69.56, H 7.36, Cl 12.00, N 4.69.
a) l-(p-Fluorphenyl)-2-methyl-2-benzalaminopropan 167,2 g a,»-Dimethyl-/3-(p-fluorphenyl)-äthylamin werden unter Rühren innerhalb von 30 Minuten in eine auf 400C erwärmte Lösung von 111,5 g Benzaldehyd in 550 ml Methanol eingetropft und anschließend 1 Stunde erhitzt. Nach dem Abdestillieren des Lösungsmittels wird der Rückstand destilliert. Das gebildete l-(p-Fluorphenyl)-2-methyl-2-benzalaminopropan siedet bei Kp.0i3 = 135° C. Es erstarrt beim Abkühlen und schmilzt dann bei 45 bis 46° C. Ausbeute 94% der Theorie.a) l- (p-fluorophenyl) -2-methyl-2-benzalaminopropan 167.2 ga, '- dimethyl / 3- (p-fluorophenyl) ethylamine are heated with stirring within 30 minutes in a 40 0 C Solution of 111.5 g of benzaldehyde in 550 ml of methanol was added dropwise and then heated for 1 hour. After the solvent has been distilled off, the residue is distilled. The l- (p-fluorophenyl) -2-methyl-2-benzalaminopropane formed boils at boiling point 0.13 = 135 ° C. It solidifies on cooling and then melts at 45 to 46 ° C. Yield 94% of theory.
b) N-Benzyl-«,«-dimethyl-/?-(p-fluorphenyl)-äthylamin-hydrochlorid b) N-Benzyl - «,« - dimethyl - /? - (p-fluorophenyl) ethylamine hydrochloride
383 g vorstehender Verbindung werden in 21 CH3OH aufgenommen und an 7,5 g Platinoxyd nach Adams — Shriner hydriert. Nach Aufnahme der theoretischen Wasserstoffmenge wird vom Katalysator abfiltriert, das Lösungsmittel abdestilliert und der Rückstand mit der berechneten Menge 3n-Salzsäure vei setzt. Das nach 12stündigem Stehen auskristallisierende N-Benzyl-«,a-dimethyl-/3-(p-fluorphenyi)-äthylamin-hydrochlorid schmilzt nach der Rekristallisation aus Wasser bei 220 bis 2210C. Die Ausbeute beträgt 93,5% der Theorie.383 g of the above compound are taken up in 21 CH 3 OH and hydrogenated on 7.5 g of platinum oxide according to Adams-Shriner. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off, the solvent is distilled off and the residue is mixed with the calculated amount of 3N hydrochloric acid. The crystallizes after standing for 12 hours N-benzyl - «, a-dimethyl- / 3- (p-fluorphenyi) -ethylamine hydrochloride melts after recrystallization from water at 220-221 0 C. The yield is 93.5% of theory.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DET24221A DE1199779B (en) | 1963-07-02 | 1963-07-02 | Process for the preparation of N-benzyl-alpha, alpha-dimethyl-beta- (p-fluorophenyl) -aeth and its salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DET24221A DE1199779B (en) | 1963-07-02 | 1963-07-02 | Process for the preparation of N-benzyl-alpha, alpha-dimethyl-beta- (p-fluorophenyl) -aeth and its salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1199779B true DE1199779B (en) | 1965-09-02 |
Family
ID=7551365
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DET24221A Pending DE1199779B (en) | 1963-07-02 | 1963-07-02 | Process for the preparation of N-benzyl-alpha, alpha-dimethyl-beta- (p-fluorophenyl) -aeth and its salts |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1199779B (en) |
-
1963
- 1963-07-02 DE DET24221A patent/DE1199779B/en active Pending
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