CA1196342A - Process for preparing benzylalcohol derivatives - Google Patents

Process for preparing benzylalcohol derivatives

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CA1196342A
CA1196342A CA000415011A CA415011A CA1196342A CA 1196342 A CA1196342 A CA 1196342A CA 000415011 A CA000415011 A CA 000415011A CA 415011 A CA415011 A CA 415011A CA 1196342 A CA1196342 A CA 1196342A
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iii
derivative
formula
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Ikuo Iijima
Akio Nakao
Mitsunori Gaino
Tokuro Ohishi
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Tanabe Seiyaku Co Ltd
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Tanabe Seiyaku Co Ltd
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    • 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
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    • 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
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    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

ABSTRACT

There are disclosed novel processes for preparing a benzylalcohol derivative of the formula:

wherein R1 is hydrogen or aralkyl, via a thioacetamide derivative of the formula:

Description

This invention relates to a novel process for preparing a benzylalcohol derivative of the formula:

OE~

R1 ~ H CH~CH2 ~ CCOCH3 ~I) wherein R1 is hydrogen or aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
The benzylalcohol derivative (I) or a pharmaceutically acceptable acid addition salt thereof is known to be useful as a cardiotonic or anti diabetic agent (U.S. Patent No.
4032575).
U.S. Patent 4032575 discloses that the compound (I) can be prepared by the steps of condensing an ~-halo-monobenzyl-oxyacetophenone (A) with 3,4 dimethoxyphenethylamine (B) to give an ~-~3,4-dimethoxyphenethylamino)monoben~yloxy aceto-phenone (C), optionally reducing the compound (C) to give ~9~3'~;Z

an ~-(3,4-dimethoxyphenethylaminomethyl)mono~enzyloxyben~yl~
alcohol (n)~ and then subjecting the compound (C) or (D) to catalytic hydrogena-tion.
As a result of further investigations, however, we have now found a novel process for preparing the benzylalcohol derivative (I)~
According to the present invention, the benzylalcohol derivative (I) can be prepared by the steps of:
(a) reacting an acetophenone derivative oE the ~ormula:

R O ~ C 3 (II) wherein R2 is hydrogen, alkanoyl or aralkyl, with a thionyl halide, (b) reacting the resultant product with 3,4-dimethoxy-phenethylamine to give a thioacetamide derivative of the formula:

R20 ~ ~ ~H-C32c3z ~ OC~3 (III) wherein R2 is the same as defined above, and 3L ~ L~ Z~

~ ~3 (c-l) subjecting the compound (III) to reductive desulfuriæation, or `
(c 2) alkylating the compound (III) to give an acetophenone derivative of the ~ormula:

O '~
2 ~ ~ S-R3 ~ OCH3 ~IV) R O ~ N CH2CH2 ~ 0CH3 wherein R3 is alkyl and R2 is the same as defined above, and subjecting the compound (IV) to reductive desulfurization, or (c-3) reducing the compound (III) to give a benzyl-alcohol derivative of th~ formula:

OH

R10 ~ NH CH2CH2 ~ 0CoCH3 ~V~

wherein R1 is the same as defined abover alkylating the compound (V) to give a benzylalcohol derivative of the formula:

OH
~ S R ~ OCH3 (VI) R10 ~ N CH2CH2 ~ OCH3 :1~9~ 2 -4~
wherein R1 and R3 are the same as defined above, and su~jecting the compound IVI) to reductive desulfurization.
In the acetophenone derivative (II) which is used as the starting material in the method of the present invention, preferred examples of R2 include hydrogen; lower alkanoyl such as 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 R3 include lower alkyl such as methyl or ethyl.
The reaction of the acetophenone derivative (II) with the thionyl halide is accomplished 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 o~ an organic base. Suitable examples of such organic base include pyridine, triethylamine, dimethyl aniline and the like. Suitable amount of the thionyl halide to be used is about 3 to 10 moles per mole of the acetophenone derivative (II). It is preferred to carry out the reaction at a temperature between 10 and 50C. The reaction product thus obtained, which is presumed to be a~
mixture of the following two compounds:

O O

~ ~ CHS-X C=S
R20 ~ ~ X and R20 ~ X

:~31 9tj3~;~

wherein X is halogen and R2 is the same as defined above, should preferably be used in the subsequent step without isolation and/or purification from the reaction solution.
The reaction of the above~mentioned product with 3,4-dimethoxyphenethylamine can be accomplished 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, dimethylàniline or N-methyl-pyrrolidine and inorganic bases such as potassium car~onate, sodium carbonate, sodium bicarbonate or sodium hydroxide.
An organic solvent ~e.g., benzene, chloroform, methylene chloride, ethyl acetate, dimethylformamidè) or a mixture of said organic solvent and water are suitable as the solvent.
It is preferred to carry out the reaction at a temperature between 0 and 30C.
The benzylalcohol derivative (I) can be prepared from the thus-obtained thioacetamide derivative (III) according to either one of the aforementioned methods (c 1), (c-2) and (c-3).
Namely, according to Method (c-1), the benzylalcohol derivative (I) is prepared by subjecting the compound (III) to reductive desulfurization. The reductive desulfurization of the compound (III) can be accomplished 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, ferrous chloride, stannous chloride,
3~

~ ~6 zinc chloride, cobalt chloride and the like. Suitable examples o~ -the reducing agent include alkali metal borohydrides such as sodium borohydride, lithium borohydride and the like. ~lkanols le.g-, methanol, ethanolJ propanol~, tetra hydrofuran, dioxane, dimethoxyethane and the like are suitable as the solvent. It is pre~erred to carry out the reaction at a temperature between 20 and 50C. During this reaction procedure, the desulfurization of the compound IIII) and the reduction of oxo group at the 2nd~position thereof take place simultaneously. Moreover, when the compound (III) in which R2 is alkanoyl is used in this reaction, the alkanoyl group is further hydrolyzed simul-taneously with said desul furi~ation and reduction reactions to give the benzylalcohol derivative (I) in which R1 is hydrogen.
According to Method (c=2), the benzylalcohol derivative tI) is prepared by alkylating the compound ~III), and subjecting the resultant compound (IV) to reductive desulfurization.
The alkylation of the 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. Suitable examples of the alkylating agent include lower alkyl halides such as methyl iodide or ethyl bromide; tri(lower alkyl)oxonium-fluoroborates such as trimethyloxoniumfluoroborate or triethyloxoniumfluoroborate; and di(lower alkyl) sul~ates such as dimethyl sulfate or diethyl sulfate. Suitable examples of the acid acceptor include inorganic bases such ;3~

as potassium carbonate, sodium carbonate or sodium bicarbonate and organic bases such as pyridine, triethylamine or 1,5-diaza-bicyclo[5.4~0.~-5-undecene. Methylene chloride, acetone, chloroform, methanol, ethanol, ether, dimethylformamide, tetrahydrofuran and the like are suitable as the solven-t.
It is preferred to carry out the reaction at a temperature between 0 and 30C. By this reaction, the acetophenone derivative (IV) is prepared. The compound`(IV) thus obtained can be preferably used in the subsequent step without isolation and/or purification thereof from the reaction solution.
- The reductive desulfurization of the compound (IV) can . . .
be accomplished by treating it with a reducing agent in a suitable solvent. Suitable examples of the reducing agent include alkali metal borohydride (e.g., sodium borohydride, lithium borohydride), lithium aluminium hydride and the like. Alkanols (e.g., methanol, ethanol, propanol), tetra-hydrofuran, dioxane and dimethoxyethane are suitable as the solvent. It is preferred to carry out the reaction at a temperature between 0 and 30C. By this reaction step, the alkylthio group of the compound (IV) is removed simul- *
taneously with the reduction of oxo group thereof. When the compound (IV) in which R2 is alkanoyl is used in this step, said alkanoyl group is also hydrolyzed simultaneously with the above mentioned reactions.
Alternatively, the benzylalcohol derivative (I) may be prepared according to Method (c 3), i.e., by the steps of ~L19ti;~

reducin~ the compound ~III) to give a benzylalcohol derivative IV), alkylating the compound ~V) to give a benzylalc`ohol derivative (VI), and subjecting the compound (VI) to reductive desulfurization.
The reduction of the compound (III) can be accomplished by treating it with a reducing agent in a suitable solvent.
Suitable examples of the reducing agent include alkali metal borohydrides such as sodium borohydride, lithium borohydride and the like. Alkanols (e.g., methanol,~ethanol, propanol), tetrahydrofuran and dioxane are suitable as the solvent.
Tt is preferred to carry out the reaction at a temperature between 0 and 30C. When the compound (III~ in which R2 is alkanoyl is used in this reaction step, the reduction of oxo group of the compound (III) takes place simultaneously with the hydrolysis of said alkanoyl group.
The subsequent alkylation of the compound (V) and reductive desulfurization of the compound (VI) can be accom~
plished under the same conditions as used in the alkylation of the compound (III) or reductive desulfurization of the compound (IV) in Method (c~2), respectively.
The ben2ylalcohol derivative (I) prepared according to the present invention may be, if reguired~ converted into a pharmaceutically acceptable acid addition sal-t thereof.
Suitable examples of the salt include inorganic acid addition salts such as hydrochloride, hydrobromide, perchlorate, nitrate, sulfate or phosphate; and organic acid addition 1~9~3~

salts such-as ace~ate, propionate, glycolate, lactate, ascorbate, maleate, fumalate, malonate, succinate, oxalate, citrate, ~ethansulfonate, benzenesulfonate, aminobenzoate, I
sulfami~ate, aspartate, glutamate or nicotinate. I -The aforementioned method of the present invention enables to prepare the benzylalcohol derivative (I) in a high yield without undesired side reactions and is advantageous for preparing said benzylalcohol derivative ~I) in an industrial scale. Moreover, since the intermediate product (III) of the invention is quite stable and is readily isolated and purified in conventional manners, the method of the invention is also advantageous in that the benzylalcohol derivative (I) is obtained in a high purity without contamination with undesirable byoproducts.
Throughout the specification and claims, the term ~lower alkyl" and "lower alkanoyl" should preferably be interpreted as refering to straight or branched alkyl and alkanoyl group having one to four carbon atoms.
Practical and presentlyopreferred embodiments of the present invention are illustratively shown in 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 is added thereto. The mixture is stirred at room temperature for 5 3~

~ -10 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 an aqueous 10 ~ potassium carbonate solution and 50 ml of ben2ene, 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 ben~ene solution and the ethyl acetate extract are combined, and washed with water, lO ~ hydrochloric acid and water, successively. The organic layer is dried and evaporated under reduced pressure. The residue is recrystallized _`r from ethanol. 7.67 g of 2~(4-benzyloxyphenyl)-2oxo=N-(3,4-dimethoxyphenethyl~thioacetamide are obtained as pale yellow needles. Yield: 80.1 M.p. 132 133C
(2) 500 mg of 2~(4sbenzyloxyphenyl)-2~oxo-N~(3,4-di~
methoxyphenethyl)thioacetamide and 610 mg of nickel chloride hexahydrate are dissolved in 30 ml of methanol, and 700 mg of sodium borohydride are added thereto 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 resi~ue is treated with ethanolic hydrogen chloride, and the crystalline ~ 9634'~

precipitates are collected by iltration. 360 mg of ~-(3,4~ ¦
dimethoxyphenethylaminomethyl)-4~enzyloxybenzylalcohol hydrochloride are obtained. Yield: 70 M.p. 168 - 170C.
Example 2 2.0 g of 20 ~ 4benzyloxyphenyl)-2oxooN(3,4dimethoxy-phenethyl)thioacetamide are dissolved in 40 ml of methylene chloride, and 1.05 g of triethyloxoniumfluQroborate are added thereto. After the mixture is stirred at room tem perature for 1.5 hours, said mixture is concentrated under reduced pressure. The residue is dissolved in 30 ml of ethanol, and 2.1 g of sodium borohydride are added thereto.
The mixture is stirred at room temperature for one hour.
Water is poured into the reaction mixture, and the mixture is concentrated under reduced pressure. Crystalline precip itates are collected by filtration, and the crystals are washed with water and then recrystallized from isopropanol.
1.45 g of ~o~3,4-dimethox~rphenethylaminomethyl) 4benzyloxy benzyl alcohol (free base) are obtained as colorless needles.
Yield: 77.5 ~
M.p. 114.5 - 116C
Example 3 2.2 g of 20(4benzyloxyphenyl)o2oxoN (3,4dimethoxy phenethyl)thioacetamide are dissolved in 30 ml of acetone, and 850 mg of potassium carbonate and 1.0 g of methyl iodide are added thereto. The mixture is stirred at room temperature . _ _ 1~9634~

overnight. Insoluble materials are filtered oEf, 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 thereto. The mixture is stirred at room temperature for 30 minutes. Then, the reaction mixture is treated :Ln the same manner as described in Example 2. 1.65 g of ~-(3,4 dimethoxyphenethylaminomethyl) 4 benzyloxybenzylalcohol (free base) are obtained as colorless needles. Yield: 80 ~
The physicoochemical properties of this product are identical with those of the sample obtained in Example 2.
Example 4 (1) 8.0 g of 2 ` ( 4 benzyloxyphenyl)~200xo- N~(3,4 dimethoxy phenethyl)thioacetamide are dissolved in 150 ml of methanol, and 500 mg of sodium borohydride are added thereto. The mixture is stirred at room temperature for one 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 recrystal lized from isopropanol. 7.5 g of 2D(4-benzyloxyphenyl) 2 hydroxyoN-(3,4-dimethoxyphenethyl)thioacetamide are obtained as colorless needles. Yield: 93 %
M.p. 82 84C
(2) 1.0 g of 2(4~benzyloxyphenyl) 2-hydroxy-~-(3,4-dimethoxyphenethyl)thioacetamide is dissolved in 20 ml of methylene chloride, and 460 mg of triethyloxoniumfluoroborate .

;3~

` -13 are added thereto. ~fter the mixture i5 stirred at room temperature for 30 minutes, said mixture is concentràted ....
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 thereto. The mixture is stirred at room temperature for one hour. Then, the reaction mixture is treated in the same manner as described in Example 2. 780 mg of ~ ~3,4-dimethoxyphenethylaminomethyl)~
4-benzyloxybenzylalcohol (free base) are obtained as colorless needles. Yield: 84 ~
The physico-chemical properties of this product are identical with those of the sample obtained in Exampie 2.
Example 5 (1) 5.34 g of 4 acetoxyacetophenone, 20 ml of thionyl chloride, 0.03 ml of pyridine and 6.Sl g of 3,4-dimethoxy-phenethylamine are treated in the same manner as described in Example lo(l). 8.5 g of 2-(4acetoxyphenyl) o200xo~N- ( 3,4 dimethoxyphenethyl)thioacetamide are obtained as pale yellow oil. Yield: 73 %
IR ~laxq (cm 1): 1755, 1665 Mass m/e: 387 (M ) NMR (CDC13)~ 2.30 (s, 3H, CH3C00), 3.00 (t, 2HI J=
7.5 Hz, -CH2-CH2-), 3.84 (s, 6H, -OCH3X2 ) (2) 1.94 g of 2(4Dacetoxyphenyl) 2-oxo~N-(3,4=dimethoxyo phenethyl)thioacetamide, 1.14 g of triethyloxoniumfluoroborate and 1.0 g of sodium borohydride are treated in the same . , .

manner as described in Example 2. 1.47 g of ~-(3,4-dimethoxy-phenethylaminomethyl)~4-hydroxybenzylalcohol are obtained as colorless prisms. Yield: 92 %
M.p. 151 - 153C
Example 6 I1) 4.08 g of 4-hydroxyacetophenone, 12 ml of thionyl chloride, 0.06 ml of pyridine and 6.51 g of 3,4~dimethoxy~
phenethylamine are treated in the same manner as described in Example 1-(13. 3.1 g of 2-(4-hydroxyphenyl)-2 oxo-N (3,4-dimethoxyphenethyl)thioacetamide are obtained as pale yellow needles. Yield: 30 %
M.p. 179 180C (recrystallized from ethanol) (2) 1.0 g of 2 (4-hydroxyphenyl)~2-oxo N (3,4-dimethoxy~-phenethyl)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 ~-(3,4-di-methoxyphenethylaminomethyl)-4;hydroxyben~ylalcohol are obtained as colorless prisms. Yield: 25 ~
The physico chemical properties of this product are identical with those of the sample obtained in Example
5-(2).
Example 7 1.58 g of 2~(4 hydroxyphenyl) 2-oxo~N-~3,4 dimethoxy-phenethyl)thioacetamide, 1.13 g of triethyloxoniumfluoroborate and 870 mg of sodium borohydride are treated in the same manner as described in Example 2. 940 mg of ~-(3,4-dimethoxy 1 ~9ti,3~2 ~ -15 phenethylaminomethyl) 4~hydroxybenzylalcohol ara obtained as colorless prisms. Yield: 65 ~
...~, The physico-chemical properties of this product are identical with those of the sample ob~ained in Example 5-(2).
Example 8 (1) 6.78 g of 2benzyloxyacetophenone, 21 ml of thionyl chloride, 0.05 ml of pyridine and 6.54 g of 3,4-dimethoxy phenethylamine are treated in the same manner as described in Example 1 (1). 10.3 g of 20t2 benzyloxyphenyl)2 oxo-N~
(3,4-dimethoxyphenethyl~thioacetamide are obtained as pale yellow prisms. Yield: 79 %
M.p. 112 114C
(2) 500 mg of 2-(2-benzyloxyphenyl)~2oxo~N~(3,4 dimethoxy-phenethyl)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 ~ (3,4 dimethoxyphenethylaminomethyl)~2 benzyloxybenzylalcohol hydrochloride are obtained as colorless needles. Yield: 32 -, M.p. 159 - 160C
Example 9 2.0 g of 2-(2~benzyloxyphenyl) 2--oxo~N-(3,4dimethoxy-phenethyl)thioacetamide, 1.13 g of triethyloxoniumfluoroborate and 870 mg of sodium borohydride are treated in the same manner as described in Example 2. 1.65 g of d-(3/4dimethoxy-li9~

ol6'-phenethylaminomethyl)-2~ben2yloxyben2ylalcohol (free base) are obtained as colorless needles. Yield: 82 %
M.p. 95 97C (recrystalli~ed from isopropanol Example 10 2.2 g of 2(2-benzyloxyphenyl)2oxooN(3,4 dimethoxy phenethyl)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 y of ~-(3,4 dimethoxyphenethylaminomethyl) 2benzyloxybenzyl alcohol (free base) are obtained as colorless needles.
Yield: 53 ~
The physicochemical properties of this product are identical with those of the sample obtained in Example 9.
Example 11 (1) 2.73 g of 2~hydroxyacetophenone, 8 ml of thionyl chloride, 0.03 ml of pyridine and 2.53 g of 3,4dimethoxy~
phenethylamine are treated in the same manner as described in Example 1-~1). 4.0 g of 2(2hydroxyphenyl)2-oxo~N(3,4 dimethoxyphenethyl)thioacetamide are obtained as pale red brown needles. Yield: 58 % ~=
M.p. 166 168C (recrystallized from ethanol) (2) 1.58 g of 2(2hydroxyphenyl)-2 oxo-N(3,4~dimethoxy phenethyl)thioacetamide, 1.13 g of triethyloxoniumfluoroborate and 1.4 g of sodium borohydride are treated in the same manner as described in Example 2. 850 mg of ~o(3,4Ddimethoxyo phenethylaminomethyl)~20hydroxybenzylalcohol are obtained as colorless oil. Yield: 58 %

Oxalate of this product:
M.p. 17; - 176C
Example 12 (1) 1.78 g of 2acetoxyacetophenone, 6 ml of thionyl chloride, 0.02 ml of pyridine and 1.27 g of 3,40dimethoxyo phenethylamine are treated in the same manner as described in Example 1-(1). 1.37 g o. 2t2acetoxyphenyl)2oxooNo(3,4O
dimethoxyphenethyl)thioacetamide are obtained as pale yellow oil. Yield: 35.4 %
IR ~CHacxl3 (cm 1): 1760, 1670 Mass m/e: 387 (M ) ~CDC13)3: 2.20 (s, 3H, CH3C00), 2.94 (t, 2~, J=
7.5 Hz, oCH2rCH2-), 3.85 (s, 6H, oOCH3X2) (2) 2-(2acetoxyphenyl~o2OoxooNo(3,4Odimethoxyphenethyl) thioacetamide, triethyloxoniumfluoroborate and sodium borohydride are treated in the same manner as described in Example 2.
~(3,40dimethoxyphenethylaminomethyl) 2hydroxybenzylalcohol is obtained.
The physicoochemical properties of this product are identical with those of the sample obtained Example 110(2).

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a benzylalcohol derivative of the formula:

(I) wherein R1 is hydrogen or aralkyl, or a pharmaceutically acceptable acid addition salt thereof, which comprises the steps of:
(a) reacting an acetophenone derivative of the formula:

(II) wherein R2 is hydrogen, alkanoyl or aralkyl, with a thionyl halide, (b) reacting the resultant product with 3,4-dimethoxy phenethylamine to give a thioacetamide derivative of the formula:

(III) wherein R2 is the same as defined above, and (c)-i) subjecting the compound (III) to reductive desulfurization, or -ii) alkylating the compound (III) to give an acetophenone derivative of the formula:

(IV) wherein R3 is alkyl and R2 is the same as defined above, and subjecting the compound (IV) to reductive desulfurization, or -iii) reducing the compound (III) to give a benzyl-alcohol derivative of the formula:
(V) wherein R1 is the same as defined above, alkylating the compound (V) to give a benzylalcohol derivative of the formula:

(VI) wherein R1 and R3 are the same as defined above, and subjecting the compound (VI) to reductive desulfurization, and then (d) if required, further converting the thus obtained benzylalcohol derivative (I) into a pharmaceutically acceptable acid addition salt thereof.
2. The process according to Claim 1, wherein the reductive desulfurization of the compound (III) is carried out by the use of an alkali metal borohydride as a reducing agent in the presence of a metal halide (said metal halide being selected from the group consisting of nickel chloride, ferrous chloride, stannous chloride, zinc chloride and cobalt chloride) in a solvent; the alkylation of the compound (III) or compound (V) is carried out by the use of an alkylating agent (said alkylating agent being selected from the group consisting of lower alkyl halide, lower alkyloxoniumfluoro-borate and di(lower alkyl) sulfate)in the presence or absence of an acid acceptor in a solvent; the reductive desulfurization of the compound (IV) or compound (VI) is carried out by the use of a reducing agent (said reducing agent being selected from the group consisting of alkali metal brohydride and lithium aluminium hydride) in a solvent.
3. The process according to Claim 2, wherein the reductive desulfurization of the compound (III) is carried out at a temperature between 20° and 50°C; the alkylation of the compound (III) or compound (V) is carried out at a temperature between 0° and 30°C; and the reductive desulfurization of the compound (IV) or compound (VI) is carried out at a temperature between 0° and 30°C.
CA000415011A 1981-11-12 1982-11-05 Process for preparing benzylalcohol derivatives Expired CA1196342A (en)

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DK163660B (en) 1992-03-23
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