SE454775B - SET TO MAKE BENZYL ALCOHOL derivatives - Google Patents

SET TO MAKE BENZYL ALCOHOL derivatives

Info

Publication number
SE454775B
SE454775B SE8206352A SE8206352A SE454775B SE 454775 B SE454775 B SE 454775B SE 8206352 A SE8206352 A SE 8206352A SE 8206352 A SE8206352 A SE 8206352A SE 454775 B SE454775 B SE 454775B
Authority
SE
Sweden
Prior art keywords
compound
iii
lower alkyl
benzyl alcohol
och
Prior art date
Application number
SE8206352A
Other languages
Swedish (sv)
Other versions
SE8206352D0 (en
SE8206352L (en
Inventor
I Iijima
A Nakao
M Gaino
T Ohishi
Original Assignee
Tanabe Seiyaku Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tanabe Seiyaku Co filed Critical Tanabe Seiyaku Co
Publication of SE8206352D0 publication Critical patent/SE8206352D0/en
Publication of SE8206352L publication Critical patent/SE8206352L/en
Publication of SE454775B publication Critical patent/SE454775B/en

Links

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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • 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
    • 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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

Description

15 20 25 30 35 454 775 2 R2 CH3 (II) vari R2 betecknar väte, lägre alkanoyl eller fenyl-lägre alkyl, med en tionylhalogenid, (b) omsättning av den erhållna produkten med 3,4-dimetoxi- fenetylamin för framställning av ett tioacetamidderivat med formeln 0 S ocH3 2 R 0 NH-cH2cH2 OCH3 vari R2 har samma betydelse som ovan, och (III) (C-l) (c-2) omsättning av föreningen (III) med lägre alkylhalogenid reduktiv avsvavling av föreningen (III) eller eller tri(lägre alkyl)oxoniumfluoroborat för framställning av ett acetofenonderivat med formeln 3 S-R OCH _ (rv) NH CHZCHZ OCH3 2 vari R3 är lägre alkyl och R har samma betydelse som ovan, och reduktiv avsvavling av föreningen (IV) eller (c-3) reduktion av föreningen (III) med alkalimetallborhydrid för framställning av ett bensylalkoholderivat med formeln H S ocH3 (V) R10 NH-cnzcuz C53 10 15 20 25 30 35 3 454 775 vari R1 har samma betydelse som ovan, omsättning av föreningen (V) med lägre alkylhalogenid eller tri(lägre alkyl)oxoniumfluorid för framställning av ett bensylalkoholderivat med formeln OH _ S'R3 OCH3 1 R o (VI) N*CH2CH2 OCH3 vari Rl och R3 har samma betydelse som ovan, och reduktiv av- svavling av föreningen (VI). R 2 CH 3 (II) wherein R 2 represents hydrogen, lower alkanoyl or phenyl-lower alkyl, with a thionyl halide, (b) reacting the product obtained with 3,4-dimethoxyphenethylamine to produce a thioacetamide derivatives of the formula O S and H 3 2 R 0 NH-cH 2 cH 2 OCH 3 wherein R 2 has the same meaning as above, and (III) (Cl) (c-2) reaction of the compound (III) with lower alkyl halide reductive desulfurization of the compound (III) or or tri (lower alkyl) oxonium fluoroborate for the preparation of an acetophenone derivative of the formula 3 SR AND - (rv) NH CH 2 CH 2 OCH 3 2 wherein R 3 is lower alkyl and R has the same meaning as above, and reductive desulfurization of the compound (IV) or (c- 3) reduction of the compound (III) with alkali metal borohydride to produce a benzyl alcohol derivative of the formula HS ocH 3 (V) R 10 NH-cnzcuz C53 10 15 20 25 30 35 3 454 775 wherein R 1 has the same meaning as above, reaction of the compound (V) with lower alkyl halide or tri (lower alkyl) oxonium fluoride for fram pouring a benzyl alcohol derivative of the formula OH - S'R 3 OCH 3 1 R o (VI) N * CH 2 CH 2 OCH 3 wherein R 1 and R 3 have the same meaning as above, and reductive desulfurization of the compound (VI).

I acetofenonderivatet (II), som användes som utgångsmaterialet vid förfarandet enligt föreliggande uppfinning, inkluderar föredragna exempel på R2 väte, acetyl, propionyl; och fenyl-lägre alkyl såsom bensyl. Å andra sidan användes företrädesvis tionyl- klorid som ovan nämnda tionylhalogenid. Föredragna exempel på R3 är metyl eller etyl.In the acetophenone derivative (II) used as the starting material in the process of the present invention, preferred examples of R 2 include hydrogen, acetyl, propionyl; and phenyl-lower alkyl such as benzyl. On the other hand, thionyl chloride is preferably used as the above-mentioned thionyl halide. Preferred examples of R 3 are methyl or ethyl.

Omsättningen av acetofenonderivatet (II) med tionylhalogeniden åtföljs av upplösning av föreningen (II) i tionylhalogeniden och omrörning av lösningen. Denna reaktion utföres företrädes- vis i närvaro av en katalytisk mängd av en organisk bas. Lämp- liga exempel på sådana organiska baser inkluderar pyridin, tri- etylamin, dimetylanilin och liknande. Lämplig mängd av tionyl- halogenid att användas är ca 3 till l0nnl per mol av acetofenon- derivatet (II). Det föredrages att utföra omsättningen vid en temperatur mellan 10 och SOOC. Den så erhållna reaktionsproduk- ten, som antages vara en blandning av följande tvâ föreningar 0 K _. / c=s se « i x \\ .f R O vari X betecknar halogen och R2 har ovan angiven betydelse, skall företrädesvis användas i det följande steget utan isole- ring och/eller rening från reaktionsblandningen. 10 15 20 25 30 35 40 454 775 4 Omsättningen av ovan nämnda produkt med 3,4-dimetoxifenetyl- amin kan ske i närvaro eller frånvaro av en syraacceptor i ett lämpligt lösningsmedel. Lämpliga exempel på syraacceptorn inkluderar organiska baser såsom pyridin, trietylamin, dimetyl- anilin eller N-metylpyrrolidin och oorganiska baser såsom kaliumkarbonat, natriumkarbonat, natriumbikarbonat eller nat- riumhydroxid.The reaction of the acetophenone derivative (II) with the thionyl halide is accompanied by dissolving the compound (II) in the thionyl halide and stirring the solution. This reaction is preferably carried out in the presence of a catalytic amount of an organic base. Suitable examples of such organic bases include pyridine, triethylamine, dimethylaniline and the like. The appropriate amount of thionyl halide to be used is about 3 to 10l / l per mole of the acetophenone derivative (II). It is preferred to carry out the reaction at a temperature between 10 and 5 ° C. The reaction product thus obtained, which is believed to be a mixture of the following two compounds. / c = s see «i x \\ .f R 0 wherein X represents halogen and R 2 has the meaning given above, should preferably be used in the following step without isolation and / or purification from the reaction mixture. The reaction of the above product with 3,4-dimethoxyphenethylamine can take place in the presence or absence of an acid acceptor in a suitable solvent. Suitable examples of the acid acceptor include organic bases such as pyridine, triethylamine, dimethylaniline or N-methylpyrrolidine and inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate or sodium hydroxide.

Ett organiskt lösningsmedel (t.ex. bensen, kloro form, metylenklorid, etylacetat, dimetylformamid) eller en blandning av detta organiska lösningsmedel och vatten är lämp- ligt som lösningsmedel. Det föredrages att utföra omsättningen vid en temperatur mellan 0 och 30°C.An organic solvent (eg benzene, chloroform, methylene chloride, ethyl acetate, dimethylformamide) or a mixture of this organic solvent and water is suitable as solvent. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C.

Bensylalkoholderivatet (I) kan framställas från det så erhållna tioacetamidderivatet (III) enligt något av de ovan nämnda för- farandena(c-l), (c-2) och (c-3).The benzyl alcohol derivative (I) can be prepared from the thioacetamide derivative (III) thus obtained according to any of the above-mentioned processes (c-1), (c-2) and (c-3).

Enligt förfarandet (c-1) framställes nämligen bensylalkohol- derivatet (I) genom att föreningen (III) utsättes för reduktiv avsvavling. Den reduktiva avsvavlingen av föreningen (III) kan ske genom behandling av den med ett reducerande medel i närvaro av en metallhalogenid i ett lämpligt lösningsmedel. Lämpliga exempel på metallhalogeniden inkluderar nickelklorid, järn(II)klo- rid, tenn(II)klorid, zinkklorid, koboltklorid och liknande.Namely, according to process (c-1), the benzyl alcohol derivative (I) is prepared by subjecting the compound (III) to reductive desulfurization. The reductive desulfurization of the compound (III) can be effected by treating it with a reducing agent in the presence of a metal halide in a suitable solvent. Suitable examples of the metal halide include nickel chloride, ferric chloride, stannous chloride, zinc chloride, cobalt chloride and the like.

Lämpliga exempel på reduktionsmedlet inkluderar alkalimetall- borhydrider såsom natriumborhydrid, litiumborhydrid och liknan- de. Alkanoler (t.ex. metanol, etanol, propanol), tetrahydro- furan, dioxan, dimetoxietan och liknande är lämpliga som lös- ningsmedlet. Det föredrages att utföra omsättningen vid en temperatur mellan 20 och 50°C. Under detta reaktionsförfarande sker avsvavlingen av föreningen (III) och reduktionen av oxo- gruppen i 2-ställningen samtidigt. Dessutom, när en förening (III), vari R2 betecknar alkanoyl, användes vid denna reaktion, hydrolyseras alkanoylgruppen vidare samtidigt med avsvavlingen och reduktionsreaktioner och ger bensylalkoholderivatet (I), vari Rl betecknar väte.Suitable examples of the reducing agent include alkali metal borohydrides such as sodium borohydride, lithium borohydride and the like. Alkhanols (eg methanol, ethanol, propanol), tetrahydrofuran, dioxane, dimethoxyethane and the like are suitable as the solvent. It is preferred to carry out the reaction at a temperature between 20 and 50 ° C. During this reaction process, the desulfurization of the compound (III) and the reduction of the oxo group in the 2-position take place simultaneously. In addition, when a compound (III), wherein R 2 represents alkanoyl, is used in this reaction, the alkanoyl group is further hydrolyzed simultaneously with the desulfurization and reduction reactions to give the benzyl alcohol derivative (I), wherein R 1 represents hydrogen.

Enligt metoden (c-2) framställes bensylalkoholderivatet (I) genom alkylering av föreningen (III) och reduktiv avsvavling av den erhållna föreningen (IV)- (III) i närvaro eller frånvaro av en syraacceptor i ett lämpligt Alkyleringen av föreningen sker genom behandling därav med ett alkyleringsmedel 10 15 20 25 30 5 454 775 lösningsmedel. Alkyleringsmedlet väljs bland lägre alkylhalo- genider såsom metyljodid eller etylbromid; tri(lägre alkyl)- oxoniumfluoroborauu'såxm1trimetyloxoniumfluoroborat eller trietyloxoniumfluoroborat. Lämpliga exempel på syraacceptorn inkluderar oorganiska baser såsom kaliumkarbonat, natriumkarbonat eller natriumbikarnonat och organiska baser såsom pyridin, trietylamin eller 1,5-diazabicyklo¿š.4.0¿7-5-undeken. Metylen- klorid, aceton, kloroform, metanoL etanol, eter, dimetylformamid, tetrahydrofuran och liknande är lämpliga som lösningsmedel. Det föredrages att utföra omsättningen vid en temperatur mellan 0 och 30°C. med denna reaktion framställes acetofenonderivatet (IV).According to method (c-2), the benzyl alcohol derivative (I) is prepared by alkylation of the compound (III) and reductive desulfurization of the obtained compound (IV) - (III) in the presence or absence of an acid acceptor in a suitable alkylation of the compound by treatment thereof. with an alkylating agent 10 15 20 25 30 5 454 775 solvent. The alkylating agent is selected from lower alkyl halides such as methyl iodide or ethyl bromide; tri (lower alkyl) -oxonium fluoroboraux oxymethyltrimethyloxonium fluoroborate or triethyloxonium fluoroborate. Suitable examples of the acid acceptor include inorganic bases such as potassium carbonate, sodium carbonate or sodium bicarbonate and organic bases such as pyridine, triethylamine or 1,5-diazabicyclo4.4.0¿7-5-undecane. Methylene chloride, acetone, chloroform, methanol, ethanol, ether, dimethylformamide, tetrahydrofuran and the like are suitable as solvents. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C. with this reaction the acetophenone derivative (IV) is prepared.

Den så erhållna föreningen (IV) kan företrädesvis användas i det följande steget utan isolering och/eller rening därav från reaktionslösningen.The compound (IV) thus obtained can preferably be used in the following step without isolation and / or purification thereof from the reaction solution.

Den reduktiva avsvavlingen av föreningen (IV) kan ske genom att den behandlas med ett reducerande medel i ett lämpligt lösnings- medel. Lämpliga exempel på det reducerande medlet inkluderar alkalimetallborhydrid (t.ex. natriumborhydrid, litiumborhydrid), litiumaluminiumhydrid och liknande. Alkanoler (t.ex. metanol, etanol, propanol), tetrahydrofuran, dioxan och dimetoxietan är lämpliga som lösningsmedel. Det föredrages att utföra reaktio- nen vid en temperatur mellan 0 och 30°C. Med detta reaktions- steg avlägsnas alkyltiogruppen från föreningen (IV) samtidigt med reduktionen av dess oxogrupp. När en förening (IV), vari R2 betecknar alkanoyl, användes i detta steg, hydrolyseras även alkanoylgruppen samtidigt med de ovan nämnda reaktionerna.The reductive desulfurization of the compound (IV) can be effected by treating it with a reducing agent in a suitable solvent. Suitable examples of the reducing agent include alkali metal borohydride (eg, sodium borohydride, lithium borohydride), lithium aluminum hydride, and the like. Alkhanols (eg methanol, ethanol, propanol), tetrahydrofuran, dioxane and dimethoxyethane are suitable as solvents. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C. With this reaction step, the alkylthio group is removed from the compound (IV) simultaneously with the reduction of its oxo group. When a compound (IV), wherein R 2 represents alkanoyl, is used in this step, the alkanoyl group is also hydrolyzed simultaneously with the above-mentioned reactions.

Alternativt kan bensylalkoholderivatet (I) framställas med metoden (c-3), dvs. genom de steg. som innebär reduktion av föreningen (III) för framställning av ett bensylalkoholderivat (V), alkylering av föreningen (V) för framställning av ett bensylalkoholderivat (VI) och reduktiv avsvavling av föreningen (VI).Alternatively, the benzyl alcohol derivative (I) can be prepared by the method (c-3), i.e. through the steps. which involves reduction of the compound (III) to produce a benzyl alcohol derivative (V), alkylation of the compound (V) to produce a benzyl alcohol derivative (VI) and reductive desulfurization of the compound (VI).

Reduktionen av föreningen (III) sker genom att den behandlas med ett reduktionsmedel i ett lämpligt lösningsmedel. Reduk- tionsmedlet väljs bland alkalimetallborhydrider såsom natrium- borhydrid, litiumborhydrid och liknande. Alkanoler 10 15 20 25 30 35 454 775 s (t.ex. metanol, etanol, propanol), tetrahydrofuran och dioxan är lämpliga som lösningsmedel. Det föredrages att utföra om- sättningen vid en temperatur mellan 0 och 30°C. När föreningen GII); vari R är alkanoyl, användes i detta reaktionssteg, sker reduktionen av oxogruppen i föreningen (III) samtidigt med hydrolysen av alkanoylgruppen.The reduction of the compound (III) takes place by treating it with a reducing agent in a suitable solvent. The reducing agent is selected from alkali metal borohydrides such as sodium borohydride, lithium borohydride and the like. Alkanolols (eg methanol, ethanol, propanol), tetrahydrofuran and dioxane are suitable solvents. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C. When the compound GII); wherein R is alkanoyl, used in this reaction step, the reduction of the oxo group in the compound (III) takes place simultaneously with the hydrolysis of the alkanoyl group.

Den efterföljande alkyleringen av föreningen (V) och den reduk- tiva avsvavlingen av föreningen (VI) kan ske under samma be- tingelser som användes vid alkyleringen av föreningen (III) eller den reduktiva avsvavlingen av föreningen (IV) i metod (c-2).The subsequent alkylation of the compound (V) and the reductive desulfurization of the compound (VI) can take place under the same conditions as used in the alkylation of the compound (III) or the reductive desulfurization of the compound (IV) in method (c-2). ).

Bensylalkoholderivatet (I) framställt enligt föreliggande upp- finning kan, om så erfordras, omvandlas till ett farmaceutiskt godtagbart syraadditionssalt därav. Lämpliga exempel pâ salt inkluderar oorganiska syraadditionssalter såsom hydroklorid, hydrobromid, perklorat, nitrat, sulfat eller fosfat; och orga- niska syraadditionssalter såsom acetat, propionat, glykolat, laktat, askorbat, maleat, fumarat, malonat, succinat, oxalat, citrat, metansulfonat, bensensulfonat, aminobensoat, sulfami- nat, aspartat, glutamat eller nikotinat.The benzyl alcohol derivative (I) prepared according to the present invention can, if necessary, be converted into a pharmaceutically acceptable acid addition salt thereof. Suitable examples of salt include inorganic acid addition salts such as hydrochloride, hydrobromide, perchlorate, nitrate, sulfate or phosphate; and organic acid addition salts such as acetate, propionate, glycolate, lactate, ascorbate, maleate, fumarate, malonate, succinate, oxalate, citrate, methanesulfonate, benzenesulfonate, aminobenzoate, sulfaminate, aspartate, glutamate or nicotinate.

Ovanstående förfarande enligt föreliggande uppfinning gör det möjligt att framställa bensylalkoholderivatet (I) med ett högt utbyte utan icke önskade bireaktioner och är fördelaktigt för framställning av bensylalkoholderivatet (I) i industriell skala.The above process according to the present invention makes it possible to produce the benzyl alcohol derivative (I) in a high yield without undesired side reactions and is advantageous for the production of the benzyl alcohol derivative (I) on an industrial scale.

Dessutom, eftersom mellanprodukten (III) enligt uppfinningen är ganska stabil och lätt att isolera och.rena på vanligt sätt, är förfarandet enligt uppfinningen även fördelaktigt genom att bensylalkoholderivatet (I) erhålles med hög renhet utan konta- minering med oönskvärda biprodukter.In addition, since the intermediate (III) according to the invention is quite stable and easy to isolate and purify in the usual way, the process according to the invention is also advantageous in that the benzyl alcohol derivative (I) is obtained in high purity without contamination with undesirable by-products.

I beskrivningen och kraven skall uttrycket "lägre alkyl“och “lägre alkanoyl“ företrädesvis förstås som rak eller grenad alkyl och alkanoylgrupp med l till 4 kolatomer.In the description and claims, the terms "lower alkyl" and "lower alkanoyl" are preferably understood as straight or branched alkyl and alkanoyl group having 1 to 4 carbon atoms.

Praktiska och för närvarande föredragna utföringsformer av före- liggande uppfinning illustreras av följande exempel. 10 l5 20 25 30 35 40 7 454 775 Exempel 1 (1) 4,97 g 4-bensyloxiacetofenon löses i 15 ml tionylklorid, och 0,02 ml pyridin tillsättes. temperatur under 5 timmar.Practical and presently preferred embodiments of the present invention are illustrated by the following examples. Example 1 (1) 4.97 g of 4-benzyloxyacetophenone are dissolved in 15 ml of thionyl chloride, and 0.02 ml of pyridine are added. temperature for 5 hours.

Blandningen omröres vid rums- Blandningen koncentreras under sänkt tryck för avlägsnande av överskott av tionylklorid. stoden upplöses i 30 ml bensen. Åter- Lösningen sättes till en bland- ning av 4,78 g 3,4-dimetoxifenetylamin, 90 ml av en 10-procentig kaliumkarbonatlösning och 50 ml bensen och blandningen omröres vid rumstemperatur 1 4 timmar. Bensenlösningen uppsamlas från reaktionsblandningen och vattenskiktet extraheras med etyl- acetat. Bensenlösningen och etylacetatextraktet förenas och tvättas successivt med vatten, 10 % saltsyra och vatten. Det organiska skiktet torkas och indunstas under sänkt tryck. stoden omkristalliseras ur etanol. Åter- 7,67 g 2-(4-bensyloxifenyl)- -2-oxo-N-(3,4-dimetoxifenetyl)-tioacetamid erhålles som blekgula nålar. Utbyte: 80,1 %. smp. 132 - 133°c1 (2) 500 mg 2-(4-bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)- -tioacetamid och 610 mg nickelkloridhexahydrat löses i 30 ml metanol och 700 mg natriumborhydrid tillsättes vid rumstempera- tur. Blandningen omröres vid samma temperatur under 1,5 timmar.The mixture is stirred at room temperature. The mixture is concentrated under reduced pressure to remove excess thionyl chloride. the column is dissolved in 30 ml of benzene. The solution is added to a mixture of 4.78 g of 3,4-dimethoxyphenethylamine, 90 ml of a 10% potassium carbonate solution and 50 ml of benzene, and the mixture is stirred at room temperature for 4 hours. The benzene solution is collected from the reaction mixture and the aqueous layer is extracted with ethyl acetate. The benzene solution and the ethyl acetate extract are combined and washed successively with water, 10% hydrochloric acid and water. The organic layer is dried and evaporated under reduced pressure. the column is recrystallized from ethanol. 7.67 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are obtained as pale yellow needles. Yield: 80.1%. m.p. 132 - 133 ° C1 (2) 500 mg of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide and 610 mg of nickel chloride hexahydrate are dissolved in 30 ml of methanol and 700 mg of sodium borohydride are added at room temperature - lucky. The mixture is stirred at the same temperature for 1.5 hours.

Olösligt material filtreras av, och filtratet koncentreras under sänkt tryck. Återstoden upplöses i kloroform, tvättas med vat- ten, torkas och indunstas därefter under sänkt tryck. Åter- stoden behandlas med etanolisk saltsyra, och den kristallinafäll~ ningen uppsamlas genom filtrering. 360 mg Q -(3,4-dimetoxi- fenetylaminometyl)-4-bensyloxibensylalkoholhydroklorid erhålles.Insoluble material is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried and then evaporated under reduced pressure. The residue is treated with ethanolic hydrochloric acid, and the crystalline precipitate is collected by filtration. 360 mg of Q- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol hydrochloride are obtained.

Utbyte: 70 %. smp. 168 - 17o°c.Yield: 70%. m.p. 168-170 ° C.

Exempel 2 2,0 g 2-(4-bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)-tio- acetamid löses i 40 ml metylenklorid, och l,05 g trietyloxonium- fluoroborat tillsättes. Sedan blandningen omrörts vid rums- temperatur under 1,5 timme, koncentreras blandningen under sänkt tryck. Återstoden upplöses i 30 ml etanol, och 2,1 g natrium- borhydrid tillsättes. Blandningen omröres vid rumstemperatur under l timme. Vatten hälles i reaktionsblandningen, och bland- 10 15 20 25 30 35 40 454 775 ningen koncentreras under sänkt tryck. Kristallin fällning uppsamlas genom filtrering, och kristallerna tvättas med vat- ten och omkristalliseras därefter ur isopropanol. 1,45 g of-(3,4-dimetoxifenetylaminometyl)-4-bensyloxibensylalkohol (fri bas) erhålles som färglösa nålar. Utbyte: 77,5 %. smp. 114,5 - 11a°c.Example 2 2.0 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are dissolved in 40 ml of methylene chloride, and 1.05 g of triethyloxonium fluoroborate are added. After the mixture is stirred at room temperature for 1.5 hours, the mixture is concentrated under reduced pressure. The residue is dissolved in 30 ml of ethanol, and 2.1 g of sodium borohydride are added. The mixture is stirred at room temperature for 1 hour. Water is poured into the reaction mixture, and the mixture is concentrated under reduced pressure. Crystalline precipitate is collected by filtration, and the crystals are washed with water and then recrystallized from isopropanol. 1.45 g of or- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield: 77.5%. m.p. 114.5 - 11a ° C.

Exempel 3 2,2 g 2-(4-bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)-tio- acetamid löses i 30 ml aceton, och 850 mg kaliumkarbonat och 1,0 g metyljodid tillsättes. peratur över natt.Example 3 2.2 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are dissolved in 30 ml of acetone, and 850 mg of potassium carbonate and 1.0 g of methyl iodide are added. perature overnight.

Blandningen omröres vid rumstem- Olösligt material filtreras av, och filtra- tet koncentreras under sänkt tryck. Aterstoden upplöses i 50 ml metanol, och 300 mg natriumborhydrid tillsättes. omröres vid rumstemperatur under 30 minuter.The mixture is stirred at room temperature. Insoluble material is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in 50 ml of methanol, and 300 mg of sodium borohydride are added. Stir at room temperature for 30 minutes.

Blandningen Därefter behand- las reaktionsblandningen på samma sätt som beskrevs i exempel 2. 1,65 g 0(-(3,4-dimetoxifenetylaminometyl)-4-bensyloxiben- sylalkohol (fri bas) erhålles som färglösa nålar. Utbyte: 80 %.The mixture The reaction mixture is then treated in the same manner as described in Example 2. 1.65 g of 0 (- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield: 80%.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de för det prov, som erhölls i exempel 2.The physicochemical properties of this product are identical to those of the sample obtained in Example 2.

Exempel 4 (1) 8,0 g 2-(4-bensyloxifenyl)-2-oxo-N*(3,4-dimetoxifenetyl)- -tioacetamid löses i 150 ml metanol, och 500 mg natriumborhyd- rid tillsättes. Blandningen omröres vid rumstemperatur under l timme. Blandningen koncentreras under sänkt tryck. Åter- stoden upplöses i kloroform, tvättas med vatten, torkas och indunstas under sänkt tryck. Återstoden omkristalliseras ur 7,5 g 2-(4-bensyloxifenyl)-2-hydroxi-N-(3,4-di- metoxifenetyl)-tioacetamid erhålles som färglösa nålar. Ut- byte: 93 %. _ smp. 82 - 84%. isopropanol. (2) l,0 g 2-(4-bensyloxifenyl)-2-hydroxi-N-(3,4-dimetoxifene- tyl)-tioacetamid löses i 20 ml metylenklorid, och 460 ml tri- etyloxoniumfluoroborat tillsättes. Sedan blandningen omrörts vid rumstemperatur under 30 minuter, koncentreras den under sänkt tryck. Aterstoden upplöses i en blandning av 20 ml meta- 10 15 20 25 30 35 40 454 775 nol och 20 ml kloroform, och 440 mg natriumborhydrid tillsättes.Example 4 (1) 8.0 g of 2- (4-benzyloxyphenyl) -2-oxo-N * (3,4-dimethoxyphenethyl) -thioacetamide are dissolved in 150 ml of methanol, and 500 mg of sodium borohydride are added. The mixture is stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried and evaporated under reduced pressure. The residue is recrystallized from 7.5 g of 2- (4-benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) -thioacetamide to give colorless needles. Yield: 93%. _ m.p. 82 - 84%. isopropanol. (2) 1.0 g of 2- (4-benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) -thioacetamide are dissolved in 20 ml of methylene chloride, and 460 ml of triethyloxonium fluoroborate are added. After the mixture is stirred at room temperature for 30 minutes, it is concentrated under reduced pressure. The residue is dissolved in a mixture of 20 ml of methanol and 20 ml of chloroform, and 440 mg of sodium borohydride are added.

Blandningen omröres vid rumstemperatur under en timme. Därefter behandlas reaktionsblandningen på samma sätt som beskrevs i exempel 2. 780 ml CX- (3,4 - dimetoxifenetylaminometyl) ~ 4 - - besyloxibensylalkohol (fri bas) erhålles som färglösa nålar.The mixture is stirred at room temperature for one hour. Thereafter, the reaction mixture is treated in the same manner as described in Example 2. 780 ml of CX- (3,4-dimethoxyphenethylaminomethyl) -4--besyloxybenzyl alcohol (free base) are obtained as colorless needles.

Utbyte: 84 %.Yield: 84%.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de för det prov, som erhölls i exempel 2.The physicochemical properties of this product are identical to those of the sample obtained in Example 2.

Exemgel 5 (1) 5,34 g 4 - acetoxiacetofenon, 20 ml tionylklorid, 0,03 ml pyridin och 6,51 g 3,4 ~ dimetoxifenetylamin behandlas på samma sätt som beskrevs i exempel 1 - (1). 8,5 g 2 ~ (4 - acetoxifenyl) - - 2 - oxo - N - (3,4 - dimetoxifenetyl)tioacetamid erhålles som blekgul olja. Utbyte: 73 %. vätska -1 ITläX .Example 5 (1) 5.34 g of 4-acetoxyacetophenone, 20 ml of thionyl chloride, 0.03 ml of pyridine and 6.51 g of 3,4-dimethoxyphenethylamine are treated in the same manner as described in Example 1- (1). 8.5 g of 2- (4-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide are obtained as a pale yellow oil. Yield: 73%. liquid -1 ITläX.

IR g; (cm )= 1755, 1665 Massa m/e: 387 (M+) NMR (cDc13)g = 2,30 (s, 3H, cg3coo-), 3,00 (t, zu, J = 7,5 Hz, -cgz-CH2-), 3,84 (S, 6n, -ocg3x2) (2) 1,94 g 2 - (4 - acetoxifenyl) ~ 2 - oxo - N -(3,4 - dimetoxi- fenetyl)tioacetamid, 1,14 g trietyloxoniumfluoroborat och 1,0 g natriumborhydrid behandlas på samma sätt som beskrevs i exempel 2. 1,47 g d- (3,4 - dimetoxífenetylaminometyl) - 4 - - hydroxibensylalkohol erhålles som färglösa prismor. Utbyte: 92 %. smp. 151 - 153°c.IR g; (cm) = 1755, 1665 Mass m / e: 387 (M +) NMR (cDc13) g = 2.30 (s, 3H, cg3coo-), 3.00 (t, zu, J = 7.5 Hz, - cgz-CH2-), 3.84 (S, 6n, -ocg3x2) (2) 1.94 g 2- (4-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1 , 14 g of triethyloxonium fluoroborate and 1.0 g of sodium borohydride are treated in the same manner as described in Example 2. 1.47 g of d- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol are obtained as colorless prisms. Yield: 92%. m.p. 151-153 ° C.

Exemgel 6 (1) 4,08 g 4 ~ hydroxiacetofenon, 12 ml tionylklorid, 0,06 ml pyridin och 6,51 g 3,4 - dimetoxifenetylamin behandlas på samma 3,1 g 2 - (4 - hydroxifenyl)- - 2 - oxo - N ~ (3,4 ~ dimetyloxifenetyl)tioacetamid erhålles som blekgula nålar. Utbyte: 30 %. sätt som beskrevs i exempel 1-(1). 10 15 20 25 30 35 454 775 10 smp; 179 - 1ao°c (omkristalliseraa ur etanol). (2) 1,0 g 2-(4-hydroxifenyl)-2-oxo~N-(3,4-dimetoxifenetyl)tio- acetamid, 1,37 g nickelklorid-hexahydrat och 1,1 g natriumbor- hydrid behandlas på samma sätt som beskrevs i exempel 1 -(2). 230 mg ew-(3,4-dimetoxifenetylaminometyl)~4-hydroxibensylalko- hol erhålles som färglösa prismor. Utbyte: 25 %.Example gel 6 (1) 4.08 g of 4-hydroxyacetophenone, 12 ml of thionyl chloride, 0.06 ml of pyridine and 6.51 g of 3,4-dimethoxyphenethylamine are treated in the same 3.1 g of 2- (4-hydroxyphenyl) -2- oxo-N- (3,4-dimethyloxyphenethyl) thioacetamide are obtained as pale yellow needles. Yield: 30%. methods described in Example 1- (1). 10 15 20 25 30 35 454 775 10 m.p.; 179 DEG-100 DEG C. (recrystallized from ethanol). (2) 1.0 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.37 g of nickel chloride hexahydrate and 1.1 g of sodium borohydride are treated in the same manner. methods described in Example 1 - (2). 230 mg of ew- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol are obtained as colorless prisms. Yield: 25%.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de för det prov, som erhölls i exempel 5 - (2).The physicochemical properties of this product are identical to those of the sample obtained in Example 5 - (2).

Exempel 7 1,58 g 2-(4-hydroxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)tioacetamid, 1,13 g trietyloxoniumfluoroborat och 870 g natriumborhydrid be- handlas på samma sätt, som beskrevs i exempel 2. 940 mg d-(3,4-dimetoxifenetylaminometyl)~4-hydroxibensylalkohol erhålles som färglösa prismor. Utbyte: 65 %.Example 7 1.58 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 g of sodium borohydride are treated in the same manner as described in Example 2. 940 mg of d- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol are obtained as colorless prisms. Yield: 65%.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de hos det prov, som erhölls i exempel 5 - (2).The physico-chemical properties of this product are identical to those of the sample obtained in Example 5 - (2).

Exempel 8 (1) 6,78 g 2-bensyloxiacetofenon, 21 ml tionylklorid, 0,05 ml pyridin och 6,54 g 3,4-dimetoxifenetylamin behandlas på samma (1). 10,3 g fenyl)-2-oxo-N-(3,4-dimetoxifenetyl)-tioacetamid erhålles som sätt som beskrevs i exempel 1 - 2*l2-benSylOXi- blekgula prismor. Utbyte: 79 %. smp. 112 - 114°c. (2) 500 mg -tioacetamid, 2-(2-bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)~ 900 ml nickelklorid-hexahydrat och 700 mg natrium- borhydrid behandlas på samma sätt, som beskrevs i exempel 1 ~(2). 165 mg de(3,4-dímetoxifenetylaminometyl)-2-bensyloxibensylalko- hol-hydroklorid erhålles som färglösa nålar. Utbyte: 32 %. smp. 159 - 1so°c. 10 15 20 25 30 35 40 454 775 11 Exemgel 9 2,0 g 2-(2-bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)- -tioacetamid, 1,13 g trietyloxoniumfluoroborat och 870 mg natriumborhydrid behandlas på samma sätt som i exempel 2. 1,65 g ex-(3,4-dimetoxifenetylaminometyl)-2-bensyloxibensyl- alkohol (fri bas) erhålles som färglösa nålar. Utbyte: 82 %.Example 8 (1) 6.78 g of 2-benzyloxyacetophenone, 21 ml of thionyl chloride, 0.05 ml of pyridine and 6.54 g of 3,4-dimethoxyphenethylamine are treated in the same manner (1). 10.3 g of phenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are obtained as described in Example 1-2-22-benzylOxy-pale yellow prisms. Yield: 79%. m.p. 112-114 ° C. (2) 500 mg of -thioacetamide, 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) ~ 900 ml of nickel chloride hexahydrate and 700 mg of sodium borohydride are treated in the same manner as described in Example 1 ~ (2). 165 mg of the (3,4-dimethoxyphenethylaminomethyl) -2-benzyloxybenzyl alcohol hydrochloride are obtained as colorless needles. Yield: 32%. m.p. 159-150 ° C. Example 15 2.0 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 mg of sodium borohydride treated in the same manner as in Example 2. 1.65 g of ex- (3,4-dimethoxyphenethylaminomethyl) -2-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield: 82%.

Smp. 95 - 97°C (omkristalliserad ur isopropanol).M.p. 95-97 ° C (recrystallized from isopropanol).

Exemgel 10 2,2 g 2-(2~bensyloxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)- -tioacetamid, 850 mg kaliumkarbonat, 1,0 g metyljodid och 300 mg natriumborhydrid behandlas på samma sätt som beskrevs i exempel 3. 1,1 q :#-(3,4-dimetoxifenetylaminometyl)-2-ben- syloxibensylalkohol (fri bas) erhålles som färglösa nålar.Example 10 2.2 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide, 850 mg of potassium carbonate, 1.0 g of methyl iodide and 300 mg of sodium borohydride are treated in the same manner as described. in Example 3. 1,1 q: #- (3,4-dimethoxyphenethylaminomethyl) -2-benzyloxybenzyl alcohol (free base) are obtained as colorless needles.

Utbyte: 53 %.Yield: 53%.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de som erhölls i exempel 9.The physicochemical properties of this product are identical to those obtained in Example 9.

Exemgel 11 (1) 2,73 g 2-hydroxiacetofenon, 8 ml tionylklorid, 0,03 ml pyridin och 2,53 g 3,4-dimetoxifenetylamin behandlas på samma sätt som beskrevs i exempel 1 -(1). 4,0 g 2~(2-hydroxifenyl)- -2-oxo-N-(3,4-dimetoxifenetyl)-tioacetamid erhålles som blek- rödbruna nålar. Utbyte: 58 %.Example 11 (1) 2.73 g of 2-hydroxyacetophenone, 8 ml of thionyl chloride, 0.03 ml of pyridine and 2.53 g of 3,4-dimethoxyphenethylamine are treated in the same manner as described in Example 1 - (1). 4.0 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are obtained as pale red-brown needles. Yield: 58%.

Smp. 166 - 168°C (omkristalliserad ur etanol). (2) 1,58 g -tioacetamid, 1,13 g trietyloxoniumfluoroborat och 1,4 g 2-(2-hydroxifenyl)-2~oxo-N-(3,4-dimetoxifenetyl)- natriumborhydrid behandlas på samma sätt som beskrevs i exempel 2. 850 mg a'-(3,4-dimetoxifenetylaminometyl)-2-hydroxibensyl- alkohol erhålles som färglös olja. Utbyte: 58 %. o Oxalatet av denna produkt: Smp. 175 - 176 C.M.p. 166 - 168 ° C (recrystallized from ethanol). (2) 1.58 g of thioacetamide, 1.13 g of triethyloxonium fluoroborate and 1.4 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) sodium borohydride are treated in the same manner as described in Example 2. 850 mg of α '- (3,4-dimethoxyphenethylaminomethyl) -2-hydroxybenzyl alcohol are obtained as a colorless oil. Yield: 58%. o The oxalate of this product: M.p. 175 - 176 C.

Exempel 12 (1) 1,78 g 2-acetoxiacetofenon, 6 ml tionylklorid, 0,02 ml 10 15 454 775 12 pyridin och 1,27 g 3,4-dimetoxifenetylamin behandlas på samma sätt som beskrevs i exempel 1 - (1). 1,37 g 2-(2-acetoxifenyl)- -2-oxo-N-(3,4-dimetoxifenetyl)-tioacetamid erhålles som blekgul olja. Utbyte: 35,4 %.Example 12 (1) 1.78 g of 2-acetoxyacetophenone, 6 ml of thionyl chloride, 0.02 ml of pyridine and 1.27 g of 3,4-dimethoxyphenethylamine are treated in the same manner as described in Example 1 - (1) . 1.37 g of 2- (2-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are obtained as a pale yellow oil. Yield: 35.4%.

CHCI max 1 IR 3 (cm- ): 1760, 1670 Massa m/e: 387 (M+) NMR (CDCI3) -CE = 2,20 (s, an, c§3coo-), 2,94 (t, 2H, J = 7,5 Hz, z-cflz-L 3,85 (s, en, -ocg3x2) (2) 2-(2-acetoxifenyl)-2-oxo-N-(3,4-dimetoxifenetyl)-tioacetamid, trietyloxoníumfluoroborat och natriumborhydrid behandlas på samma sätt, som beskrevs i exempel 2. aminometyl)-2-hydroxibensylalkohol erhålles.CHCl 3 1 IR 3 (cm -1): 1760, 1670 Mass m / e: 387 (M +) NMR (CDCl 3) -CE = 2.20 (s, an, c § 3 coo-), 2.94 (t, 2H , J = 7.5 Hz, z-c fl z-L 3.85 (s, en, -ocg3x2) (2) 2- (2-acetoxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide , triethyloxonium fluoroborate and sodium borohydride are treated in the same manner as described in Example 2. aminomethyl) -2-hydroxybenzyl alcohol is obtained.

De fysikaliskt-kemiska egenskaperna hos denna produkt är iden- tiska med de hos det prov, som erhölls i exempel 11 -(2).The physicochemical properties of this product are identical to those of the sample obtained in Example 11 - (2).

Claims (3)

10 15 20 25 30 35 454 775 Patentkrav10 15 20 25 30 35 454 775 Patent claims 1. Sätt att framställa ett bensylalkoholderivat med formeln ' on OCH3 (I) R Na-cnzcnz bcn3 vari R1 betecknar väte eller fenyl-lägnealkyl, eller ett farmaceutiskt godtagbart syraadditionssalt därav, k ä n n e t e c k n a t av att (a) ett acetofenonderivat med formeln O CH3 (II) vari R2 betecknar väte, lägre alkanoyl eller fenyl~lägre alkyl, omsättes med en tionylhalogenid, (b) den erhållna produkten omsättes med 3,4-dimetoxifenetyl- amin för framställning av ett tioacetamidderivat med formeln 3 (Il-fl) NH-cxzcnz OCH vari R2 har ovan angiven betydelse, och (c)-i) föreningen (III) utsättes för reduktiv avsvavling eller -ii) föreningen (III) omsättes med lägre alkylhalogenid eller trilägre alkyl)oxoniumfluoroborat så att man erhåller ett aceto- fenonderivat med formeln ~R 3 (IV) R20 N-cazcaz OCH3 10 15 20 25 30 35 40 454 775 14 vari R3 betecknar lägre alkyl och R2 har ovan angiven betydelse, och föreningen (IV) utsättes för reduktiv avsvavling, eller -iii) föreningen (III) reduceras med alkalimetallborhydrid så att man erhåller ett bensylalkoholderivat med formeln OH S OCH V 1/ 3 n R O-- NH-CHZCHZ OCH3 vari R har ovan angiven betydelse, föreningen (V) omsättes med lägre alkylhalogenid eller tri(lägre alkyl)oxoniumfluoroborat för framställning av ett bensylalkoholderivat med formeln ' on - 3 "R 0CH3 (VI ) 1 . R o N-ca2cH2 ocH3 1 3 vari R och R har ovan angiven betydelse, och föreningen (VI) utsättes för reduktiv avsvavling, och därefter (d) om så erfordras, omvandlas det så erhållna bensylalkohol- derivatet (I) till ett farmaceutiskt godtagbart syraaddition- salt därav.A process for the preparation of a benzyl alcohol derivative of the formula 'on OCH 3 (I) R (II) wherein R 2 represents hydrogen, lower alkanoyl or phenyl-lower alkyl, is reacted with a thionyl halide, (b) the product obtained is reacted with 3,4-dimethoxyphenethylamine to give a thioacetamide derivative of the formula 3 (II-fl) NH and wherein (c) -i) the compound (III) is subjected to reductive desulfurization or -ii) the compound (III) is reacted with lower alkyl halide or tri-lower alkyl) oxonium fluoroborate to give an acetophenone derivative with the formula - R 3 (IV) R 20 N-cazcaz OCH 3 wherein R 3 represents lower alkyl and R 2 has the meaning given above, and the compound (IV) is subjected to reductive desulphurisation, or -iii) the compound (III) is reduced by al potassium metal borohydride to give a benzyl alcohol derivative of the formula OH S OCH V 1/3 n R O - NH-CH 2 CH 2 OCH 3 wherein R is as defined above, the compound (V) is reacted with lower alkyl halide or tri (lower alkyl) oxonium fluoroborate to produce a benzyl alcohol derivative of the formula 'on - 3 "R OCH 3 (VI) 1. Wherein R and R have the meaning given above, and the compound (VI) is subjected to reductive desulphurisation, and then (d) if necessary, the benzyl alcohol derivative (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt thereof. 2. Sätt enligt krav 1, k ä n n e t e c k n a t av att den reduktiva avsvavlingen av föreningen (III) utföres med använd- ning av en alkalimetallborhydrid såsom reduktionsmedel i närvaro av en metallhalogenid (vilken metallhalogenid väljs från den grupp, som utgöres av nickelklorid, järn(II)klorid, tenn(II)klorid, zinkklorid och koboltklorid) i ett lösningsmedel; alkyleringen av föreningen (III) eller föreningen (V) utföres i närvaro av eller frånvaro av en syraacceptor i ett lösningsmedel.2. A method according to claim 1, characterized in that the reductive desulfurization of the compound (III) is carried out using an alkali metal borohydride as a reducing agent in the presence of a metal halide (which metal halide is selected from the group consisting of nickel chloride, iron ( II) chloride, stannous chloride, zinc chloride and cobalt chloride) in a solvent; the alkylation of the compound (III) or the compound (V) is carried out in the presence or absence of an acid acceptor in a solvent. 3. Sätt enligt krav 2, k ä n n e t e c k n a t av att den reduktiva avsvavlingen av föreningen (III) utföres vid en temperatur mellan 20 och SOOC; omsättningen av föreningen (III) eller föreningen (V) med lägre alkylhalogenid eller' tri(lägre alkyl)oxoniumfluoroborat utföres vid en temperatur 15 454 775 mellan 0 och 30°C; och den reduktiva avsvavlingen av föreningen (IV) eller föreningen (VI) utföres vid en temperatur mellan o och 3o°c.3. A method according to claim 2, characterized in that the reductive desulfurization of the compound (III) is carried out at a temperature between 20 and 50 ° C; the reaction of the compound (III) or the compound (V) with lower alkyl halide or tri (lower alkyl) oxonium fluoroborate is carried out at a temperature between 0 and 30 ° C; and the reductive desulfurization of the compound (IV) or the compound (VI) is carried out at a temperature between 0 and 30 ° C.
SE8206352A 1981-11-12 1982-11-09 SET TO MAKE BENZYL ALCOHOL derivatives SE454775B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP56181951A JPS5883661A (en) 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative

Publications (3)

Publication Number Publication Date
SE8206352D0 SE8206352D0 (en) 1982-11-09
SE8206352L SE8206352L (en) 1983-05-13
SE454775B true SE454775B (en) 1988-05-30

Family

ID=16109721

Family Applications (1)

Application Number Title Priority Date Filing Date
SE8206352A SE454775B (en) 1981-11-12 1982-11-09 SET TO MAKE BENZYL ALCOHOL derivatives

Country Status (10)

Country Link
JP (1) JPS5883661A (en)
KR (1) KR870000471B1 (en)
AT (1) AT382866B (en)
CA (1) CA1196342A (en)
CH (1) CH650247A5 (en)
DK (1) DK163660C (en)
ES (1) ES8401013A1 (en)
HU (1) HU189190B (en)
IT (1) IT1191227B (en)
SE (1) SE454775B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4579972A (en) * 1983-04-28 1986-04-01 Smithkline Beckman Corporation Intermediates for preparing secondary amines
JPH0735693U (en) * 1993-12-14 1995-07-04 協和電機化学株式会社 Seal for sealing the butt of glass doors
US7985168B2 (en) 2009-03-25 2011-07-26 Graa Innovations, Llc Power stride apparatus and method of training therefor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5310974B2 (en) * 1974-06-10 1978-04-18
JPS6241829Y2 (en) * 1980-03-28 1987-10-26

Also Published As

Publication number Publication date
AT382866B (en) 1987-04-27
CH650247A5 (en) 1985-07-15
ES517297A0 (en) 1983-12-01
IT8268332A0 (en) 1982-11-11
JPS5883661A (en) 1983-05-19
JPS6121620B2 (en) 1986-05-28
SE8206352D0 (en) 1982-11-09
KR870000471B1 (en) 1987-03-11
ES8401013A1 (en) 1983-12-01
KR840002343A (en) 1984-06-25
DK502682A (en) 1983-05-13
ATA409882A (en) 1986-09-15
HU189190B (en) 1986-06-30
DK163660B (en) 1992-03-23
DK163660C (en) 1992-08-17
SE8206352L (en) 1983-05-13
CA1196342A (en) 1985-11-05
IT1191227B (en) 1988-02-24

Similar Documents

Publication Publication Date Title
EP0452143B1 (en) Process for preparing optically active 3-hydroxypyrrolidine derivatives
KR0176010B1 (en) Process for producing 1-amino-1,2,3-triazole
CA2020097C (en) Azetidines, their preparation and their application as intermediates for the preparation of compounds with antimicrobial activity
SE454775B (en) SET TO MAKE BENZYL ALCOHOL derivatives
US5399763A (en) Process for preparing optically active 2-aminopropanal
US4540794A (en) Method for preparing 5-mercapto-1,2,3-thiadiazole salts
HU220971B1 (en) Process for producing 0-(3-amino-2-hidroxy-propyl)-hidroxim acid halogenids
JPS58172344A (en) Manufacture of phenylalkanoic acid
US4816580A (en) Improved method for preparing penicillanic acid derivatives
EP4249468A1 (en) A method for synthesis of halide salts
EP0916656B1 (en) A method for production of pyrrolidinone derivatives
US4294970A (en) Oxidation of alpha-alkylated, benzyl-substituted 2-thiopyridine 1-oxides
SE431644B (en) PREPARATION OF PYRROLIDIN-2-ONER AND 3-PYRROLIN-2-ONER
US4153631A (en) Process for processing silver halide developing agents
EP0094691B1 (en) Method for preparing 8-acylthio-1,2,3,4,5,6-hexahydro-2,6-methano-3,6(e),11(a)-trimethyl-3-benzazocines
KR100209298B1 (en) Novel amino-cyclic compound
Casper et al. Synthesis of N4‐substituted [1, 3, 4] oxadiazinan‐2‐ones derived from norephedrine
US4363920A (en) Process for the preparation of N-[2-(-thenoyl)thiopropionyl]-glycine
KR940002713B1 (en) Process for the preparation of photosensitive diazo-type compounds
EP0976735B1 (en) Process for producing piperidinecarboxylic acid amides
EP0051956B1 (en) Preparation of l-aspartic acid n-thiocarboxyanhydride
KR100288404B1 (en) 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same
EP0141560B1 (en) Chemical process
SU357730A1 (en) Method of producing thiazole derivatives
KR830000271B1 (en) Method for preparing 1,2,3-thiadiazol-5-yl urea

Legal Events

Date Code Title Description
NAL Patent in force

Ref document number: 8206352-0

Format of ref document f/p: F

NUG Patent has lapsed

Ref document number: 8206352-0

Format of ref document f/p: F