NO140297B - PROCEDURES FOR THE PREPARATION OF ALFA1-T-BUTYLAMINOMETHYL-4-HYDROXY-M-XYLENE-ALFA1, ALFA3-DIOL - Google Patents
PROCEDURES FOR THE PREPARATION OF ALFA1-T-BUTYLAMINOMETHYL-4-HYDROXY-M-XYLENE-ALFA1, ALFA3-DIOL Download PDFInfo
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- NO140297B NO140297B NO751034A NO751034A NO140297B NO 140297 B NO140297 B NO 140297B NO 751034 A NO751034 A NO 751034A NO 751034 A NO751034 A NO 751034A NO 140297 B NO140297 B NO 140297B
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- Norway
- Prior art keywords
- formula
- derivative
- diol
- butylaminomethyl
- alfa1
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title description 5
- 150000002466 imines Chemical class 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- -1 sodium aluminum diethyl hydride Chemical class 0.000 claims description 6
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 5
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 238000007792 addition Methods 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229910052711 selenium Inorganic materials 0.000 description 9
- 239000011669 selenium Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical class O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 208000005279 Status Asthmaticus Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
Classifications
-
- 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
- C07C215/56—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 further substituted by hydroxy groups
- C07C215/58—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 further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—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 further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av terapeutisk aktiv a.1-t-butylaminomethyl-4-hydroxy-m - 1 3 The present invention relates to a new method for the production of therapeutically active a.1-t-butylaminomethyl-4-hydroxy-m - 1 3
xylen-a. ,a -diol med formelen: xylene-a. ,a -diol with the formula:
og syreaddisjonssalter derav. and acid addition salts thereof.
Forbindelsene er velkjente for sine farmakologiske egenskaper The compounds are well known for their pharmacological properties
og har funnet utstrakt anvendelse ved behandling av status astmati- and has found extensive use in the treatment of status asthmaticus
cus og andre former av alvorlig bronchospasmus. cus and other forms of severe bronchospasm.
Fremstillingen av a"*" -t -butylaminomethyl-4-hydroxy -m-xylen-a 1 ,a 3-diol er beskrevet bl.a. i norsk patentskrift nr. 126 014 og britisk patentskrift nr. 1 247 370. Norsk patentskrift nr. 126 014 inne-holder en rekke mellomtrinn. Dessuten utføres i denne fremstilling estergruppens reduksjon med lithiumaluminiumhydrid i diethylether eller tetrahydrofuran, hvilket er en dyr metode og en som er farlig i teknisk målestokk på grunn av oppløsningsmidlenes antenn-elsesfare. Også britisk patentskrift nr. 1.247.370 omfatter flere trinn, hvorved en del av mellomproduktene oppstår i ytterst dårlig utbytte. I fremgangsmåten ifølge dette patentskrift anvendes den ålment kjente selendioxydoxydering. I foreliggende oppfinnelse forekommer også en lignende oxydering, men utgangsmaterialet er en annen forbindelse. I britisk patentskrift nr. 1.247-370 er som siste trinn den til industriell fremstilling uegnede lithiumalu-miniumhydridreduksjon og produktets ekstraksjon fra vannoppløsning. The production of α"*"-t-butylaminomethyl-4-hydroxy-m-xylene-α 1 ,α 3-diol is described i.a. in Norwegian Patent Document No. 126 014 and British Patent Document No. 1 247 370. Norwegian Patent Document No. 126 014 contains a number of intermediate steps. Moreover, in this preparation, the reduction of the ester group is carried out with lithium aluminum hydride in diethyl ether or tetrahydrofuran, which is an expensive method and one that is dangerous on a technical scale due to the ignition hazard of the solvents. British patent document No. 1,247,370 also includes several steps, whereby a portion of the intermediate products are produced in extremely poor yield. In the method according to this patent document, the widely known selenium dioxydeoxidation is used. In the present invention, a similar oxidation also occurs, but the starting material is a different compound. In British Patent No. 1,247-370, the last step is lithium aluminum hydride reduction, which is unsuitable for industrial production, and the product's extraction from water solution.
Med kjennskap til oppløselighetsegenskapene hos a<1->t-butylaminomethyl-4-hydroxy-ar-xylen-a 1 ,a 3-diol (som er lett oppløselig i vann, men nærmest uoppløselig i vanlige organiske oppløsningsmidler, Knowing the solubility properties of a<1->t-butylaminomethyl-4-hydroxy-ar-xylene-a 1 ,a 3-diol (which is easily soluble in water, but almost insoluble in common organic solvents,
som benzen, ethylacetat og kloroform) kan man imidlertid si at fremgangsmåten er bare realiserbar i laboratoriemålestokk. such as benzene, ethyl acetate and chloroform), however, it can be said that the method is only feasible on a laboratory scale.
Det er nå oppfunnet en for industriell fremstilling egnet fremgangsmåte hvori a"<*>"-t-butylaminomethyl-4-hydroxy-m-xylen-a 1 ,a 3-diol med letthet kan fremstilles med et utbytte som er 2-4 ganger så stort som tidligere erholdt, ved en kontinuerlig fremgangsmåte uten å isolere noen mellomprodukter. A method suitable for industrial production has now been invented in which a"<*>"-t-butylaminomethyl-4-hydroxy-m-xylene-a 1,a 3-diol can be easily produced with a yield that is 2-4 times as large as previously obtained, by a continuous process without isolating any intermediates.
Foreliggende oppfinnelse angår således en ny fremgangsmåte ved fremstilling av -t-butylaminomethy1-4-hydroxy-m-xylen-a 1 ,a 3-diol med formel I, og syreaddisjonssalter derav, og fremgangsmåten kjennetegnes ved at et iminderivat med formelen: hvor R er en rettkjedet eller forgrenet hydrocarbongruppe med 1-6 carbonatomer, og Ar er en arylgruppe, ved samtidig hydrogenering og reduksjon med et organo-natrium-aluminium-hydrid-derivat med formelen (R1)2NaAlH2 hvor R<1> er alkyl eller alkoxy-alkoxy, omdannes til en forbindelse med formelen: The present invention thus relates to a new process for the production of -t-butylaminomethyl-4-hydroxy-m-xylene-a 1 ,a 3-diol of formula I, and acid addition salts thereof, and the process is characterized by an imine derivative of the formula: where R is a straight-chain or branched hydrocarbon group with 1-6 carbon atoms, and Ar is an aryl group, by simultaneous hydrogenation and reduction with an organo-sodium-aluminum-hydride derivative with the formula (R1)2NaAlH2 where R<1> is alkyl or alkoxy- Alkoxy, is converted into a compound with the formula:
fra hvilken arylmethylbeskyttelsesgruppen fjernes ved katalytisk hydrogenering. from which the arylmethyl protecting group is removed by catalytic hydrogenation.
Utgangsmaterialet ved foreliggende fremgangsmåte kan fåes ved at man går ut fra et benzoesyrederivat med formelen: The starting material for the present method can be obtained by starting from a benzoic acid derivative with the formula:
hvor R og Ar er som ovenfor angitt, som oxyderes med selendioxyd i dioxan til det tilsvarende glyoxalderivat som har formelen: og som omsettes med t-butylamin med formelen: where R and Ar are as stated above, which is oxidized with selenium dioxide in dioxane to the corresponding glyoxal derivative having the formula: and which is reacted with t-butylamine with the formula:
til iminderivatet med formel V, som er utgangsmaterialet ved foreliggende ffremgangsmåte. to the imine derivative of formula V, which is the starting material in the present process.
Ifølge oppfinnelsen er de foretrukne hydrogenerings- og reduksjonsmidler ved foreliggende fremgangsmåte natrium-bis-(2-methpxyethoxy)-aluminiumhydrid med formelen: eller natriumaluminiumdiethyldihydrid med formelen: According to the invention, the preferred hydrogenating and reducing agents in the present method are sodium bis-(2-methpxyethoxy)-aluminum hydride with the formula: or sodium aluminum diethyl dihydride with the formula:
Vesentlig ved oppfinnelsen er fremgangsmåtens kontinuitet Essential to the invention is the continuity of the method
ved at der ved fremstilling av utgangsmaterialet og ved fremgangsmåten for fremstilling av sluttproduktet anvendes reaksjonsmediumin that a reaction medium is used in the production of the starting material and in the process for the production of the final product
hvilket er oppnådd ved at den fenoliske hydroxylgruppe i benzoesyre-derivatet beskyttes med en passende arylmethylgruppe. På denne måte unngår man tapene ved isolering og rensning av mellomproduktene, og sluttproduktet fåes i en ytterst ren og lett isolerbar form. De i foreliggende fremgangsmåte dannede mellomprodukter (III, V og VIII) er også alle sammen nye forbindelser, hvis fremstilling og egenskaper ikke tidligere er angitt i litteraturen. which is achieved by protecting the phenolic hydroxyl group in the benzoic acid derivative with a suitable arylmethyl group. In this way, the losses during isolation and purification of the intermediate products are avoided, and the final product is obtained in an extremely clean and easily isolated form. The intermediate products (III, V and VIII) formed in the present process are also all new compounds, the preparation and properties of which have not previously been reported in the literature.
Ved fremstilling av utgangsmaterialet oxyderes esterderivatet (II) til å begynne med med selendioxyd i dioxan, fortrinnsvis ved opp-løsningsmidlets kokepunkt til det tilsvarende glyoxalderivat (III). I fortsettelsen kan reaksjonsblandingen anvendes som sådan, efter When preparing the starting material, the ester derivative (II) is initially oxidized with selenium dioxide in dioxane, preferably at the boiling point of the solvent, to the corresponding glyoxal derivative (III). In the continuation, the reaction mixture can be used as such, after
at selenet som ble utfelt i reaksjonen, først er frafiltrert. that the selenium that was precipitated in the reaction is first filtered off.
Ved tilsetning til filtratet av t-butylamin er det tilstrekk-elig med noen timers henstand ved værelsetemperatur for å danne det ønskede iminderivat (V). Man har således ved passende valg av oppløsningsmiddel og temperatur forhindret reaksjonen av t-butylamin med den annen reaktive ketogruppe i glyoxalderivatet (III). When t-butylamine is added to the filtrate, a few hours' standstill at room temperature is sufficient to form the desired imine derivative (V). The reaction of t-butylamine with the other reactive keto group in the glyoxal derivative (III) has thus been prevented by suitable choice of solvent and temperature.
Overraskende ved oppfinnelsen er dessuten den samtidige hydrogenering og reduksjon av carbon-nitrogen-dobbelbindingen i iminderivatet (V) samt keto- og estergruppen ved hjelp av et passende What is also surprising about the invention is the simultaneous hydrogenation and reduction of the carbon-nitrogen double bond in the imine derivative (V) as well as the keto and ester group by means of a suitable
organo-natrium-aluminiumhydridderivat. Noen slik reaksjon er tidligere ikke angitt i litteraturen. Når der som reduksjonsmiddel anvendes natrium-bis-(2-methoxyethoxy)-aluminiumhydrid eller natriumaluminiumdiethylhydrid, er oppløsningsmidlet vanligvis benzen eller toluen, som også kan anvendes i foreliggende tilfelle. Det har imidlertid overraskende vist seg at et bedre resultat opp-nåes når reaksjonen foretaes i dioxan, dvs. reaksjonsblandingen som ble anvendt ved fremstilling av iminderivatet, kan anvendes som sådan. Det er grunn til å fordampe overskuddet av t-butylamin under nedsatt trykk for å spare reduksjonsmiddel. Denne samtidige hydrogenering og reduksjon av iminderivatet (V) er bare mulig under forutsetning av at den fenoliske hydroxylgruppe på benzenringen er organo-sodium aluminum hydride deriv. No such reaction has previously been reported in the literature. When sodium bis-(2-methoxyethoxy)-aluminum hydride or sodium aluminum diethyl hydride is used as a reducing agent, the solvent is usually benzene or toluene, which can also be used in the present case. However, it has surprisingly been shown that a better result is achieved when the reaction is carried out in dioxane, i.e. the reaction mixture which was used in the preparation of the imine derivative can be used as such. There is reason to evaporate the excess of t-butylamine under reduced pressure to save reducing agent. This simultaneous hydrogenation and reduction of the imine derivative (V) is only possible under the condition that the phenolic hydroxyl group on the benzene ring is
beskyttet. Hvis ingen beskyttelsesforholdsregler er foretatt, må man ekstrahere produktet fra vannoppløsning, hvilket med kjennskap til de oppløselighetsegenskaper som ct^-t -butylaminomethyl-4-hydroxy-m-xylen-a 1 ,a 3-diol har, er en umulig oppgave i industriell målestokk, hvortil kommer at der dessuten dannes betraktelige mengder av ikke ønskelige biprodukter. -t -butylaminomethyl -4-13 - hydroxy-m-xylen-a ,a -diol er nemlig nærmest uoppløselig x vanlige organiske oppløsningsmidler som benzen, ethylacetat og kloroform, men er lett oppløselig i vann. protected. If no protective measures are taken, the product must be extracted from water solution, which, given the solubility properties of ct^-t-butylaminomethyl-4-hydroxy-m-xylene-a 1 ,a 3-diol, is an impossible task in industrial scale, to which considerable amounts of undesirable by-products are also formed. -t -butylaminomethyl -4-13 - hydroxy-m-xylene-a ,a -diol is virtually insoluble in common organic solvents such as benzene, ethyl acetate and chloroform, but is easily soluble in water.
Arylmethyl-beskyttelsesgruppen i forbindelsen (VIII) kan fjernes ved katalytisk hydrering, idet en passende katalysator er f.eks. palladium-på-carbon, og et passende oppløsningsmiddel, f.eks. alkohol. The arylmethyl protecting group in compound (VIII) can be removed by catalytic hydrogenation, a suitable catalyst being e.g. palladium-on-carbon, and a suitable solvent, e.g. alcohol.
Oppfinnelsen illustreres nedenfor ved hjelp av eksempler. The invention is illustrated below by means of examples.
Eksempel 1 Example 1
g 1 - t- butylaminomethyl- 4- benzyloxy- m- xylen- a 1, u 3- diol g 1 - t- butylaminomethyl- 4- benzyloxy- m- xylen- a 1, u 3- diol
Til 59 kg dioxan tilsettes 0,35 kg vann, og blandingen oppvarmes til 70 - 80°C. 4,39 kg selendioxyd tilsettes. Efter at selendioxydet er oppløst, tilsettes 11,8 kg ethylester av 5-aceto-2-benzyloxybenzoesyre oppløst i 35,5 kg dioxan. Reaksjonsblandingen oppvarmes under tilsetningen videre inntil reaksjonsblandingen koker (ca. 100°C). Tilbakeløpskokningen fortsettes i 6 timer. Efter kokningen får blandingen avkjøle til værelsetemperatur. Selenet frafiltreres. (Hvis man ønsker å isolere glyoxalderivatet, skjer dette ved fordampning av dioxanet, hvorved glyoxalderivatet erholdes på dette vis i form av en viskøs olje). 0.35 kg of water is added to 59 kg of dioxane, and the mixture is heated to 70 - 80°C. 4.39 kg of selenium dioxide is added. After the selenium dioxide has dissolved, 11.8 kg of ethyl ester of 5-aceto-2-benzyloxybenzoic acid dissolved in 35.5 kg of dioxane are added. The reaction mixture is further heated during the addition until the reaction mixture boils (approx. 100°C). The reflux is continued for 6 hours. After boiling, the mixture is allowed to cool to room temperature. The selenium is filtered off. (If you want to isolate the glyoxal derivative, this happens by evaporating the dioxane, whereby the glyoxal derivative is obtained in this way in the form of a viscous oil).
Til filtratet ved værelsetemperatur tilsettes 5,9 kg t-butylamin med påfølgende omrøring ved værelsetemperatur i 4 timer. Overskudd av t-butylamin avdampes under nedsatt trykk. 5.9 kg of t-butylamine is added to the filtrate at room temperature with subsequent stirring at room temperature for 4 hours. Excess t-butylamine is evaporated under reduced pressure.
Man lar reaksjonsblandingen ved værelsetemperatur og under nitrogenatmosfære renne ned i 40 kg 70%-ig benzenoppløsning av nat rium-bis-(2-methoxyethoxy)-aluminiumhydrid. Tilsetningen skjer ved ca. 6o°C. Efter tilsetningen følger tilbakeløpskokning i 1 time. Den herved dannede kompleksforbindelse av reduksjonsmidlet med produktet nedbrytes på vanlig vis ved hjelp av vann og saltsyre. Det oljeaktige produktskikt fraskilles, oppløses i kloroform, fri-gjøres fra sitt hydrokloridsalt med baseoppløsning, tørres med natriumsulfat og behandles med aktivkull. Kloroformen avdampes under nedsatt trykk. Fra residuet kan produktet om nødvendig om-kryst alliseres fra ethanol. The reaction mixture is allowed to run at room temperature and under a nitrogen atmosphere into 40 kg of a 70% benzene solution of sodium bis-(2-methoxyethoxy)-aluminum hydride. The addition takes place at approx. 6o°C. The addition is followed by reflux for 1 hour. The resulting complex compound of the reducing agent with the product is broken down in the usual way with the help of water and hydrochloric acid. The oily product layer is separated, dissolved in chloroform, freed from its hydrochloride salt with base solution, dried with sodium sulphate and treated with activated carbon. The chloroform is evaporated under reduced pressure. From the residue, the product can be recrystallized from ethanol if necessary.
Utbytte 8,5 - 9,0 kg (65 - 70% av det teoretiske), smeltepunkt ca. 135°C. Yield 8.5 - 9.0 kg (65 - 70% of the theoretical), melting point approx. 135°C.
Eksempel 2 Example 2
Begynnelsen som i eksempel 1, men efter at iminderivatet er fremstilt, avdampes oppløsningsmidlet. Ved fremstilling på denne måte fåes iminderivatet, N-[2-oxo-2-(3<*->carbethoxy-4'-benzyloxy-fenyl)-ethyliden]-t-butylimin. hvis struktur ble bevist ved NMR-spektrum, som en viskøs olje, som oppløses i 80 kg benzen. Benzen-oppløsningen lar man under nitrogenatmosfære renne ned i 40 kg 70%-ig benzenoppløsning av natrium-bis-(2-methoxyethoxy)-aluminium-hydrid. Fortsettelse som i eksempel 1. Utbyttet er 7,5 - 8,0 kg (58 - 62% av det teoretiske), smeltepunkt ca. 135°C. The beginning as in example 1, but after the imine derivative has been prepared, the solvent is evaporated. When prepared in this way, the imine derivative, N-[2-oxo-2-(3<*->carbethoxy-4'-benzyloxy-phenyl)-ethylidene]-t-butylimine is obtained. whose structure was proved by NMR spectrum, as a viscous oil, which dissolves in 80 kg of benzene. The benzene solution is allowed to drain under a nitrogen atmosphere into 40 kg of a 70% benzene solution of sodium bis-(2-methoxyethoxy)-aluminum hydride. Continue as in example 1. The yield is 7.5 - 8.0 kg (58 - 62% of the theoretical), melting point approx. 135°C.
Eksempel 3 Example 3
Som i eksempel 1 og 2, men istedenfor ethylester av 5-aceto-2-benzyloxybenzoesyre taes den ekvivalente mengde methylester. As in examples 1 and 2, but instead of ethyl ester of 5-aceto-2-benzyloxybenzoic acid, the equivalent amount of methyl ester is taken.
Eksempel 4 Example 4
g 1 - t- butylaminomethyl- 4- benzoyloxy- m- xylen- a 1, a 3- diol g 1 - t- butylaminomethyl- 4- benzoyloxy- m- xylen- a 1, a 3- diol
Til 66 kg dioxan tilsettes 0,4 kg vann, og blandingen oppvarmes til 70 - 80°C. 4,92 kg selendioxyd tilsettes. Efter at 0.4 kg of water is added to 66 kg of dioxane, and the mixture is heated to 70 - 80°C. 4.92 kg of selenium dioxide are added. After that
dette er oppløst, tilsettes 13,2 kg ethylester av 5-aceto-2-benzyl-oxybenzoesyre oppløst i 40 kg dioxan. Oppvarmningen fortsettes inntil reaksjonsblandingen koker (ca. 100°C), hvorefter følger tilbake-løpskokning i 6 timer. Under kokningens forløp blir reaksjonsblandingen sort av utfelt selen. Den får avkjøle til værelsetemperatur, og det utfelte selen frafiltreres. Til filtratet ved værelsetemperatur tilsettes 6,6 kg t-butylamin med efterfølgende omrøring ved værelsetemperatur i 4 timer. Overskuddet av t-butylamin avdampes under nedsatt trykk. this is dissolved, 13.2 kg of ethyl ester of 5-aceto-2-benzyl-oxybenzoic acid dissolved in 40 kg of dioxane are added. The heating is continued until the reaction mixture boils (approx. 100°C), after which refluxing follows for 6 hours. During the course of the boiling, the reaction mixture turns black from precipitated selenium. It is allowed to cool to room temperature, and the precipitated selenium is filtered off. 6.6 kg of t-butylamine is added to the filtrate at room temperature with subsequent stirring at room temperature for 4 hours. The excess of t-butylamine is evaporated under reduced pressure.
Dioxanoppløsningen ved værelsetemperatur tilsettes under nitrogenatmosfære til 85,5 kg 25%-ig toluenoppløsning av natriumaluminiumdiethylhydrid med en slik hastighet at temperaturen av reaksjonsblandingen ikke overstiger 25°C. Efter tilsetningen fortsettes med omrøring ved 25°C i 1 time. Den dannede kompleksforbindelse av produktet med reduksjonsmidlet spaltes på vanlig måte ved tilsetning av vann og alkalioppløsning. Tilsetningene bør skje langsomt på grunn av skumning forårsaket av det frigjorte ethan. Den organiske fase fraskilles og inndampes til tørrhet. Fra residuet kan produktet efter behov omkrystalliseres fra ethanol. The dioxane solution at room temperature is added under a nitrogen atmosphere to 85.5 kg of a 25% toluene solution of sodium aluminum diethyl hydride at such a rate that the temperature of the reaction mixture does not exceed 25°C. After the addition, stirring is continued at 25°C for 1 hour. The formed complex compound of the product with the reducing agent is split in the usual way by adding water and alkali solution. Additions should be made slowly due to foaming caused by the liberated ethane. The organic phase is separated and evaporated to dryness. From the residue, the product can be recrystallized from ethanol if necessary.
Utbyttet er 9,5 - 10,3 kg (65 - 70% av det teoretiske), smeltepunkt ca. 135°C. The yield is 9.5 - 10.3 kg (65 - 70% of the theoretical), melting point approx. 135°C.
Eksempel 5 Example 5
Som i eksempel 4» men oppløsningsmidlet avdampes efter fremstilling av iminderivatet. Herved får man iminderivatet som en viskøs olje som oppløses i 90 kg toluen, idet denne toluenoppløs-ning anvendes i fortsettelsen. Fortsettelse som i eksempel 4-Utbyttet er 8,5 - 9,1 kg (58 - 62% av det teoretiske), smeltepunkt ca. 135°C. As in example 4", but the solvent is evaporated after preparation of the imine derivative. This gives the imine derivative as a viscous oil which is dissolved in 90 kg of toluene, this toluene solution being used in the continuation. Continue as in example 4-The yield is 8.5 - 9.1 kg (58 - 62% of the theoretical), melting point approx. 135°C.
Eksempel 6 Example 6
Som i eksempel 4 og 5, men istedenfor ethylester av 5-aceto-2-benzyloxybenzoesyre anvendes den ekvivalente mengde methylester. As in examples 4 and 5, but instead of ethyl ester of 5-aceto-2-benzyloxybenzoic acid, the equivalent amount of methyl ester is used.
Eksempel 7 Example 7
1 13 1 13
g - t- butylaminomethy1- 4- hydroxy- m- xylen- a , a - diol g-t-butylaminomethyl1-4-hydroxy-m-xylene-a,a-diol
10 kg g 1 -t-butylaminomethyl-4-benzyloxy-m-xylen-g 1,a 3-diol tilsettes til 135 kg 95%-ig ethanol. Tilsetning av 0,3 kg 10%-ig palladium-på-carbon og hydrogenering ved normaltrykk inntil hydrogenopptagelsen opphører. Efter fjernelse av katalysatoren avdampes oppløsningsmidlet. Produktet krystalliseres fra residuet ved hjelp av en methanol-ethylacetatblanding. 10 kg g 1 -t-butylaminomethyl-4-benzyloxy-m-xylene-g 1,a 3-diol is added to 135 kg 95% ethanol. Addition of 0.3 kg of 10% palladium-on-carbon and hydrogenation at normal pressure until hydrogen uptake ceases. After removal of the catalyst, the solvent is evaporated. The product is crystallized from the residue using a methanol-ethyl acetate mixture.
Utbyttet er 6,5 kg (90% av det teoretiske), smeltepunkt The yield is 6.5 kg (90% of the theoretical), melting point
157 - 158°C. 157 - 158°C.
Eksempel 8 Example 8
Til 66 kg dioxan tilsettes 0,4 kg vann, og blandingen oppvarmes til 70 - 80°C. 4,92 kg selendioxyd tilsettes. Efter dets oppløsning tilsettes 13,2 kg ethylester av 5~aceto-2-benzyloxy-benzoesyre oppløst i 40 kg dioxan. Oppvarmningen fortsettes inntil reaksjonsblandingen koker (ca. 100°C), og kokes så under til-bakeløp i 6 timer. Under kokningens forløp blir reaksjonsblandingen sort av utfelt selen. Reaksjonsblandingen får avkjøle til værelsetemperatur, og det utfelte selen frafiltreres. Til filtratet tilsettes ved værelsetemperatur 6,6 kg t-butylamin, hvorefter der om-røres ved værelsetemperatur i 4 timer. Overskuddet av t-butylamin avdampes under nedsatt trykk. 0.4 kg of water is added to 66 kg of dioxane, and the mixture is heated to 70 - 80°C. 4.92 kg of selenium dioxide is added. After its dissolution, 13.2 kg of ethyl ester of 5~aceto-2-benzyloxy-benzoic acid dissolved in 40 kg of dioxane are added. The heating is continued until the reaction mixture boils (approx. 100°C), and is then boiled under reflux for 6 hours. During the course of the boiling, the reaction mixture turns black from precipitated selenium. The reaction mixture is allowed to cool to room temperature, and the precipitated selenium is filtered off. 6.6 kg of t-butylamine is added to the filtrate at room temperature, after which it is stirred at room temperature for 4 hours. The excess of t-butylamine is evaporated under reduced pressure.
Dioxanoppløsningen tilsettes ved værelsetemperatur i nitrogenatmosfære til 85,5 kg 25%-ig toluenoppløsning av natrium-aluminium-diethylhydrid med en slik hastighet at temperaturen i reaksjons-blåndingen ikke overstiger 25°C. Efter tilsetningen omrøres ved 25 C i 1 time. Den dannede kompleksforbindelse av produktet med reduksjonsmediet spaltes på normalt vis ved tilsetning av vann og alkalioppløsning. Tilsetningene bør skje langsomt på grunn av skum-ningen som forårsakes av frigjort ethan. Den organiske fase fraskilles og inndampes til tørrhet. Residuet tilsettes til 135 kg 95%-ig ethanol. Tilsetning av 0,3 kg 10%-ig palladium-på-carbon og hydrogenering ved normaltrykk inntil hydrogenopptagelsen opphører. Efter fjernelse av katalysatoren fordampes oppløsningsmidlet. Produktet krystalliseres fra residuet ved hjelp av en methanol-ethylacetatblanding. The dioxane solution is added at room temperature in a nitrogen atmosphere to 85.5 kg of a 25% toluene solution of sodium aluminum diethyl hydride at such a rate that the temperature in the reaction mixture does not exceed 25°C. After the addition, stir at 25 C for 1 hour. The formed complex compound of the product with the reducing medium is split in the normal way by adding water and alkali solution. The additions should be done slowly because of the foaming caused by liberated ethane. The organic phase is separated and evaporated to dryness. The residue is added to 135 kg of 95% ethanol. Addition of 0.3 kg of 10% palladium-on-carbon and hydrogenation at normal pressure until hydrogen uptake ceases. After removal of the catalyst, the solvent is evaporated. The product is crystallized from the residue using a methanol-ethyl acetate mixture.
Utbyttet er 6,2 - 6,7 kg (59 - 63% av det teoretiske), smeltepunkt 157 - 158°C. The yield is 6.2 - 6.7 kg (59 - 63% of the theoretical), melting point 157 - 158°C.
Eksempel 9 Example 9
g1- t- butylaminomethyl- 4- hydroxy- m- xylen- a1, g^- diol g1- t- butylaminomethyl- 4- hydroxy- m- xylen- a1, g^- diol
Til 59 kg dioxan tilsettes 0,35 kg vann, og blandingen oppvarmes til 70 - 80°C. 4,39 kg selendioxyd tilsettes. Efter dets oppløsning tilsettes 11,8 kg ethylester av 5~aceto-2-benzyloxy-benzoesyre oppløst i 35,5 kg dioxan. Reaks jonsblandingen oppvarmes under tilsetningen videre inntil reaksjonsblandingen koker (ca. 100°C). Tilbakeløpskokning fortsettes i 6 timer. Under kokningen blir reaksjonsblandingen sort av utfelt selen. Selenet frafiltreres . (Hvis man ønsker å isolere glyoxalderivatet, skjer dette ved å fordampe dioxanet, hvorved glyoxalderivatet fremstilt på denne måte fåes i form av en viskøs olje.) 0.35 kg of water is added to 59 kg of dioxane, and the mixture is heated to 70 - 80°C. 4.39 kg of selenium dioxide are added. After its dissolution, 11.8 kg of ethyl ester of 5~aceto-2-benzyloxy-benzoic acid dissolved in 35.5 kg of dioxane are added. The reaction mixture is further heated during the addition until the reaction mixture boils (approx. 100°C). Refluxing is continued for 6 hours. During boiling, the reaction mixture turns black from precipitated selenium. The selenium is filtered off. (If one wishes to isolate the glyoxal derivative, this takes place by evaporating the dioxane, whereby the glyoxal derivative produced in this way is obtained in the form of a viscous oil.)
Til filtratet ved værelsetemperatur tilsettes 5,9 kg t-butylamin, og blandingen omrøres i 4 timer. Overskuddet av t-butylamin avdampes ved nedsatt trykk. 5.9 kg of t-butylamine is added to the filtrate at room temperature, and the mixture is stirred for 4 hours. The excess of t-butylamine is evaporated at reduced pressure.
Man lar reaksjonsblandingen i nitrogenatmosfære renne ned i 40 kg 70%-ig benzenoppløsning av natrium-bis-(2-methoxyethoxy)-aluminiumhydrid. Tilsetningen skjer ved ca. 60°C. Efter tilsetningen kokes under tilbakeløp i 1 time. Den dannede kompleksforbindelse av produktet med reduksjonsmidlet spaltes på vanlig vis ved hjelp av vann og saltsyre. Det oljeaktige produktskikt fraskilles, oppløses i kloroform, frisettes fra sitt hydrokloridsalt med baseoppløsning, tørres med natriumsulfat og behandles med aktivkull. Kloroformen avdrives ved nedsatt trykk. Til residuet tilsettes 120 kg 95%-ig ethanol. Tilsetning av 0,26 kg 10%-ig palladium-på-carbon og hydrogenering ved normaltrykk inntil hydro-genabsorpsjonen er slutt. Efter fjernelse av katalysatoren fordampes oppløsningsmidlet. Produktet krystalliseres fra residuet ved hjelp av en methanol-ethylacetatblanding. The reaction mixture is allowed to run down in a nitrogen atmosphere into 40 kg of a 70% benzene solution of sodium bis-(2-methoxyethoxy)-aluminum hydride. The addition takes place at approx. 60°C. After the addition, boil under reflux for 1 hour. The formed complex compound of the product with the reducing agent is split in the usual way with the help of water and hydrochloric acid. The oily product layer is separated, dissolved in chloroform, freed from its hydrochloride salt with base solution, dried with sodium sulphate and treated with activated carbon. The chloroform is driven off at reduced pressure. 120 kg of 95% ethanol is added to the residue. Addition of 0.26 kg of 10% palladium-on-carbon and hydrogenation at normal pressure until hydrogen absorption has ended. After removal of the catalyst, the solvent is evaporated. The product is crystallized from the residue using a methanol-ethyl acetate mixture.
Utbyttet er 5, 5- 5, 9 kg (58-62% av det teoretiske), smeltepunkt 157-158°C The yield is 5.5-5.9 kg (58-62% of the theoretical), melting point 157-158°C
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI982/74A FI56673C (en) | 1974-03-29 | 1974-03-29 | NYTT FOERFARANDE FOER FRAMSTAELLNING AV ALFA-TERT-BYTYLAMINOMETHYL-4-HYDROXY-M-XYLEN-ALFA1 ALFA3-DIOL |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO751034L NO751034L (en) | 1975-09-30 |
| NO140297B true NO140297B (en) | 1979-04-30 |
| NO140297C NO140297C (en) | 1979-08-08 |
Family
ID=8504919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO751034A NO140297C (en) | 1974-03-29 | 1975-03-25 | PROCEDURES FOR THE PREPARATION OF ALFA1-T-BUTYLAMINOMETHYL-4-HYDROXY-M-XYLENE-ALFA1, ALFA3-DIOL |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5953256B2 (en) |
| CA (1) | CA1040658A (en) |
| DK (1) | DK135500C (en) |
| FI (1) | FI56673C (en) |
| NO (1) | NO140297C (en) |
| SE (1) | SE433608B (en) |
| SU (1) | SU538660A3 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CY1273A (en) | 1980-07-09 | 1985-03-08 | Draco Ab | 1-(dihydroxyphenyl)-2-amino-ethanol derivatives;preparation,compositions and intermediates |
| FI118418B (en) | 2003-04-17 | 2007-11-15 | Ecocat Oy | Aluminum-rounded catalytic converter for cleaning of gas leaks |
| JP2006528202A (en) | 2004-05-20 | 2006-12-14 | テバ ファーマシューティカル ファイン ケミカルズ ソチエタ レスポンサビリタ リミテ | Levalbuterol hydrochloride polymorph B |
| CN110963929B (en) * | 2019-11-26 | 2022-10-21 | 安徽恒星制药有限公司 | Preparation method of salbutamol hydrochloride suitable for industrial production |
-
1974
- 1974-03-29 FI FI982/74A patent/FI56673C/en active
- 1974-08-06 SU SU2051832A patent/SU538660A3/en active
- 1974-10-14 JP JP49118004A patent/JPS5953256B2/en not_active Expired
-
1975
- 1975-03-25 NO NO751034A patent/NO140297C/en unknown
- 1975-03-26 DK DK133975A patent/DK135500C/en not_active IP Right Cessation
- 1975-03-27 SE SE7503657A patent/SE433608B/en not_active IP Right Cessation
- 1975-03-27 CA CA223,245A patent/CA1040658A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5953256B2 (en) | 1984-12-24 |
| NO140297C (en) | 1979-08-08 |
| FI56673C (en) | 1981-02-04 |
| NO751034L (en) | 1975-09-30 |
| DK133975A (en) | 1975-09-30 |
| FI98274A (en) | 1975-09-30 |
| DK135500C (en) | 1977-10-24 |
| DK135500B (en) | 1977-05-09 |
| SU538660A3 (en) | 1976-12-05 |
| FI56673B (en) | 1979-11-30 |
| CA1040658A (en) | 1978-10-17 |
| SE433608B (en) | 1984-06-04 |
| JPS50130732A (en) | 1975-10-16 |
| SE7503657L (en) | 1975-09-30 |
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