CH629732A5 - Process for the preparation of acid addition salts of D-(+)-1-(3-hydroxyphenyl)-2-aminopropane with optically active acids - Google Patents
Process for the preparation of acid addition salts of D-(+)-1-(3-hydroxyphenyl)-2-aminopropane with optically active acids Download PDFInfo
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- CH629732A5 CH629732A5 CH510277A CH510277A CH629732A5 CH 629732 A5 CH629732 A5 CH 629732A5 CH 510277 A CH510277 A CH 510277A CH 510277 A CH510277 A CH 510277A CH 629732 A5 CH629732 A5 CH 629732A5
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- Prior art keywords
- hydroxyphenyl
- aminopropane
- addition salts
- acid addition
- blood pressure
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- 239000002253 acid Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000008569 process Effects 0.000 title claims description 4
- 150000007513 acids Chemical class 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 4
- 229960002748 norepinephrine Drugs 0.000 claims description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000036772 blood pressure Effects 0.000 claims 3
- 230000001766 physiological effect Effects 0.000 claims 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 229940030600 antihypertensive agent Drugs 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 claims 1
- 239000002830 appetite depressant Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 235000003642 hunger Nutrition 0.000 claims 1
- 230000011987 methylation Effects 0.000 claims 1
- 238000007069 methylation reaction Methods 0.000 claims 1
- 210000001640 nerve ending Anatomy 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 230000002889 sympathetic effect Effects 0.000 claims 1
- 210000002820 sympathetic nervous system Anatomy 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 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 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- PZYQCJTXVVWYSS-SNVBAGLBSA-N [(2R)-2-amino-3-(3-hydroxyphenyl)propyl] acetate Chemical compound OC=1C=C(C=CC=1)C[C@H](COC(C)=O)N PZYQCJTXVVWYSS-SNVBAGLBSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
-
- A—HUMAN NECESSITIES
- A63—SPORTS; GAMES; AMUSEMENTS
- A63B—APPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
- A63B22/00—Exercising apparatus specially adapted for conditioning the cardio-vascular system, for training agility or co-ordination of movements
- A63B22/0025—Particular aspects relating to the orientation of movement paths of the limbs relative to the body; Relative relationship between the movements of the limbs
- A63B2022/0033—Lower limbs performing together the same movement, e.g. on a single support element
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Der Erfindung liegt nun die Aufgabe zugrunde, ein Verfahren zur Herstellung von Verbindungen bereitszustellen, die es ermöglichen, hypotonische Kreislaufzustände unter Vergrössern des Minutenvolumens dergestalt zu behandeln, dass die Wirkung langsamer und damit schonender einsetzt und nach Verabreichung hoher Dosen der Maximaleffekt durch enzymatische Geschwindigkeit der Folgeumsetzungen im Körper begrenzt ist. Mit andern Worten, durch eine weniger plötzliche und länger anhaltende Wirkung soll die Gefahr einer Überdosierung verringert werden und ein Sym-pathikomimetikum und Hypertonikum geschaffen werden, das ausgesprochene Depotwirkung zeigt. The invention is based on the object of providing a process for the preparation of compounds which make it possible to treat hypotonic circulatory conditions by increasing the minute volume in such a way that the effect begins more slowly and therefore more gently and, after administration of high doses, the maximum effect due to the enzymatic speed of the subsequent reactions is limited in the body. In other words, a less sudden and longer lasting effect should reduce the risk of overdosing and create a sympathomimetic and hypertonic that shows pronounced depot effects.
Es wurde gefunden, dass physiologisch verträgliche Säureadditionssalze des D-(+)-l-(3-Hydroxyphenyl)-2-aminopro-pans mit optisch aktiven Säuren, insbesondere der Weinsäure, also als Bitartrat, diese Aufgabe in hervorragender Weise lösen. It has been found that physiologically compatible acid addition salts of D - (+) - l- (3-hydroxyphenyl) -2-aminopropane with optically active acids, in particular tartaric acid, that is to say as bitartrate, solve this problem in an outstanding manner.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man razemisches l-(3-Hydroxyphenyl)-2-ami-nopropan durch Einwirkung einer L-konfigurierten Säure aufspaltet. Während der Umsetzung können vorhandene Amino- und/oder Hydroxygruppen intermediär geschützt sein. Man verwendet vorzugsweise leicht abspaltbare Schutzgruppen. Die dann als Nebenprodukt anfallende L-Form kann z.B. über eine Oximbildung in das Racemat zurückverwandelt werden, das erneut der Trennung unterworfen wird. Bevorzugte Schutzgruppen sind solche, die unter Einwirkimg von Wasserstoff eine Umwandlung erfahren können, somit also voresterte oder verätherte Hydroxymethyl-und Carbonylgruppen sowie hydrogenolytisch abspaltbare Gruppen. Auch kann man, unter Schützen der Aminogruppe in der Seitenkette in den Arylrest in die 3-Stellung der D-Form die Hydroxylgruppe über die Bildung von Diazo-niumsalzen einführen. Andererseits könnte man auch von der L-Form eines Derivates ausgehen, wobei wiederum die Hydroxylgruppe des Arylrestes geschützt sein kann. Hier kommen vorzugsweise in der 2-Stellung substituierte Verbindungen, insbesondere Halogenderivate und aromatische Sulfonsäurereste in Frage, wobei man gewöhnlich mit konzentriertem Ammoniak umsetzt und nach dem SN2-Mechanis-mus eine Waldensche Umkehr in die R-Form ausführen kann. Eine Reihe dieser Verfahrensweisen werden nachfolgend anhand von Ausführungsbeispielen erläutert. The process according to the invention is characterized in that racemic l- (3-hydroxyphenyl) -2-aminopropane is split up by the action of an L-configured acid. Amino and / or hydroxyl groups present can be temporarily protected during the reaction. Easily removable protective groups are preferably used. The L-form then obtained as a by-product can e.g. be converted back into the racemate via an oxime formation, which is again subjected to the separation. Preferred protective groups are those which can undergo conversion under the action of hydrogen, that is to say thus pre-esterified or etherified hydroxymethyl and carbonyl groups and groups which can be split off by hydrogenolysis. Also, while protecting the amino group in the side chain, the hydroxyl group can be introduced into the 3-position of the D-form in the aryl group via the formation of diazo-nium salts. On the other hand, one could also start from the L-form of a derivative, which in turn may protect the hydroxyl group of the aryl radical. Compounds which are substituted in the 2-position, in particular halogen derivatives and aromatic sulfonic acid residues, are preferred, it being customary to react with concentrated ammonia and, according to the SN2 mechanism, a Waldensian reversal into the R form can be carried out. A number of these procedures are explained below using exemplary embodiments.
Beispiel 1 example 1
Trennung des Racemates von DL-l-(3-Hydroxyphenyl)-2--aminopropan Separation of the racemate from DL-1- (3-hydroxyphenyl) -2-aminopropane
Es werden 0,03 Mol (4,53 g) des Racemates und 0,03 Mol (4,5 g) L-Weinsäure in 60 ml Methanol unter Erwärmen gelöst. Nach dem Abkühlen der Lösung auf Raumtemperatur werden Impfkristalle des D-Form-bitartrates zugegeben. Man lässt über Nacht stehen. Nach dem Absaugen wird mit 10 ml eisgekühltem Methanol gewaschen. Anschliessend wird nochmals aus 20 ml Methanol umkristallisiert. Die Ausbeute beläuft sich auf 4,07 g entsprechend 90,0% des theoretischen Wertes bezogen auf die D-Form. 0.03 mol (4.53 g) of the racemate and 0.03 mol (4.5 g) of L-tartaric acid are dissolved in 60 ml of methanol while heating. After the solution has cooled to room temperature, seed crystals of the D-form bitartrate are added. You let it stand overnight. After suction, washing with 10 ml of ice-cold methanol. The mixture is then recrystallized again from 20 ml of methanol. The yield amounts to 4.07 g, corresponding to 90.0% of the theoretical value based on the D-form.
Fp = 184-185°C (unter Zersetzung). Mp = 184-185 ° C (with decomposition).
[a]D20 = 29,5°; c = 2 (H20) [a] D20 = 29.5 °; c = 2 (H20)
Aus den Mutterlaugen erhält man durch Einengen 4,2 g der L-Form entsprechend 92,9% des theoretischen Wertes bezogen auf die L-Form. 4.2 g of the L-form, corresponding to 92.9% of the theoretical value based on the L-form, are obtained from the mother liquors by concentration.
Fp = 160-165°C [a]D20 = 0,5°; c = 0,8 (HzO) Mp = 160-165 ° C [a] D20 = 0.5 °; c = 0.8 (HzO)
Die freie Base der D-Form wird aus dem Addukt unter Entfernen der L-Weinsäure vermittels Natriumbicarbonat in Freiheit gesetzt und aus Isopropanol-Ligroin umkristallisiert. The free base of the D-form is liberated from the adduct with removal of the L-tartaric acid by means of sodium bicarbonate and recrystallized from isopropanol-ligroin.
Fp = 152-154°C Mp = 152-154 ° C
[a]D21 = +14,9°; c = 1,3 (Methanol). [a] D21 = + 14.9 °; c = 1.3 (methanol).
Beispiel 2 Example 2
Hydrolyse des D-(+)-l-(3-Methoxyphenyl)-2-aminopropan Hydrolysis of D - (+) - l- (3-methoxyphenyl) -2-aminopropane
Es werden 2,42 Mol (40 g) der Verbindung in einem aus rostfreiem Stahl bestehenden Bombenrohr mit einem Fassungsvermögen von 500 ml 6 N Chlorwasserstoff säure gelöst. Bis zur Sättigimg wird in die eisgekühlte Lösung Chlorwasserstoffgas eingeleitet. Es wird sodann 2 Stunden lang auf 130°C im Luftbad erhitzt. Nach dem Abkühlen und Abtreiben der Chlorwasserstoffsäure bei geringfügig erhöhter Temperatur liegt das Hydrochlorid des 3-Hydroxyphenyl-derivates in Form eines gelblichen Sirups vor. [a]D26 = +6,9°; c = 2 (Methanol). There are 2.42 moles (40 g) of the compound in a stainless steel bomb tube with a capacity of 500 ml of 6 N hydrochloric acid dissolved. Hydrogen chloride gas is introduced into the ice-cooled solution until it is saturated. The mixture is then heated to 130 ° C. in an air bath for 2 hours. After cooling and stripping off the hydrochloric acid at a slightly elevated temperature, the hydrochloride of the 3-hydroxyphenyl derivative is in the form of a yellowish syrup. [a] D26 = + 6.9 °; c = 2 (methanol).
Die freie Base wird aus dem 'Hydrochlorid in Freiheit gesetzt, indem eine butanolische Lösimg desselben mehrmals mit Natriumbicarbonatlösung extrahiert wird. Nach Umkristallisieren aus Isopropanol-Ligroin beläuft sich die Ausbeute an D-(4-)-l-(3-Hydroxyphenyl)-2-aminopropan auf The free base is liberated from the hydrochloride by extracting a butanolic solution thereof several times with sodium bicarbonate solution. After recrystallization from isopropanol-ligroin, the yield of D- (4 -) - l- (3-hydroxyphenyl) -2-aminopropane is
5 5
10 10th
15 15
20 20th
25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
60 60
65 65
33,0 g entsprechend 90,1% der Theorie bezogen auf die D-Form. 33.0 g corresponding to 90.1% of theory based on the D form.
Fp = 152-154°C Mp = 152-154 ° C
[a]D21 = +14,9°; c = 1,3 (Methanol). [a] D21 = + 14.9 °; c = 1.3 (methanol).
Beispiel 3 Example 3
Hydrogenolyse von D-l-(3-Hydroxyphenyl)-2-amino-3-chlor-propanhydrochlorid Hydrogenolysis of D-1- (3-hydroxyphenyl) -2-amino-3-chloropropane hydrochloride
Es werden 0,04 Mol (10 g) der Verbindung in 200 ml Wasser gelöst und in eine mit Rührer, Tropftrichter und Gaseinführungsrohr versehene Hydriervorrichtung eingebracht. Nach Spülen mit Wasserstoff wird als Hydrierkatalysator Palladiumkohle in einer Menge von 10 g Aktivkohle mit einem Gehalt von 2,0 g Palladium zugesetzt. Nach Erhöhen der Temperatur auf 60°C wird das Reaktionsgemisch durch Zutropfen von 0,2 N Ammoniaklösung auf einen pH-Wert von 5,3-5,6 während der Wasserstoffaufnahme gehalten. Es werden rund 1000 ml Wasserstoff aufgenommen. Nachdem die Wasserstoffaufnahme abgeschlossen ist, wird das Reaktionsgemisch vom Katalysator abfiltriert und die Lösung eingeengt. Die Lösung wird mit Natriumbicarbonat leicht alkalisch gemacht und 0,05 Mol (5,6 ml) Benzaldehyd zugesetzt. Die ausfallende Schiffsche Base wird mit Äther extrahiert und unter Anwenden von 100 ml 2 N Chlorwasserstoffsäure wieder in das Amin hydrolysiert unter gleichzeitiger Bildung der quaternären Ammonium Verbindung D-l--(3-Hydroxyphenyl)-2-aminopropan-hydrochlorid. Vermittels Natriumbicarbonat wird hieraus die freie Base gewonnen, die in das quaternäre Ammoniumsalz der L-Weinsäure überführt wird. Die Ausbeute des so erhaltenen D-l-(3-Hydroxy-phenyl)-2-aminopropan-bitartrates beläuft sich auf 10,765 g entsprechend 79,2% des theoretischen Wertes. Fp = 183-185qC [alo26 = +29,5°; c = 0,5 (H20). 0.04 mol (10 g) of the compound is dissolved in 200 ml of water and introduced into a hydrogenation device provided with a stirrer, dropping funnel and gas introduction tube. After purging with hydrogen, palladium carbon is added as hydrogenation catalyst in an amount of 10 g of activated carbon with a content of 2.0 g of palladium. After the temperature had been raised to 60 ° C., the reaction mixture was kept at a pH of 5.3-5.6 by dropwise addition of 0.2 N ammonia solution during the uptake of hydrogen. Around 1000 ml of hydrogen are absorbed. After the hydrogen uptake is complete, the reaction mixture is filtered off from the catalyst and the solution is concentrated. The solution is made slightly alkaline with sodium bicarbonate and 0.05 mol (5.6 ml) of benzaldehyde is added. The precipitated Schiff base is extracted with ether and, using 100 ml of 2N hydrochloric acid, hydrolyzed back into the amine with simultaneous formation of the quaternary ammonium compound D-1 - (3-hydroxyphenyl) -2-aminopropane hydrochloride. The free base is obtained from this by means of sodium bicarbonate, which is converted into the quaternary ammonium salt of L-tartaric acid. The yield of the D-1- (3-hydroxyphenyl) -2-aminopropane bitartrate thus obtained is 10.765 g, corresponding to 79.2% of the theoretical value. Mp = 183-185qC [alo26 = + 29.5 °; c = 0.5 (H20).
Beispiel 4 Example 4
Hydrierung von D-(+)-l-(3-Hydroxyphenyl)-2-amino--3-acetoxypropan Hydrogenation of D - (+) - l- (3-hydroxyphenyl) -2-amino - 3-acetoxypropane
Es werden 0,02 Mol (2,58 g) der Verbindung in 60 ml Methanol gelöst und in einem mit Rührer, Tropftrichter und Gaszuführungsrohr versehene Hydriervorrichtung eingebracht. Nach Spülen mit Wasserstoff wird als Hydrierkatalysator Palladiumkohle in einer Menge von 2 g Aktivkohle mit einem Gehalt von 0,2 g Palladium zugesetzt. Nach Erhöhen der Temperatur auf 50°C wird 10 Stunden lang unter einem Druck von 1,5 kg/cm2 hydriert. Es wird in bekannter Weise aufgearbeitet und in das quaternäre Ammoniumsalz der L-Weinsäure überführt. Die Ausbeute des so erhaltenen 0.02 mol (2.58 g) of the compound is dissolved in 60 ml of methanol and introduced into a hydrogenation device provided with a stirrer, dropping funnel and gas feed pipe. After flushing with hydrogen, palladium carbon is added as hydrogenation catalyst in an amount of 2 g of activated carbon with a content of 0.2 g of palladium. After the temperature has been raised to 50 ° C., the mixture is hydrogenated for 10 hours under a pressure of 1.5 kg / cm 2. It is worked up in a known manner and converted into the quaternary ammonium salt of L-tartaric acid. The yield of the thus obtained
629732 629732
D-l-(3-Hydroxyphenyl)-2-aminopropan-bitartrates beläuft sich auf 6,110 g entsprechend 80% des theoretischen Wertes. Fp = 183-184QC [a]D20 = +29,6°; c = 0,5 (H20). D-1- (3-hydroxyphenyl) -2-aminopropane bitartrates amounts to 6.110 g, corresponding to 80% of the theoretical value. Mp = 183-184QC [a] D20 = + 29.6 °; c = 0.5 (H20).
Herstellung des Ausgangsproduktes Racemisierung von L-(—)-l-(3-Methoxyphenyl)-2-amino-propan Preparation of the starting product racemization of L - (-) - l- (3-methoxyphenyl) -2-aminopropane
Es werden 0,05 Mol (8,25 g) der Verbindung in 10 ml Methanol gelöst und mit einem Katalysator versetzt, der aus einer Lösung von 0,6 g Natriumwolframat in 10 ml Wasser besteht. In dieses Gemisch werden sodann unter Eiskühlung und Rühren tropfenweise innerhalb einer Zeitspanne von 15 Minuten 17 g Perhydrol eingetropft, wobei die Temperatur nicht über 15° ansteigt. Um die Reaktion weitestgehend quantitativ zu gestalten, wird noch 3 Stunden weiter gerührt. Das so erhaltene Rohprodukt wird in 50 ml Methanol, das 5 % Ammoniak enthält, gelöst und sodann unter Anwenden von Raney-Nickel 4 Stunden lang bei einem Druck von 60 kg/ cm2 und einer Temperatur von 80°C im Autoklaven hydriert. Das so erhaltene Racemat DL-l-(3-Methoxyphenyl)-2-ami-nopropan wird in einer Menge von 7,5 g entsprechend 90,80% der Theorie erhalten. Kp12 = 130-132°C. 0.05 mol (8.25 g) of the compound is dissolved in 10 ml of methanol and a catalyst is added which consists of a solution of 0.6 g of sodium tungstate in 10 ml of water. 17 g of perhydrol are then added dropwise to this mixture with ice cooling and stirring over a period of 15 minutes, the temperature not exceeding 15 °. In order to make the reaction largely quantitative, stirring is continued for a further 3 hours. The crude product thus obtained is dissolved in 50 ml of methanol containing 5% ammonia and then hydrogenated using Raney nickel for 4 hours at a pressure of 60 kg / cm 2 and a temperature of 80 ° C. in an autoclave. The racemate DL-1- (3-methoxyphenyl) -2-aminopropane thus obtained is obtained in an amount of 7.5 g, corresponding to 90.80% of theory. Kp12 = 130-132 ° C.
Anhand von Tierversuchen wurde festgestellt, dass zum Erzeugen einer gleich starken Vasokonstriktion bei Kaninchen die D-Form gegenüber der L-Form in einer dreifach geringeren Dosis wirksam ist. Bezüglich des Harnvolumens und der Ausscheidung von Natriumionen bei weiblichen Ratten erweist sich bei intraperitonealer Verabreichung die D-Form gegenüber der L-Form als zweimal wirksamer. Im Gegensatz zu Adrenalin und Noradrenalin, die zu einer starken Vasokonstriktion der Niere führen, wodurch die Nierenfunktion eingeschränkt wird, bedingt die erfindungsgemässe Verbindung eine Steigerung der Nierendurchblutung. Based on animal experiments, it was found that the D-form is effective in three times less dose than the L-form compared to the L-form to produce an equally strong vasoconstriction in rabbits. With regard to the urine volume and the excretion of sodium ions in female rats, the D-form proves to be twice more effective than the L-form when administered intraperitoneally. In contrast to adrenaline and noradrenaline, which lead to a strong vasoconstriction of the kidney, which limits kidney function, the compound according to the invention causes an increase in renal blood flow.
Ein weiterer Vorteil der erfindungsgemäss erhaltenen Verbindungen gegenüber Adrenalin, das peroral unwirksam ist, besteht darin, dass die neuen Verbindungen nicht nur intraperitoneal verabreicht werden können, sondern auch eine sichere orale Wirksamkeit gegeben ist, so dass ein an hy-potonen Krankheitssymptomen leidender Patient sich selber in wirksamer Weise bei einschlägigen Anfällen durch Einnahme der genannten neuen Verbindungen helfen kann. Die erfindungsgemäss hergestellten Verbindungen können für die orale Verabreichung in Form von Tabletten, Kapseln, Dragées, Sirupen, Lösungen, Suspensionen und Tropfen mit den üblichen Zusätzen angewandt werden. Auch das Einarbeiten in Suppositorien ist möglich. Another advantage of the compounds obtained according to the invention compared to adrenaline, which is orally ineffective, is that the new compounds can not only be administered intraperitoneally, but also have a safe oral activity, so that a patient suffering from hy-potonic symptoms of the disease is himself can effectively help with relevant seizures by taking the new compounds mentioned. The compounds prepared according to the invention can be used for oral administration in the form of tablets, capsules, dragées, syrups, solutions, suspensions and drops with the usual additives. Incorporation into suppositories is also possible.
Für die intravenöse Verabreichung findet bevorzugt eine Dosierung von 30 bis 50 mg und für di orale Verabreichung insbesondere eine Dosierung von 10 bis 120 mg Anwendung. A dose of 30 to 50 mg is preferably used for intravenous administration and a dose of 10 to 120 mg is particularly preferred for oral administration.
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Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT504676A AT343625B (en) | 1976-07-09 | 1976-07-09 | METHOD FOR PRODUCING NEW ACID ADDITION SALTS OF D - (+) - 1- (M-HYDROXYPHENYL) -2-AMINOPROPANE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH629732A5 true CH629732A5 (en) | 1982-05-14 |
Family
ID=3571321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH510277A CH629732A5 (en) | 1976-07-09 | 1977-04-25 | Process for the preparation of acid addition salts of D-(+)-1-(3-hydroxyphenyl)-2-aminopropane with optically active acids |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS539727A (en) |
| AR (1) | AR216467A1 (en) |
| AT (1) | AT343625B (en) |
| BE (1) | BE853332A (en) |
| CH (1) | CH629732A5 (en) |
| DE (1) | DE2712860C3 (en) |
| DK (1) | DK159203C (en) |
| ES (1) | ES457992A1 (en) |
| FR (1) | FR2357529A1 (en) |
| GB (1) | GB1527479A (en) |
| GR (1) | GR69605B (en) |
| NL (1) | NL176744C (en) |
| PT (1) | PT66752B (en) |
| SE (1) | SE440902B (en) |
| SU (1) | SU973018A3 (en) |
| ZA (1) | ZA771767B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3209788C2 (en) * | 1982-03-15 | 1984-10-04 | Rolf 1000 Berlin Sachse | Process for the preparation of 1- (3-hydroxyphenyl) -2-aminopropane |
| DK600285D0 (en) * | 1985-12-20 | 1985-12-20 | Jens Erik Sattrup | PROCEDURE FOR MANUFACTURING A DEEP PRESSURE CYLINDER |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB396951A (en) * | 1931-09-19 | 1933-08-17 | Ig Farbenindustrie Ag | Manufacture of optically active 1-monohydroxy-phenyl-2-aminopropanols(1) |
| JPS5013784A (en) * | 1973-06-08 | 1975-02-13 |
-
1976
- 1976-07-09 AT AT504676A patent/AT343625B/en not_active IP Right Cessation
-
1977
- 1977-02-25 GR GR52852A patent/GR69605B/el unknown
- 1977-03-04 SE SE7702469A patent/SE440902B/en not_active IP Right Cessation
- 1977-03-21 DE DE2712860A patent/DE2712860C3/en not_active Expired
- 1977-03-23 DK DK127277A patent/DK159203C/en not_active IP Right Cessation
- 1977-03-24 ZA ZA00771767A patent/ZA771767B/en unknown
- 1977-04-07 BE BE176488A patent/BE853332A/en not_active IP Right Cessation
- 1977-04-07 FR FR7710639A patent/FR2357529A1/en active Granted
- 1977-04-20 ES ES457992A patent/ES457992A1/en not_active Expired
- 1977-04-20 JP JP4562877A patent/JPS539727A/en active Granted
- 1977-04-25 CH CH510277A patent/CH629732A5/en not_active IP Right Cessation
- 1977-05-13 AR AR267625A patent/AR216467A1/en active
- 1977-06-01 GB GB23228/77A patent/GB1527479A/en not_active Expired
- 1977-06-14 NL NLAANVRAGE7706510,A patent/NL176744C/en not_active IP Right Cessation
- 1977-06-30 PT PT66752A patent/PT66752B/en unknown
- 1977-07-01 SU SU772502045A patent/SU973018A3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| DE2712860A1 (en) | 1978-01-12 |
| SE7702469L (en) | 1978-01-10 |
| DK127277A (en) | 1978-01-10 |
| PT66752A (en) | 1977-07-01 |
| ATA504676A (en) | 1977-10-15 |
| FR2357529B1 (en) | 1979-03-02 |
| DK159203B (en) | 1990-09-17 |
| NL176744C (en) | 1985-06-03 |
| DE2712860B2 (en) | 1980-07-10 |
| ES457992A1 (en) | 1978-07-16 |
| PT66752B (en) | 1978-11-27 |
| AT343625B (en) | 1978-06-12 |
| JPS539727A (en) | 1978-01-28 |
| GB1527479A (en) | 1978-10-04 |
| DE2712860C3 (en) | 1981-04-02 |
| FR2357529A1 (en) | 1978-02-03 |
| SU973018A3 (en) | 1982-11-07 |
| GR69605B (en) | 1982-07-05 |
| NL7706510A (en) | 1978-01-11 |
| DK159203C (en) | 1991-02-11 |
| ZA771767B (en) | 1978-03-29 |
| AR216467A1 (en) | 1979-12-28 |
| JPH0329782B2 (en) | 1991-04-25 |
| SE440902B (en) | 1985-08-26 |
| BE853332A (en) | 1977-08-01 |
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