DK163660B - PROCEDURE FOR THE PREPARATION OF BENZYLAL ALCOHOL DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents

PROCEDURE FOR THE PREPARATION OF BENZYLAL ALCOHOL DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. Download PDF

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DK163660B
DK163660B DK502682A DK502682A DK163660B DK 163660 B DK163660 B DK 163660B DK 502682 A DK502682 A DK 502682A DK 502682 A DK502682 A DK 502682A DK 163660 B DK163660 B DK 163660B
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iii
lower alkyl
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benzyl alcohol
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DK502682A (en
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Ikuo Iijima
Akio Nakao
Mitsunori Gaino
Tokuro Ohishi
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Tanabe Seiyaku Co
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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Description

iin

DK 163660 BDK 163660 B

Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af benzylalkoholderivater med formlenThe present invention relates to a particular process for the preparation of benzyl alcohol derivatives of the formula

OHOH

)—r0CH3 lA)-- NH-CH-CH-—// M--0CH, (I)) -ROCH3 (1A) - NH-CH-CH- // M - OCH, (I)

\=J\ = J

hvor R1 betyder hydrogen eller phenyl-lavere alkyl, eller 5 farmaceutisk acceptable salte deraf.wherein R 1 is hydrogen or phenyl-lower alkyl, or pharmaceutically acceptable salts thereof.

BenzylalkohoIderivaterne (I) eller deres farmaceutisk acceptable syreadditionssalte er kendt for at være anvendelige som cardiotoniske eller anti-diabetiske midler, jvf. USA--patentskrift nr. 4.032.575.The benzyl alcohol derivatives (I) or their pharmaceutically acceptable acid addition salts are known to be useful as cardiotonic or anti-diabetic agents, cf. US Patent No. 4,032,575.

10 Fra dette patentskrift er det kendt, at forbindelserne (I) kan fremstilles ved, at en a-halogen-monobenzyloxyacetophenon (A) kondenseres med 3,4-dimethoxyphenethylamin (B) til dannelse af en a-(3,4-dimethoxyphenethylamino)-monobenzyloxy-acetophenon (C), forbindelsen (C) eventuelt reduceres til 15 dannelse af en a-(3,4-dimethoxyphenethylaminomethyl)-mono-benzyloxybenzylalkohol (D), hvorpå forbindelsen (C) eller (D) underkastes katalytisk hydrogénering.From this patent it is known that the compounds (I) can be prepared by condensing an α-halo-monobenzyloxyacetophenone (A) with 3,4-dimethoxyphenethylamine (B) to give an α- (3,4-dimethoxyphenethylamino) -monobenzyloxy-acetophenone (C), the compound (C) is optionally reduced to form an α- (3,4-dimethoxyphenethylaminomethyl) -monobenzyloxybenzyl alcohol (D), and the compound (C) or (D) is subjected to catalytic hydrogenation.

Det har vist sig, at benzylalkoholderivaterne med formlen I kan fremstilles på særlig fordelagtig måde.It has been found that the benzyl alcohol derivatives of formula I can be prepared in a particularly advantageous manner.

20 I overensstemmelse hermed er fremgangsmåden ifølge opfindelsen ejendommelig ved, at a) et acetophenonderivat med formlen 0Accordingly, the process of the invention is characterized in that a) an acetophenone derivative of formula 0

r2o--IR2O - In

(II) 2(II) 2

DK 163660 BDK 163660 B

2 hvor R betyder hydrogen, alkanoyl eller phenyl-lavere alkyl, omsættes med et thionylhalogenid, b) den fremkomne forbindelse omsættes med 3,4-dimethoxyphen-ethylamin til dannelse af et thioacetamidderivat med formlen2 where R is hydrogen, alkanoyl or phenyl-lower alkyl is reacted with a thionyl halide, b) the resulting compound is reacted with 3,4-dimethoxyphenethylamine to form a thioacetamide derivative of the formula

OISLAND

2 r^VV /TT0CH3 5 RO--I NH-CH2CH2_// X)-0CH3 (III) S/ \=/ 2 hvor R har den ovenfor angivne betydning, og c-1) forbindelsen (III) underkastes reducerende afsvovling, eller c-2) forbindelsen (III) ansættes med et lavere alkylhalogenid eller 10 et tri (lavere alkyl) oxoniurafluoroborat til dannelse af et acetophenondé-rivat med formlen .. I· S-R3 \ v E20--I N-CH2CH2_// 'V-OCHj (IV)Wherein R has the meaning given above and c-1) the compound (III) is subjected to reducing desulfurization, or c-2) compound (III) is employed with a lower alkyl halide or a tri (lower alkyl) oxoniurafluoroborate to form an acetophenone derivative of the formula .. I · S-R3 \ v E20 - I N-CH2 CH2 _ // V-OCH 2 (IV)

WJWJ

3 2 hvor R betyder lavere alkyl, og R har den ovenfor angivne betydning, og forbindelsen (IV) underkastes reducerende afsvovling, eller 15 c-3) forbindelsen (III) reduceres til dannelse af et benzyl- alkoholderivat med formlenWherein R is lower alkyl and R is as defined above and the compound (IV) is subjected to reducing desulfurization, or the compound (III) is reduced to form a benzyl alcohol derivative of the formula

OHOH

i _^yVi _ ^ yV

RO--I NH-CH2CH2_// \\_OCH3 (V)RO - I NH-CH2CH2 _ // \\ OCH3 (V)

\=J\ = J

hvor R^· har den ovenfor angivne betydning, forbindelsen (V) omsættes med et lavere alkylhalogenid eller et tri(lavere 20 alkyl)oxoniumfluoroborat til dannelse af et benzylalkohol- derivat med formlenwherein R 1 is as defined above, the compound (V) is reacted with a lower alkyl halide or a tri (lower 20) oxonium fluoroborate to form a benzyl alcohol derivative of the formula

DK 163660 BDK 163660 B

3 OH ,3 OH,

li S-Rli S-R

-t-och3 RX0--I N-CH2CH2_// \\-OCH3 (VI) v=/ 1 3 hvor R og R har den ovenfor angivne betydning, og forbindelsen (VI) underkastes reducerende afsvovling.-t-och3 RX0 - I N-CH2CH2 _ // \\ - OCH3 (VI) v = / 1 3 where R and R have the meaning given above and the compound (VI) is subjected to reducing desulfurization.

22

Foretrukne eksempler på R i det acetophenonderivat (II), 5 der anvendes som udgangsmateriale ved den her omhandlede fremgangsmpde, indbefatter hydrogen, acetyl og propionyl, samt phenyl-lavere alkyl, såsom benzyl. Desuden anvendes thionylchlorid fortrinsvis som ovennævnte thionylhalogenid. Foretrukne eksempler på R3 er methyl og ethyl.Preferred examples of R in the acetophenone derivative (II) used as starting material in the process of this invention include hydrogen, acetyl and propionyl, and phenyl-lower alkyl such as benzyl. In addition, thionyl chloride is preferably used as the above thionyl halide. Preferred examples of R 3 are methyl and ethyl.

10 Omsætningen af acetophenonderivatet (II) med thionylhalo-genidet gennemføres ved opløsning af forbindelsen (II) i thionylhalogenidet og omrøring af opløsningen. Denne omsætning gennemføres fortrinsvis i nærværelse af en katalytisk mængde af en organisk base. Eksempler på egnede 15 sådanne organiske baser indbefatter pyridin, tri- ethylamin og dimethylanilin. En hensigtsmæssig mængde af det thionylhalogenid, der skal anvendes, ligger på ca.The reaction of the acetophenone derivative (II) with the thionyl halide is carried out 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. Examples of suitable 15 such organic bases include pyridine, triethylamine and dimethylaniline. A suitable amount of the thionyl halide to be used is about

3-10 mol pr. mol acetophenonderivat (II). Det foretrækkes at gennemføre omsætningen ved en temperatur mellem 10 20 og 50°C. Det på denne måde fremkomne reaktionsprodukt, der antages at være en blanding af nedenstående to forbindelser:3-10 moles per mole of acetophenone derivative (II). It is preferred to carry out the reaction at a temperature between 10 and 50 ° C. The reaction product thus obtained, which is believed to be a mixture of the following two compounds:

0 O0 O

II IIII II

cH-s-x c~s r1o--I i 03 r1o— I x hvor X betyder halogen, og R har den ovenfor angivne betydning, bør fortrinsvis anvendes i det efterfølgende trin 25 uden isolering og/eller rensning fra reaktionsopløsningen.cH-s-x c ~ s r10 - I in 03 r10 - I x where X means halogen and R has the meaning given above should preferably be used in the subsequent step 25 without isolation and / or purification from the reaction solution.

DK 163660 BDK 163660 B

44

Omsætningen af ovennævnte produkt med 3f4-dimethoxypheneth-ylamin kan gennemføres i nærværelse eller fraværelse af en syreacceptor i et egnet opløsningsmiddel. Eksempler på egnede syreacceptorer indbefatter organiske baser, såsom pyri-5 din, triethylamin, dimethylanilin og N-methylpyrrolidin, og uorganiske baser, såsom kaliumcarbonat, natriumcarbonat, natriumhydrogencarbonat og natriumhydroxid. Et organisk opløsningsmiddel, f.eks. benzen, chloroform, methylenchlorid, ethylacetat og dimethylformamid, eller en blanding af det 10 organiske opløsningsmiddel og vand er egnet som opløsningsmidlet. Det foretrækkes at gennemføre omsætningen ved en temperatur mellem 0 og 30°C.The reaction of the above product with 3β-dimethoxyphenethylamine may be carried out in the presence or absence of an acid acceptor in a suitable solvent. Examples of suitable acid acceptors include organic bases such as pyridine, triethylamine, dimethylaniline and N-methylpyrrolidine, and inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate and sodium hydroxide. An organic solvent, e.g. benzene, chloroform, methylene chloride, ethyl acetate and dimethylformamide, or a mixture of the organic solvent and water are suitable as the solvent. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C.

Benzylalkoholderivatet (I) kan fremstilles ud fra det på denne måde fremkomne thioacetamidderivat (III) ved en hvil-15 ken som helst af de ovennævnte fremgangsmåder c-1), c-2) og c-3) .The benzyl alcohol derivative (I) can be prepared from the thioacetamide derivative (III) thus obtained by any of the above processes c-1), c-2) and c-3).

Ved fremgangsmåde c-1) fremstilles benzylalkoholderivatet (I) nemlig ved, at forbindelsen (III) underkastes reducerende afsvovling. Den reducerende afsvovling af forbindel-20 sen (III) kan gennemføres ved behandling af forbindelsen med et reduktionsmiddel i nærværelse af et metalhalogenid i et egnet opløsningsmiddel. Eksempler på egnede metalhå-logenider indbefatter nikkelchlorid, ferrochlorid, stanno-chlorid, zinkchlorid og cobaltchlorid.· Eksempler på egne-25 de reduktionsmidler indbefatter alkalimetalborhydrider, såsom natriumborhydrid og lithiumborhydrid. Alkanoler, såsom methanol, ethanol og propanol, tetrahydrofuran, dioxan og dimethoxyethan er egnede som opløsningsmidlet. Det foretrækkes at gennemføre omsætningen ved en temperatur mellem 30 20 og 50°C. Under denne omsætningsproces sker afsvovlingen af forbindelsen (III) og reduktionen af oxogruppen i nabostillingen samtidigt. Når der ved denne omsætning anvendes 2 en forbindelse (III) , hvor R betyder alkanoyl·, hydrolyseres alkanoylgruppen endvidere samtidigt med afsvovlings-In process c-1) the benzyl alcohol derivative (I) is prepared, namely, that the compound (III) is subjected to reducing desulfurization. The reducing desulfurization of the compound (III) can be accomplished by treating the compound with a reducing agent in the presence of a metal halide in a suitable solvent. Examples of suitable metal halogenides include nickel chloride, ferrochloride, stannous chloride, zinc chloride and cobalt chloride. Examples of proprietary reducing agents include alkali metal borohydrides such as sodium borohydride and lithium borohydride. Alkanols such as methanol, ethanol and propanol, tetrahydrofuran, dioxane and dimethoxyethane are suitable as the solvent. It is preferred to carry out the reaction at a temperature between 30 and 50 ° C. During this reaction process, the desulfurization of the compound (III) and the reduction of the oxo group in the neighboring position occur simultaneously. Furthermore, when this reaction is used 2 a compound (III) wherein R is alkanoyl ·, the alkanoyl group is hydrolyzed simultaneously with the desulphurisation process.

DK 163660BDK 163660B

5 og reduktionsreaktionerne til dannelse af benzylalkoholde- rivatet (I), hvor R betyder hydrogen.5 and the reduction reactions to form the benzyl alcohol derivative (I) wherein R is hydrogen.

Ifølge fremgangsmåde c-2) fremstilles benzylalkoholderiva-tet (I) ved, at forbindelsen (III) alkyleres, og den frem-5 komne forbindelse (IV) underkastes reducerende afsvovling.According to process c-2) the benzyl alcohol derivative (I) is prepared by alkylating the compound (III) and the resulting compound (IV) is subjected to reducing desulfurization.

Alky leringen af forbindelsen (III) kan gennemføres ved behandling af denne med et alkyleringsmiddel i nærværelse eller fraværelse af en syreacceptor i et egnet opløsningsmiddel. Eksempler på egnede alky leringsmidler indbefatter 10 lavere alkylhalogenider, såsom methyliodid eller ethyl-bromid, og tri-(lavere alkyl)-oxoniumfluorborater, såsom trimethyloxoniumfluorborat eller triethyloxoniumfluor-borat. Eksempler på egnede syreacceptorer indbefatter uorganiske baser, såsom kaliumcarbonat, natriumcarbonat 15 eller natriumhydrogencarbonat, og organiske baser, såsom pyridin, triethylamin eller l,5-diazabicyclo[4,5,0]-5-un-decen. Methylenchlorid, acetone, chloroform, methanol, ethanol, ether, dimethyIformamid, tetrahydrofuran og lignende er egnede som opløsningsmidler. Det foretrækkes at 20 gennemføre omsætningen ved en temperatur mellem 0 og 30°C.The alkylation of compound (III) can be accomplished by treating it with an alkylating agent in the presence or absence of an acid acceptor in a suitable solvent. Examples of suitable alkylating agents include lower alkyl halides such as methyl iodide or ethyl bromide and tri- (lower alkyl) oxonium fluoroborates such as trimethyloxonium fluoroborate or triethyloxonium fluoroborate. Examples of suitable acid acceptors include inorganic bases such as potassium carbonate, sodium carbonate or sodium bicarbonate, and organic bases such as pyridine, triethylamine or 1,5-diazabicyclo [4,5,0] -5-undecene. 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.

Ved denne omsætning fremstilles acetophenonderivatet (IV).In this reaction the acetophenone derivative (IV) is prepared.

Den på denne måde fremkomne forbindelse (IV) kan fortrinsvis anvendes på det efterfølgende trin uden isolering og/-eller rensning fra reaktionsopløsningen.The compound (IV) thus obtained can preferably be used in the subsequent step without isolation and / or purification from the reaction solution.

25 Den reducerende afsvovling af forbindelsen (IV) kan gennemføres ved at behandle denne med et reduktionsmiddel i et egnet opløsningsmiddel. Eksempler på egnede reduktionsmidler indbefatter alkalimetalborhydrider, f.eks. natriumbor-hydrid og lithiumborhydrid, samt lithiumaluminiumhydridi 30 Alkanoler, f.eks. methanol, ethanol og propanol, tetrahydrofuran, dioxan og dimethoxyethan er egnede som opløsningsmidlet. Det foretrækkes at gennemføre reaktionen ved en temperatur mellem 0 og 30°C. Ved dette reaktionstrin fjernes alkylthiogruppen i forbindelsen (IV) samtidigt med reduk-The reducing desulfurization of compound (IV) can be accomplished by treating it with a reducing agent in a suitable solvent. Examples of suitable reducing agents include alkali metal borohydrides, e.g. sodium borohydride and lithium borohydride, as well as lithium aluminum hydride. methanol, ethanol and propanol, tetrahydrofuran, dioxane and dimethoxyethane are suitable as the solvent. It is preferred to carry out the reaction at a temperature between 0 and 30 ° C. In this reaction step, the alkylthio group of the compound (IV) is removed simultaneously with the reducing agent.

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6 tionen af oxogruppen deri. Når der i dette trin anvendes 2 en forbindelse (IV) , hvor R betyder alkanoyl, hydrolyseres denne alkanoylgruppe også samtidigt med ovennævnte reaktioner .6 of the oxo group therein. When in this step 2 is used a compound (IV) wherein R is alkanoyl, this alkanoyl group is also hydrolyzed simultaneously with the above reactions.

5 Alternativt kan benzylalkoholderivatet (I) fremstilles ved fremgangsmåde c-3), dvs. ved at reducere forbindelsen (III) til dannelse af et benzylalkoholderivat (V), alkylere forbindelsen (V) til dannelse af et benzylalkoholderivat (VI) og underkaste forbindelsen (VI) reducerende afsvovling.Alternatively, the benzyl alcohol derivative (I) can be prepared by process c-3), i. by reducing the compound (III) to form a benzyl alcohol derivative (V), alkylating the compound (V) to form a benzyl alcohol derivative (VI) and subjecting the compound (VI) to reducing desulfurization.

10 Reduktionen af forbindelsen (III) kan gennemføres ved at behandle« denne med et reduktionsmiddel i et egnet opløsningsmiddel. Eksempler på egnede reduktionsmidler indbefatter alkalimetalborhydrider/ såsom natriumborhydrid og lithium-borhydrid. Alkanoler, f.eks. methanol, ethanol og propanol, 15 tetrahydrofuran og dioxan er egnede som opløsningsmidler.The reduction of compound (III) can be accomplished by treating it with a reducing agent in a suitable solvent. Examples of suitable reducing agents include alkali metal borohydrides / such as sodium borohydride and lithium borohydride. Alkanols, e.g. methanol, ethanol and propanol, tetrahydrofuran and dioxane are suitable as solvents.

Det foretrækkes at gennemføre reaktionen ved en temperatur o mellem 0 og 30 C. Når der i dette reaktionstrin anvendes 2 en forbindelse (III), hvor R betyder alkanoyl, sker reduktionen af oxogruppen i forbindelsen (III) samtidigt med 20 hydrolysen af alkanoylgruppen.It is preferred to carry out the reaction at a temperature o between 0 and 30 C. When in this reaction step 2 is used a compound (III) wherein R is alkanoyl, the reduction of the oxo group in the compound (III) occurs simultaneously with the hydrolysis of the alkanoyl group.

Den efterfølgende alkylering af forbindelsen (V) og reducerende afsvovling af forbindelsen (VI) kan gennemføres under samme betingelser som anvendt ved henholdsvis alkylerin-gen af forbindelsen-'(III) eller-den.reducerende afsvovling 25 af forbindelsen (IV) ved fremgangsmåde c-2).Subsequent alkylation of the compound (V) and reducing desulfurization of the compound (VI) can be carried out under the same conditions as used respectively for the alkylation of the compound - (III) or the reducing desulfurization of the compound (IV) by process c -2).

De benzylalkcholderivater (I), der fremstilles ved den her omhandlede fremgangsmåde, kan om nødvendigt omdannes til farmaceutisk acceptable syreadditionssalte deraf. Eksempler på egnede salte indbefatter uorganiske syreadditionssalte, 30 såsom hydrochlorid, hydrobromid, perchlorat, nitrat, sulfat og phosphat, og organiske syreadditionssalte, såsom acetat, propionat, glycolat, lactat, ascorbat, maleat, fumarat, ma-lonat, succinat, oxalat, citrat, methansulfonat, benzensul-The benzyl alcohol cholesterol derivatives (I) prepared by the process of this invention can be converted into pharmaceutically acceptable acid addition salts thereof if necessary. Examples of suitable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, perchlorate, nitrate, sulfate and phosphate, and organic acid addition salts such as acetate, propionate, glycolate, lactate, ascorbate, maleate, fumarate, malonate, succinate, oxalate, , methanesulfonate, benzene sulfate

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7 fonat, aminobenzoat, sulfaminat, aspartat, glutamat og ni-cotinat.7 phonate, aminobenzoate, sulfaminate, aspartate, glutamate and nicotinate.

Den ovenfor beskrevne, her omhandlede fremgangsmåde· gør det muligt at fremstille benzylalkoholderivater (I) i et højt 5 udbytte uden uønskede sidereaktioner, og den er hensigtsmæssig til fremstilling af disse benzylalkoholderivater (I) i industriel målestok. Eftersom mellemprodukterne (III) ifølge opfindelsen er helt stabile og let kan isoleres og renses på konventionelle måder/ er den her omhandlede frem-10 gangsmåde endvidere også fordelagtig, fordi benzylalkohol-derivaterne (I) fremkommer i høj renhed uden forurening med uønskede biprodukter.The process described hereinabove · allows benzyl alcohol derivatives (I) to be prepared in a high yield without undesirable side reactions, and is suitable for the production of these benzyl alcohol derivatives (I) on an industrial scale. Furthermore, since the intermediates (III) of the invention are quite stable and readily isolated and purified in conventional ways, the process of the present invention is also advantageous because the benzyl alcohol derivatives (I) appear in high purity without contamination with unwanted by-products.

I den foreliggende beskrivelse og krav skal udtrykket "lavere alkyl" og "lavere alkanoyl" fortrinsvis betyde lige-15 kædet eller forgrenet alkyl og alkanoyl aoed 1-4 car-bonatomer.In the present specification and claims, the term "lower alkyl" and "lower alkanoyl" preferably means straight-chain or branched-chain alkyl and alkanoyl or 1-4 carbon atoms.

Nedenstående eksempler tjener til illustrering af fremgangsmåden ifølge den foreliggende opfindelse:The following examples serve to illustrate the process of the present invention:

Eksempel 1 20 1) 4,97 g 4-benzyloxyacetophenon opløses i 15 ml thionyl- chlorid/ og 0,02 ml pyridin tilsættes. Blandingen omrøres ved s tuetemperatur i 5 timer. Blandingen koncentreres under formindsket tryk til fjernelse af overskud af thionylchlorid. Remanensen opløses i 30 ml benzen. Opløsningen sættes til en 25 blanding af 4,78 g 3,4-dimethoxyphenethylamin, 90 ml vandig 10%'s kaliumcarbonatopløsning og 50 ml benzen, og blandingen omrøres ved stuetemperatur i 4 timer. Benzenopløsningen skilles fra reaktionsblandingen, og det vandige lag ekstra-heres med ethylacetat. Benzenopløsningen og ethylacetateks-30 trakten forenes og vaskes successivt med vand, 10%’s saltsyre og vand. Det organiske lag tørres og inddampes underExample 1 20 1) 4.97 g of 4-benzyloxyacetophenone is dissolved in 15 ml of thionyl chloride / and 0.02 ml of pyridine is added. The mixture is stirred at room temperature for 5 hours. The mixture is concentrated under reduced pressure to remove excess thionyl chloride. The residue 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 aqueous 10% potassium carbonate solution and 50 ml of benzene, and the mixture is stirred at room temperature for 4 hours. The benzene solution is separated from the reaction mixture and the aqueous layer is extracted with ethyl acetate. The benzene solution and ethyl acetate extract are combined and washed successively with water, 10% hydrochloric acid and water. The organic layer is dried and evaporated underneath

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8 formindsket tryk. Remanensen omkrystalliseres fra ethanol.8 reduced pressure. The residue is recrystallized from ethanol.

Der fremkommer 7,67 g 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4--dimethoxyphenethyl)-thioacetamid i form af bleggule nåle. Udbytte: 80,1%. Smp.: 132 - 133°C.7.67 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide are obtained in the form of pale yellow needles. Yield: 80.1%. Mp: 132 - 133 ° C.

5 2) 500 mg 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphen- ethyl)-thioacetamid og 610 mg nikkelchlorid, hexahydrat opløses i 30 ml methanol, og 700 mg natriumborhydrid tilsættes ved stuetemperatur. Blandingen omrøres ved samme temperatur i 1,5 timer. Uopløselige materialer frafiltreres, og 10 filtratet koncentreres under formindsket tryk. Remanensen opløses i chloroform, vaskes med vand, tørres og inddampes dernæst under formindsket tryk. Remanensen behandles med ethanolisk saltsyre, og de krystallinske udfældede materialer opsamles ved filtrering. Der fremkommer 360 mg a-(3,4-15 -dime thoxyphenethylaminome thyl) -4-benzyloxybenzylalkohol- -hydrochlorid.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. The mixture is stirred at the same temperature for 1.5 hours. Insoluble materials are 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 precipitated materials are collected by filtration. 360 mg of α- (3,4-15-dime thoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol hydrochloride are obtained.

Udbytte: 70%. Smp.: 168 - 170°C.Yield: 70%. Mp: 168-170 ° C.

Eksempel 2 2,0 g 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)-20 -thioacetamid opløses i 40 ml methylenchlorid, og 1,05 g triethyloxoniumfluorborat tilsættes. Efter omrøring af blandingen ved stuetemperatur i 1,5 time koncentreres blandingen under formindsket tryk. Remanensen opløses i 30 ml ethanol, og der tilsættes 2,1 g natriumborhydrid. Blandingen omrøres 25 ved stuetemperatur i 1 time. Vand hældes ud i reaktionsblandingen, og blandingen koncentreres under formindsket tryk.Example 2 2.0 g of 2- (4-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -20-thioacetamide are dissolved in 40 ml of methylene chloride and 1.05 g of triethyloxonium fluoroborate is added. After stirring the mixture 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 is 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.

De krystallinske, udfældede materialer opsamles ved filtrering, og krystallerne vaskes med vand og omkrystalliseres dernæst fra isopropanol. Der fremkommer 1,45 g a-(3,4-di-30 methoxyphenethylaminomethyl) -4-benzyloxybenzylalkohol (fri base) i form af farveløse nåle.The crystalline precipitated materials are collected by filtration and the crystals are washed with water and then recrystallized from isopropanol. 1.45 g of α- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzyl alcohol (free base) is obtained in the form of colorless needles.

Udbytte: 77,5%. Smpi.: 114,5 - 116°C.Yield: 77.5%. Mp: 114.5 - 116 ° C.

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99

Eksempel 3 2,2 g 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)--thioacetamid opløses i 30 ml acetone, og 850 mg kalium-carbonat og 1,0 g methyliodid tilsættes. Blandingen’ omrøres 5 ved stuetemperatur natten over. Uopløselige materialer fra-filtreres, og filtratet koncentreres under formindsket tryk. Remanensen opløses i 50 ml methanol, og der tilsættes 300 mg natriumborhydrid. Blandingen omrøres ved stuetemperatur i 30 minutter. Dernæst behandles reaktionsblandingen på samme 10 måde som beskrevet i eksempel 2. Der fremkommer 1,65 g a- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzylal-kohol (fri base) i form af farveløse nåle.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. The mixture is stirred at room temperature overnight. Insoluble materials are 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 is added. The mixture is stirred at room temperature for 30 minutes. Next, the reaction mixture is treated in the same manner as described in Example 2. 1.65 g of α- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzylalcohol (free base) is obtained in the form of colorless needles.

Udbytte: 80 %.Yield: 80%.

De fysisk-kemiske egenskaber af dette produkt er identiske 15 med de fysisk-kemiske egenskaber af den i eksempel 2 fremstillede forbindelse.The physicochemical properties of this product are identical to the physicochemical properties of the compound prepared in Example 2.

Eksempel 4 1) 8,0 g 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphen-ethyl)-thioacetamid opløses i 150 ml methanol, og 500 ml 20 natriumborhydrid tilsættes. Blandingen omrøres ved stuetemperatur i 1 time. Blandingen koncentreres under formindsket tryk. Remanensen opløses i chloroform, vaskes med vand, tørres og inddampes under formindsket tryk. Remanensen omkrystalliseres fra isopropanol. Der fremkommer 7,5 g 2-(4-25 -benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) - thio acetamid i form af farveløse nåle.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 ml 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 isopropanol. 7.5 g of 2- (4-25-benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) -thio acetamide are obtained in the form of colorless needles.

Udbytte: 93%. Smp.: 82 - 84°C.Yield: 93%. Mp: 82 - 84 ° C.

2) 1,0 g 2-(4-benzyloxyphenyl)-2-hydroxy-N-(3,4-dimethoxyphenethyl)-thioacetamid opløses i 20 ml methylenchlorid, og 30 460 mg triethyloxoniumfluorborat tilsættes. Efter omrøring af blandingen ved stuetemperatur i 30 minutter koncentreres blandingen under formindsket tryk. Remanensen opløses i en blanding af 20 ml methanol og 20 ml chloroform, og 440 mg2) 1.0 g of 2- (4-benzyloxyphenyl) -2-hydroxy-N- (3,4-dimethoxyphenethyl) thioacetamide is dissolved in 20 ml of methylene chloride and 460 mg of triethyloxonium fluoroborate is added. After stirring the mixture at room temperature for 30 minutes, the mixture 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

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10 natriumborhydrid tilsættes. Blandingen omrøres ved stuetemperatur i 1 time. Dernæst behandles reaktionsblandingen på samme måde som beskrevet i eksempel 2. Der fremkommer 780 mg a-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzylal-5 kohol (fri base) i form af farveløse nåle.10 sodium borohydride is added. The mixture is stirred at room temperature for 1 hour. Next, the reaction mixture is treated in the same manner as described in Example 2. 780 mg of α- (3,4-dimethoxyphenethylaminomethyl) -4-benzyloxybenzylalcohol (free base) is obtained in the form of colorless needles.

Udbytte: 84%.Yield: 84%.

De fysisk-kemiske egenskaber af dette produkt er identiske med de fysisk-kemiske egenskaber af den i eksempel 2 fremstillede forbindelse.The physicochemical properties of this product are identical to the physicochemical properties of the compound of Example 2.

10 Eksempel 5 1) 5,34 g 4-acetoxyacetophenon, 20 ml thionylchlorid, 0,03 ml pyridin og 6,51 g 3,4-dimethoxyphenethylamin behandles på samme måde som beskrevet i eksempel 1, 1) . Der fås 8,5 g 2-(4-acetoxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)- 15 -thioacetamid i form af en bleggul olie.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) -15-thioacetamide are obtained as a pale yellow oil.

Udbytte: 73%.Yield: 73%.

IR V (om”1): 1755, 1665 max.IR V (about ”1): 1755, 1665 max.

Masse m/e: 387 (M+) NMR (CDCl3)<f: 2,30 (s, 3H, CH3COO-) , 3,00 (t, 2H, J=7,5 Hz, 20 -CH2-CH2-), 3,84 (s, 6H, -OCH3x2).Mass m / e: 387 (M +) NMR (CDCl3) <f: 2.30 (s, 3H, CH3 COO-), 3.00 (t, 2H, J = 7.5 Hz, 20 -CH2-CH2-) , 3.84 (s, 6H, -OCH3x2).

2) 1,94 g 2-(4-acetoxyphenyl)-2-oxo-N-(3,4-dimethoxyphen-ethyl)-thioacetamid, 1,14 g triethyloxoniumfluorborat og 1,0 g natriumborhydrid behandles på samme måde som beskrevet i eksempel 2. Der fremkommer 1,47 g a-(3,4-dimethoxy- 25 phenethylaminomethyl) -4-hydroxybenzylalkohol i form af farveløse prismer.2) 1.94 g of 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 α- (3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzyl alcohol is obtained in the form of colorless prisms.

Udbytte: 92%. Smp.: 151 - 153°C.Yield: 92%. Mp: 151 - 153 ° C.

Eksempel 6 1) 4,08 g 4-hydroxyacetophenon, 12 ml thionylchlorid, 30 0,06 ml pyridin og 6,51 g 3,4-dimethoxyphenethylamin behand les på samme måde som beskrevet i eksempel 1, 1) . Der frem-Example 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 manner as described in Example 1, 1). There,

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11 kommer 3,1 g 2-(4-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphen-ethyl)-thioacetamid i form af bleggule nåle.11, 3.1 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide are obtained in the form of pale yellow needles.

Udbytte: 30%. Smp.: 179 - 180°C (omkrystallisation fra ethanol).Yield: 30%. Mp: 179-180 ° C (recrystallization from ethanol).

5 2) 1,0 g 2-(4-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphen- ethyl)-thioacetamid, 1,37 g nikkelchlorid, hexahydrat og 1,1 g natriumborhydrid behandles på samme måde som beskrevet i eksempel 1, 2). Der fremkommer 230 mg a-(3,4-dimeth-oxyphenethylaminomethyl)-4-hydroxybenzylalkohol i form af 10 farveløse prismer.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. as described in Example 1, 2). 230 mg of α- (3,4-dimethoxy-phenylaminomethyl) -4-hydroxybenzyl alcohol are obtained in the form of 10 colorless prisms.

Udbytte: 25%.Yield: 25%.

De fysisk-kemiske egenskaber af dette produkt er identiske med de fysisk-kemiske egenskaber af den i eksempel 5, 2) fremstillede forbindelse.The physicochemical properties of this product are identical to the physicochemical properties of the compound of Example 5, 2).

15 Eksempel 7 1,58 g 2-(4-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)--thioacetamid, 1,13 g triethyloxoniumfluorborat og 870 mg natriumborhydrid behandles på samme måde som beskrevet i eksempel 2. Der fremkommer 940 mg a-(3,4-dimethoxyphen-20 ethylaminomethyl)-4-hydroxybenzylalkohol i form af farveløse prismer.Example 7 1.58 g of 2- (4-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 mg of sodium borohydride are treated in the same manner as described in Example 2 940 mg of α- (3,4-dimethoxyphen-20-ethylaminomethyl) -4-hydroxybenzyl alcohol are obtained in the form of colorless prisms.

Udbytte: 65%.Yield: 65%.

De fysisk-kemiske egenskaber af dette produkt er identiske med de fysisk-kemiske egenskaber af den i eksempel 5, 2) 25 fremstillede forbindelse.The physicochemical properties of this product are identical to the physicochemical properties of the compound prepared in Example 5, 2).

Eksempel 8 1) 6,78 g 2-benzyloxyacetophenon, 21 ml thionylchlorid, 0,05 ml pyridin og 6,54 g 3,4-dimethoxyphenethylamin behandles på samme måde som beskrevet i eksempel 1, 1). Der frem-30 kommer 10,3 g 2-(2-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl) -thioacetamid i form af bleggule prismer.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 as described in Example 1, 1). 10.3 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide are obtained in the form of pale yellow prisms.

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1212

Udbytte: 79%. Smp.: 112 - 114°C.Yield: 79%. Mp: 112 - 114 ° C.

2) 500 mg 2-(2-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxy- phenethyD-thioace tamid, 900 mg nikkelchlorid, hexahydrat og 700 mg natriumborhydrid behandles på samme måde som be-5 skrevet i eksempel 1, 2). Der fremkommer 165 mg a-(3,4-di-methoxyphenethylaminomethyl)-2-benzyloxybenzylalkohol-hy-drochlorid i form af farveløse nåle.2) 500 mg of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide, 900 mg 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 α- (3,4-di-methoxyphenethylaminomethyl) -2-benzyloxybenzyl alcohol hydrochloride are obtained in the form of colorless needles.

Udbytte: 32%. Smp.: 159 - 160°C.Yield: 32%. Mp: 159 - 160 ° C.

Eksempel 9 10 2,0 g 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dime thoxy phene thyl) - -thioacetamid, 1,13 g triethyloxoniumfluorborat og 870 mg natriumborhydrid behandles på samme måde som beskrevet i eksempel 2. Der fremkommer 1,65 g a-(3,4-dimethoxyphenethyl-aminomethyl)-2-benzyloxybenzylalkohol (fri base) i form af 15 farveløse nåle.Example 9 2.0 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dime thoxyphenyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 870 mg of sodium borohydride are treated in the same manner as described. Example 2. 1.65 g of α- (3,4-dimethoxyphenethyl-aminomethyl) -2-benzyloxybenzyl alcohol (free base) are obtained in the form of 15 colorless needles.

Udbytte: 82%. Smp.: 95 - 97°C (omkrystallisation fra iso-propanol).Yield: 82%. Mp: 95-97 ° C (recrystallization from iso-propanol).

Eksempel 10 2,2 g 2-(2-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)-20 -thioacetamid, 850 mg kaliumcarbonat, 1,0 g methyliodid og 300 mg natriumborhydrid behandles på samme måde som beskrevet i eksempel 3. Der fremkommer 1,1 g a-(3,4-dimethoxy-phenethylaminomethyl)-2-benzyloxybenzyllakohol (fri base) i form af farveløse nåle.Example 10 2.2 g of 2- (2-benzyloxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -20-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 g of α- (3,4-dimethoxy-phenethylaminomethyl) -2-benzyloxybenzyl alcohol (free base) is obtained in the form of colorless needles.

25 Udbytte: 53%.Yield: 53%.

De fysisk-kemiske egenskaber af dette produkt er identiske med de fysisk-kemiske egenskaber af den i eksempel 9 fremstillede forbindelse« * Eksempel 11 30 1) 2,73 g 2-hydroxyacei:ophenon, 8 ml thionylchlorid, 0,03 ml pyridin og 2,53 g 3,4-dimethoxyphenethylamin behandles påThe physicochemical properties of this product are identical to the physicochemical properties of the compound prepared in Example 9. * Example 11 30 1.) 2.73 g of 2-hydroxyacetic: ophenone, 8 ml of thionyl chloride, 0.03 ml of pyridine and 2.53 g of 3,4-dimethoxyphenethylamine are treated

DK 163660 BDK 163660 B

13 samme måde som beskrevet i eksempel 1, 1). Der fremkommer 4,0 g 2-(2-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)--thioacetamid i form af bleg-rødbrune nåle.13 in the same manner as described in Examples 1, 1). 4.0 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) -thioacetamide are obtained in the form of pale reddish-brown needles.

Udbytte: 58%. Smp.: 166 - 168°C (omkrystallisation fra eth-5 anol).Yield: 58%. Mp: 166 - 168 ° C (recrystallization from ethanol).

2) 1,58 g 2-(2-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphen- ethyl)-thioacetamid, 1,13 g triethyloxoniumfluorborat og 1,4 g natriumborhydrid behandles på samme måde som beskrevet i eksempel 2. Der fremkommer 850 mg a-(3,4-dimethoxy-10 phenethylaminomethy1)-2-hydroxybenzylalkohol i form af en farveløs olie.2) 1.58 g of 2- (2-hydroxyphenyl) -2-oxo-N- (3,4-dimethoxyphenethyl) thioacetamide, 1.13 g of triethyloxonium fluoroborate and 1.4 g of sodium borohydride are treated in the same manner as described in Example 2. 850 mg of α- (3,4-dimethoxy-10-phenethylaminomethyl) -2-hydroxybenzyl alcohol is obtained in the form of a colorless oil.

Udbytte: 58%.Yield: 58%.

Oxalat af produktet: Smp.: 175 - 176°C.Oxalate of the product: mp: 175 - 176 ° C.

Eksempel 12 15 1) 1,78 g 2-acetoxyacetophenon, 6 ml thionylchlorid, 0,02 ml pyridin og 1,27 g 3,4-dimethoxyphenethylamin behandles på samme måde som beskrevet i eksempel 1, 1). Der fremkommer 1,37 g 2-(2-acetoxyphenyl)-2-oxo-N-(3,4-dimethoxy-phenethyl)-thioacetamid i form af en bleggul olie.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-dimethoxy-phenethyl) -thioacetamide are obtained as a pale yellow oil.

20 Udbytte: 35,4%.Yield: 35.4%.

IRp^13 (cm"1): 1760, 1670IRp 13 (cm -1): 1760, 1670

IumX ♦IumX ♦

Hasse m/e: 387 (M+) NMR (CDC13) s · 2,20 (s, 3H, CH-jCOO-) , 2,94 (t, 2H, J=7,5 Hz, -CH2-CH2-), 3,85 (s, 6H,-OCH3x2).Hasse m / e: 387 (M +) NMR (CDCl3) s · 2.20 (s, 3H, CH-jCOO-), 2.94 (t, 2H, J = 7.5 Hz, -CH2-CH2-) , 3.85 (s, 6H, -OCH3x2).

25 2) 2-(2-Acetoxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)- -thioacetamid, triethyloxoniumfluorborat og natriumbor-hydrid behandles på samme måde som beskrevet i eksempel 2.2) 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.

Der fremkommer a- (3,4-dime thoxy phenethy laminomethy 1)-2--hydroxybenzylalkohol.There is a- (3,4-dime thoxy phenethylamino-1) -2-hydroxybenzyl alcohol.

30 De fysisk-kemiske egenskaber af dette produkt er identiske med de fysisk-kemiske egenskaber af den i eksempel 11, 2) fremstillede forbindelse.The physicochemical properties of this product are identical to the physicochemical properties of the compound of Example 11, 2).

Claims (3)

1. Fremgangsmåde til fremstilling af benzylalkoholderivater med formlen OH 1 'T°CE3 Έ^Ο--I NH-CH2CH 2J! νθΟΗ3 (I) A=/ 5 hvor R^ betyder hydrogen eller phenyl-lavere alkyl, eller farmaceutisk acceptable syreadditionssalte deraf, kende-t.e g n e t ved, at a) et acetophenonderivat med formlen \ r1o--t (II) 2 10 hvor R betyder hydrogen, alkanoyl eller phenyl-lavere alkyl, omsættes med et thionylhalogenid, b) den fremkomne forbindelse omsættes med 3,4-dimethoxyphen-ethylamin til dannelse af et thioacetamidderivat med formlen 0 II J-r-0CH3 R10--I NH-CH2CHA process for the preparation of benzyl alcohol derivatives of the formula OH 1 'T ° CE3 Έ ^ Ο - In NH-CH 2 CH 2 J! wherein R ^ is hydrogen or phenyl-lower alkyl, or pharmaceutically acceptable acid addition salts thereof, characterized in that a) an acetophenone derivative of the formula \ R10 - t (II) 2 wherein R means hydrogen, alkanoyl or phenyl-lower alkyl, is reacted with a thionyl halide, b) the resulting compound is reacted with 3,4-dimethoxyphenethylamine to form a thioacetamide derivative of the formula 0 II Jr-OCH 3 R 10 - I NH-CH 2 CH 2-J! ^V0CH3 (111) \=J 15 hvor R har den ovenfor angivne betydning, og c-1) forbindelsen (III) underkastes reducerende afsvovling eller c-2) forbindelsen (III) omsættes med et lavere alkylhaloge-nid eller et tri(lavere alkyl)oxoniumfluoroborat til dannelse af et acetophenonderivat med formlen DK 163660 B 15 0 ? . *1 S-R3 /-t0CH3 R10--j N-CH2CH2 —P \y_0CH3 (IV) X=J 3 2 hvor R betyder lavere alkyl, og R har den ovenfor angivne betydning, og forbindelsen (IV) underkastes reducerende afsvovling, eller 5 c-3) forbindelsen (III) reduceres til dannelse af et benzyl- alkoholderivat med formlen ,--^-och3 rX0 —— I nh-ch2ch2-// '\_och3 (V) \=/ hvor R·*· har den ovenfor angivne betydning, forbindelsen (V) ansættes med et lavere alkylhalogenid eller et tri (lavere alkyl) oxonium-10 fluoroborat til dannelse af et benzylalkoholderivat med formlen OH ^ f^VV 1-r0CH3 R1©--I N-CH2CH2—(j n_OCH3 (VI) \=J 1 3 hvor R og R har den ovenfor angivne betydning, og forbindelsen (VI) underkastes reducerende afsvovling, hvorefter, d) om ønsket, det på denne måde fremkomne benzylalkoholderi-15 vat (I) omdannes til et farmaceutisk acceptabelt syreadditionssalt deraf. Fremgangsmåde ifølge krav 1,kendetegnet ved, at den reducerende afsvovling af forbindelsen (III) gennemføres ved anvendelse af et alkalimetalborhydrid som reduk-20 tionsmiddel i nærværelse af et metalhalogenid, valgt blandt nikkelchlorid, ferrochlorid, stannochlorid, zinkchlorid og DK 163660 B 16 cobaltchlorid, i et opløsningsmiddel, alkyleringen af forbindelsen (III) eller forbindelsen (V) gennemføres i nærværelse eller fraværelse af en syreacceptor i et opløsningsmiddel .2-J! Where R has the meaning given above and c-1) the compound (III) is subjected to reducing desulfurization or c-2) the compound (III) is reacted with a lower alkyl halide or a tri (lower) alkyl) oxonium fluoroborate to form an acetophenone derivative of the formula DK 163660 B 15 0? . * 1 S-R 3 / -TOCH 3 R 10 - j N-CH 2 CH 2 - P \ y_OCH 3 (IV) X = J 3 2 where R is lower alkyl and R is as defined above and compound (IV) is subject to reducing desulfurization, or (c-3) the compound (III) is reduced to form a benzyl alcohol derivative of the formula, - ^ - and 3 rX0 - - I nh-ch 2ch 2 - // '\ _ and 3 (V) \ = / where R · * · has the meaning given above, the compound (V) is employed with a lower alkyl halide or a tri (lower alkyl) oxonium fluoroborate to form a benzyl alcohol derivative of the formula OH ^ f ^ VV 1 -ROCH3 R1 © - I N-CH2CH2- (j n_OCH3 (VI) \ = J 1 3 where R and R have the meaning given above and the compound (VI) is subjected to reducing desulfurization, whereupon, d) if desired, the benzyl alcohol containing (I) thus obtained is converted to a pharmaceutically acceptable acid addition salt thereof. Process according to claim 1, characterized in that the reducing desulfurization of the compound (III) is carried out using an alkali metal borohydride as reducing agent in the presence of a metal halide selected from nickel chloride, ferrochloride, stannous chloride, zinc chloride and cobalt chloride. in a solvent, the alkylation of compound (III) or compound (V) is carried out in the presence or absence of an acid acceptor in a solvent. 3. Fremgangsmåde ifølge krav 2, kendetegnet ved, at den reducerende afsvovling af forbindelsen (III) gennemføres ved en temperatur mellem 20 og 50°C, omsætningen af forbindelsen (III) eller forbindelsen (V) med lavere alkyl-halogenid eller tri(lavere alkyl)oxoniumfluoroborat gennemføres ved en temperatur mellem 0 og 30°C, og den reducerende afsvovling af forbindelsen (IV) eller (VI) gennemføres ved en temperatur mellem 0 og 30°C.Process according to claim 2, characterized in that the reducing 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 conducted at a temperature between 0 and 30 ° C and the reducing desulfurization of compound (IV) or (VI) is carried out at a temperature between 0 and 30 ° C.
DK502682A 1981-11-12 1982-11-11 PROCEDURE FOR PREPARING BENZYLAL ALCOHOL DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. DK163660C (en)

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JP56181951A JPS5883661A (en) 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative
JP18195181 1981-11-12

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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)
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US4579972A (en) * 1983-04-28 1986-04-01 Smithkline Beckman Corporation Intermediates for preparing secondary amines
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US7985168B2 (en) 2009-03-25 2011-07-26 Graa Innovations, Llc Power stride apparatus and method of training therefor

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ATA409882A (en) 1986-09-15
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ES8401013A1 (en) 1983-12-01
KR870000471B1 (en) 1987-03-11
DK163660C (en) 1992-08-17
IT8268332A0 (en) 1982-11-11
IT1191227B (en) 1988-02-24
AT382866B (en) 1987-04-27
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JPS6121620B2 (en) 1986-05-28
DK502682A (en) 1983-05-13
HU189190B (en) 1986-06-30

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