CA1150316A - Process for the preparation of benzyl alcohol derivatives - Google Patents
Process for the preparation of benzyl alcohol derivativesInfo
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- CA1150316A CA1150316A CA000371226A CA371226A CA1150316A CA 1150316 A CA1150316 A CA 1150316A CA 000371226 A CA000371226 A CA 000371226A CA 371226 A CA371226 A CA 371226A CA 1150316 A CA1150316 A CA 1150316A
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- benzyl alcohol
- alpha
- benzyl
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- 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
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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
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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
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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
- C07C213/08—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
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- 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
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- 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
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- 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
- C07C217/62—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 at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
PROCESS FOR THE PREPARATION OF BENZYL ALCOHOL DERIVATIVES
Abstract of the Disclosure The invention relates to a process for the preparation of benzyl alcohol derivatives of the formula:
which compounds have an excellent blood sugar lowering activity and a cardiotonic acitivity. The process com-prises subjecting an .alpha.-halogenoacetophenone derivative of the formula:
wherein R1 is a hydroxy group-protecting group and x is a halogen atom, and a 3,4-dimethoxyphenethylamine derivative of the formula:
Abstract of the Disclosure The invention relates to a process for the preparation of benzyl alcohol derivatives of the formula:
which compounds have an excellent blood sugar lowering activity and a cardiotonic acitivity. The process com-prises subjecting an .alpha.-halogenoacetophenone derivative of the formula:
wherein R1 is a hydroxy group-protecting group and x is a halogen atom, and a 3,4-dimethoxyphenethylamine derivative of the formula:
Description
~1~3~6 This invention relates to a novel process for preparing benzyl alcohol derivatives of the formula:
OH
HO ~ NH CH2 2~oc 3 The above compounds [I] have advantageous properties.
For example, ~-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol has an excellent blood sugar lowering activity, and ~-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol has an excellent cardiotonic activity, and hence, these compounds are useful as medicines.
It is known that the benzyl alcohol derivatives [I]
can be prepared by various methods. For example, U.S.
Patent 4,032,575 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)monobenzyloxy-acetophenone (C), optionally reducing the compound (C) to give an ~-(3,4-dimethoxyphenethylaminoethyl)-monobenzyloxy-benzyl alcohol (D), and then subjecting the compound (C) or (D) to catalytic hydrogenation. However, the method disclosed in this U.S. Patent has the drawbacks that the yield of the condensation product (C) decreases unless the valuable starting amine (B) is used in an excess amount, since the condensation product (C) is unstable and susceptible to self-condensation or further phenacylation;
:~151~316 and that the use of an excess amount of the amine does not necessarily result in high yield.
As a result of investigations made by the present inventors, it has now been found that, when one of the starting materials, i.e. the 3,4-dimethoxyphenethylamine derivative, is used after protecting the amino group, the reaction can proceed without undesirable side reactions and therefore the desired compounds [I~ can be prepared in high yield and purity.
According to the present invention, the desired compounds [I] can be prepared by subjecting an ~-halogen-acetophenone derivative [IIl and a 3,4-dimethoxyphenethyl-amine derivative [III] to a condensation reaction to give an ~-(3,4-dimethoxyphenethylamino)acetophenone derivative [IV] and subjecting the resulting compound to catalytic hydrogenation either directly or after converting the compound [IV] to an ~-3,4-dimethoxyphenethylaminomethyl)-benzyl alcohol derivative [V] by treating it with a reducing agent, as shown by the following reaction scheme:
o R O ~ XC330 ~ NH_R2 [II] \~ ~ [III]
. .
~5~316 Rl ~J N_CH2_CH2_~--OOCH3 [IV]
OH
Rl ~ N-cH2-cR2 ~ oC33 [v]
[I]
wherein Rl is a hydroxy group-protecting group which is removable by catalytic hydrogenation, R2 is an amino group-protecting group which is removable by catalytic hydrogenation, and X is a halogen atom.
In the above formula [I~] and [III], the group R
includes, for example, aralkyl groups (e.g. benzyl), ,., aralkyloxycarbonyl groups (e.g. benzyloxycarbonyl or p-methoxybenzyloxycarbonyl), and the like. A suitable example of the group Rl is benzyl. On the other hand, the group R2 includes, for example, aralkyloxycarbonyl groups (e.g. benzyloxycarbonyl or p-methoxybenzyloxy-carbonyl), aralkyl groups (e.g. benzyl or triphenylmethyl), and the like. Suitable examples of the group R2 are benzyl and benzyloxycarbonyl.
The process of the present invention is explained in more detail with reference to the above reaction steps as follows:
.
.
~15~316 [II] + [III] ~ [IV]
The condensation reaction of the ~-halogenoacetophenone derivative [II] and the 3,4-dimethoxyphenethylamine deriva-tive [III] is preferably carried out in an appropriate solvent in the presence or absence of an acid acceptor.
Suitable examples of the acid acceptor are organic bases, e.g. pyridine or triethylamine, and inorganic bases, e.g.
potassium carbonate or sodium hydroxide. When the organic bases are used in an excess amount as the acid acceptor, additional solvent is not required. However, examples of appropriate solvents are lower alkanols (e.g. methanol or ethanol), acetone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methylene chloride, chloroform, and the like. The reaction proceeds readily at a temperature of 0 to 100C, preferably l5 to 50C.
[IV] ~[V]
The reduction of the resultant ~-(3,4-dimethoxyphen-ethylamino)acetophenone derivative [IV] is carried out by treating it with a reducing agent in a suitable solvent.
Suitable examples of the reducing agent are alkali metal borohydrides (e.g. sodium borohydride, or lithium boro-hydride), lithium aluminum hydride and diborane, prefer-ably sodium borohydride. Examples of the solvent are lower alkanols (e.g. methanol or ethanol), ether, tetrahydrofuran and dioxane which are inert solvent. The reaction proceeds readily at a temperature of 0 to 80C, preferably 0 to 25C.
-~15~316 [IV]~ [I] and [V] ~[I]
The catalytic hydrogenation of the ~-(3,4-dimethoxyphen-ethylamino)acetophenone derivative [IV] and the ~-(3,4-dimethoxyphenethylaminomethyl)benzyl alcohol derivative [V] obtained above can be carried out by the conventional method, that is, by dissolving the compound [IV] (or [V]) or a salt thereof in an appropriate solvent, and shaking the mixture under a stream of hydrogen or stirring the mixture under hydrogen pressure in the presence of a catalyst, by which the protecting groups can readily be removed from the compounds. Suitable examples of the catalyst are platinum or palladium catalysts, e.g. platinum, platinum oxide, palladium black, palladium-carbon colloidal palladium, and the like. Suitable examples of the solvent are lower alkanols (e.g. methanol or ethanol), water, acetic acid, and the like. The reaction proceeds readily at a temperature of 0 to 50C and under hydrogen pressure of 1 to 5 kg/cm2.
The desired compounds [I] prepared according to the above procedure can readily be isolated from the reaction mixture in the usual manner, for instance, by filtering the reaction mixture to remove the catalyst, concentrating the filtrate under reduced pressure, and crystallizing the resulting residue from an appropriate solvent. Optionally, the crys-talline thus obtained is treated with an acid in the usual manner to obtain the desired compounds [I] in the form of a salt with an acid.
' ~L~5a:~3~6 The present invention is illustrated by the following Examples but is not limited thereto.
Example 1 (1) ~-Bromo-2-benzyloxyacetophenone (1.53 g), N-benzyl-3, 4-dimethoxyphenethylamine (1.50 g) and triethylamine (1.11 g) were dissolved in 15 ml of dimethylformamide, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 10 ~ hydrochloric acid, saline solution and aqueous sodium bicarbonate succes-sively and further washed with saline solution, and then dried and concentrated under reduced pressure to give oily-N-benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone (2.2 g~ 88.8 ~).
IR v lcmq-l 1670 Mass m/e : 495 (M ) NMR (CDC13,~ ): 3.82 (6H, s, OCH3), 5.05 (2H, s), 5.15 (2H, s) This product was converted into 1/2 oxalate in the usual manner, and recrystallized from methanol to give colorless needles, m.p. 213 - 215C (decomp.).
OH
HO ~ NH CH2 2~oc 3 The above compounds [I] have advantageous properties.
For example, ~-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol has an excellent blood sugar lowering activity, and ~-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol has an excellent cardiotonic activity, and hence, these compounds are useful as medicines.
It is known that the benzyl alcohol derivatives [I]
can be prepared by various methods. For example, U.S.
Patent 4,032,575 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)monobenzyloxy-acetophenone (C), optionally reducing the compound (C) to give an ~-(3,4-dimethoxyphenethylaminoethyl)-monobenzyloxy-benzyl alcohol (D), and then subjecting the compound (C) or (D) to catalytic hydrogenation. However, the method disclosed in this U.S. Patent has the drawbacks that the yield of the condensation product (C) decreases unless the valuable starting amine (B) is used in an excess amount, since the condensation product (C) is unstable and susceptible to self-condensation or further phenacylation;
:~151~316 and that the use of an excess amount of the amine does not necessarily result in high yield.
As a result of investigations made by the present inventors, it has now been found that, when one of the starting materials, i.e. the 3,4-dimethoxyphenethylamine derivative, is used after protecting the amino group, the reaction can proceed without undesirable side reactions and therefore the desired compounds [I~ can be prepared in high yield and purity.
According to the present invention, the desired compounds [I] can be prepared by subjecting an ~-halogen-acetophenone derivative [IIl and a 3,4-dimethoxyphenethyl-amine derivative [III] to a condensation reaction to give an ~-(3,4-dimethoxyphenethylamino)acetophenone derivative [IV] and subjecting the resulting compound to catalytic hydrogenation either directly or after converting the compound [IV] to an ~-3,4-dimethoxyphenethylaminomethyl)-benzyl alcohol derivative [V] by treating it with a reducing agent, as shown by the following reaction scheme:
o R O ~ XC330 ~ NH_R2 [II] \~ ~ [III]
. .
~5~316 Rl ~J N_CH2_CH2_~--OOCH3 [IV]
OH
Rl ~ N-cH2-cR2 ~ oC33 [v]
[I]
wherein Rl is a hydroxy group-protecting group which is removable by catalytic hydrogenation, R2 is an amino group-protecting group which is removable by catalytic hydrogenation, and X is a halogen atom.
In the above formula [I~] and [III], the group R
includes, for example, aralkyl groups (e.g. benzyl), ,., aralkyloxycarbonyl groups (e.g. benzyloxycarbonyl or p-methoxybenzyloxycarbonyl), and the like. A suitable example of the group Rl is benzyl. On the other hand, the group R2 includes, for example, aralkyloxycarbonyl groups (e.g. benzyloxycarbonyl or p-methoxybenzyloxy-carbonyl), aralkyl groups (e.g. benzyl or triphenylmethyl), and the like. Suitable examples of the group R2 are benzyl and benzyloxycarbonyl.
The process of the present invention is explained in more detail with reference to the above reaction steps as follows:
.
.
~15~316 [II] + [III] ~ [IV]
The condensation reaction of the ~-halogenoacetophenone derivative [II] and the 3,4-dimethoxyphenethylamine deriva-tive [III] is preferably carried out in an appropriate solvent in the presence or absence of an acid acceptor.
Suitable examples of the acid acceptor are organic bases, e.g. pyridine or triethylamine, and inorganic bases, e.g.
potassium carbonate or sodium hydroxide. When the organic bases are used in an excess amount as the acid acceptor, additional solvent is not required. However, examples of appropriate solvents are lower alkanols (e.g. methanol or ethanol), acetone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methylene chloride, chloroform, and the like. The reaction proceeds readily at a temperature of 0 to 100C, preferably l5 to 50C.
[IV] ~[V]
The reduction of the resultant ~-(3,4-dimethoxyphen-ethylamino)acetophenone derivative [IV] is carried out by treating it with a reducing agent in a suitable solvent.
Suitable examples of the reducing agent are alkali metal borohydrides (e.g. sodium borohydride, or lithium boro-hydride), lithium aluminum hydride and diborane, prefer-ably sodium borohydride. Examples of the solvent are lower alkanols (e.g. methanol or ethanol), ether, tetrahydrofuran and dioxane which are inert solvent. The reaction proceeds readily at a temperature of 0 to 80C, preferably 0 to 25C.
-~15~316 [IV]~ [I] and [V] ~[I]
The catalytic hydrogenation of the ~-(3,4-dimethoxyphen-ethylamino)acetophenone derivative [IV] and the ~-(3,4-dimethoxyphenethylaminomethyl)benzyl alcohol derivative [V] obtained above can be carried out by the conventional method, that is, by dissolving the compound [IV] (or [V]) or a salt thereof in an appropriate solvent, and shaking the mixture under a stream of hydrogen or stirring the mixture under hydrogen pressure in the presence of a catalyst, by which the protecting groups can readily be removed from the compounds. Suitable examples of the catalyst are platinum or palladium catalysts, e.g. platinum, platinum oxide, palladium black, palladium-carbon colloidal palladium, and the like. Suitable examples of the solvent are lower alkanols (e.g. methanol or ethanol), water, acetic acid, and the like. The reaction proceeds readily at a temperature of 0 to 50C and under hydrogen pressure of 1 to 5 kg/cm2.
The desired compounds [I] prepared according to the above procedure can readily be isolated from the reaction mixture in the usual manner, for instance, by filtering the reaction mixture to remove the catalyst, concentrating the filtrate under reduced pressure, and crystallizing the resulting residue from an appropriate solvent. Optionally, the crys-talline thus obtained is treated with an acid in the usual manner to obtain the desired compounds [I] in the form of a salt with an acid.
' ~L~5a:~3~6 The present invention is illustrated by the following Examples but is not limited thereto.
Example 1 (1) ~-Bromo-2-benzyloxyacetophenone (1.53 g), N-benzyl-3, 4-dimethoxyphenethylamine (1.50 g) and triethylamine (1.11 g) were dissolved in 15 ml of dimethylformamide, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 10 ~ hydrochloric acid, saline solution and aqueous sodium bicarbonate succes-sively and further washed with saline solution, and then dried and concentrated under reduced pressure to give oily-N-benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone (2.2 g~ 88.8 ~).
IR v lcmq-l 1670 Mass m/e : 495 (M ) NMR (CDC13,~ ): 3.82 (6H, s, OCH3), 5.05 (2H, s), 5.15 (2H, s) This product was converted into 1/2 oxalate in the usual manner, and recrystallized from methanol to give colorless needles, m.p. 213 - 215C (decomp.).
(2) N-Benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyl-oxyacetophenone (2.0 g) obtained in (1) was dissolved in 40 ml of methanol and sodium borohydride (1.2 9) was added in portions to the solution, and the mixture was stirred under ice-cooling for 4 hours. The mixture was poured B
.
- .~
~54~316 into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to give N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybènzyl alcohol (2.0 g) as an oily substance in quantitative yield.
IR vliq-l: 3480 cm Mass m/e : 497 (M+), 284 (base) NMR (CDC13, ~): 3.3 (lH, bs., OH), 3.74 (3H, s, OCH3),
.
- .~
~54~316 into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to give N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybènzyl alcohol (2.0 g) as an oily substance in quantitative yield.
IR vliq-l: 3480 cm Mass m/e : 497 (M+), 284 (base) NMR (CDC13, ~): 3.3 (lH, bs., OH), 3.74 (3H, s, OCH3),
3.80 (3H, s, OCH3), 5.02 (2H, s, OCH2pH), 5.0 - 5.3 (lH,>~H ), 6.5 7.7 (17H, aromatic H) (3) Crude N-benzyl-~-(3,4-dimethoxyphenethylamino-methyl)-2-benzyloxybenzyl alcohol (1.9 g) obtained in (2) was dissolved in 40 ml of methanol and subjected to cata-lytic hydrogenation with 10 % palladium carbon (500 mg) in hydrogen gas stream under atmospheric pressure. After the reaction, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give ~-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxy benzyl alcohol (1.1 g) as an oily substance. After converting the resultant oil into its succinate, the salt was recrystal-lized from methanol/ether to give crystalline ~-(3,4-di-methoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol succinate (1.33 g), m.p. 142 - 143C.
The hydrochloride of this product had a m.p. of 141 -143C (recrystallized from ethanol/ether).
-- .
~15~)316 Example 2 N-Benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxy-acetophenone (600 mg), which was prepared in the same manner as described in Example 1 - (1), was dissolved in 30 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (300 mg) until the stoichio-metric amount of hydrogen was absorbed. The reaction mixture was treated in the same manner as described in Example 1 - (3), whereby ~-(3,4-dimethoxyphenethylamino-methyl)-2-hydroxybenzyl alcohol succinate (280 mg) was obtained as colorless crystals, m.p. 142 - 143C.
The hydrochloride of this product had a m.p. of 141 -143C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
Example 3 (1) ~-Chloro-4-benzyloxyacetophenone (2.35 9), N-benzyl-3,4-dimethoxyphenethylamine (2.7 9) and triethyl-amine (2.0 g) was dissolved in 50 ml of ethanol and the mixture was refluxed for 18 hours. The reaction mixture was concentrated under the reduced pressure. The obtained residue was purified by silica gel chromatography (solvent;
ether : hexane = 1 : 1), whereby N-benzyl-~-(3,4-dimethoxyphenethylamino)-4-benzyloxyacetophenone (3.0 g, 60.6 %) was obtained as an oily substance.
:~5~3~6 g After converting the resultant oil to crystalline 1/2 oxalate, this salt was recrystallized from methanol to give colorless needles, m.p. 122 - 125C.
IR v NcUm-~ : 1695, 1600 Mass m/e : 495 (M ) NMR (CDC13,~; 3.77 (3H, s, OCH3), 3.82 (3H, s, OCH3),
The hydrochloride of this product had a m.p. of 141 -143C (recrystallized from ethanol/ether).
-- .
~15~)316 Example 2 N-Benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxy-acetophenone (600 mg), which was prepared in the same manner as described in Example 1 - (1), was dissolved in 30 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (300 mg) until the stoichio-metric amount of hydrogen was absorbed. The reaction mixture was treated in the same manner as described in Example 1 - (3), whereby ~-(3,4-dimethoxyphenethylamino-methyl)-2-hydroxybenzyl alcohol succinate (280 mg) was obtained as colorless crystals, m.p. 142 - 143C.
The hydrochloride of this product had a m.p. of 141 -143C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
Example 3 (1) ~-Chloro-4-benzyloxyacetophenone (2.35 9), N-benzyl-3,4-dimethoxyphenethylamine (2.7 9) and triethyl-amine (2.0 g) was dissolved in 50 ml of ethanol and the mixture was refluxed for 18 hours. The reaction mixture was concentrated under the reduced pressure. The obtained residue was purified by silica gel chromatography (solvent;
ether : hexane = 1 : 1), whereby N-benzyl-~-(3,4-dimethoxyphenethylamino)-4-benzyloxyacetophenone (3.0 g, 60.6 %) was obtained as an oily substance.
:~5~3~6 g After converting the resultant oil to crystalline 1/2 oxalate, this salt was recrystallized from methanol to give colorless needles, m.p. 122 - 125C.
IR v NcUm-~ : 1695, 1600 Mass m/e : 495 (M ) NMR (CDC13,~; 3.77 (3H, s, OCH3), 3.82 (3H, s, OCH3),
4.46 (2H, s), 4.63 (2H, s), 5.12 (2H, s, OCH2ph ) (2) N-Benzyl-~-(3,4-dimethoxyphenethylamino)-4-benzyl-oxyacetophenone.l/2 oxalate (1.3 g) obtained in (1) was dissolved in 50 ml of methanol, and sodium borohydride (2.0 g) was added in portions to the solution under ice-cooling and the mixture was stirred overnight. After the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to give N-benzyl-~-~3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (1.2 g) as a crude oil substance.
IR v lcm-l : 3440 Mass m/e : 497 (M+), 284 (base) NMR (CDC13,~): 3.75 (6H, s, OCH3), 3.93 (lH, bs, OH), 4.57 (lH, t, J = 6Hz, XoHH)t 4.97 (2H, s, OCH2ph), 6.5 - 7.5 (17H, aromatic H).
(3) N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (1.2 g) obtained in (2) was dissolved in 40 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (400 mg) in a o .. :- ,.. . . ..
-3L15~316 - 10 ~
hydrogen gas stream under atmospheric pressure. After the reaction, the catalyst was removed by filtration.
The filtrate was concentrated under reduced pressure to give a-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol as an oily substance. The resultant oil was dissolved in ethyl acetate and hydrogen chloride in ether was added to the solution under ice-cooling. The precipit-ating amorphous substance was recrystallized from ethanol/
ether to give ~-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol hydrochloride (657 mg) as colorless needles, m.p. 164 - 167C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
Example 4 N-Benzyl-a- (3,4-dimethoxyphenethylamino)-4-benzyloxy-acetophenone (500 mg), which was prepared in the same manner as described in Example 3 - (3) was dissolved in 30 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (250 mg) until the stoichio-metric amount of hydrogen was absorbed. The reaction mixture was treated in the same manner as described in Example 3 - (3), whereby a-(3,4-dimethoxyphenethylamino-methyl)-4-hydroxybenzyl alcohol hydrochloride (180 mg) was obtained as colorless needles, m.p. 164 - 167C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
, '
IR v lcm-l : 3440 Mass m/e : 497 (M+), 284 (base) NMR (CDC13,~): 3.75 (6H, s, OCH3), 3.93 (lH, bs, OH), 4.57 (lH, t, J = 6Hz, XoHH)t 4.97 (2H, s, OCH2ph), 6.5 - 7.5 (17H, aromatic H).
(3) N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (1.2 g) obtained in (2) was dissolved in 40 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (400 mg) in a o .. :- ,.. . . ..
-3L15~316 - 10 ~
hydrogen gas stream under atmospheric pressure. After the reaction, the catalyst was removed by filtration.
The filtrate was concentrated under reduced pressure to give a-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol as an oily substance. The resultant oil was dissolved in ethyl acetate and hydrogen chloride in ether was added to the solution under ice-cooling. The precipit-ating amorphous substance was recrystallized from ethanol/
ether to give ~-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol hydrochloride (657 mg) as colorless needles, m.p. 164 - 167C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
Example 4 N-Benzyl-a- (3,4-dimethoxyphenethylamino)-4-benzyloxy-acetophenone (500 mg), which was prepared in the same manner as described in Example 3 - (3) was dissolved in 30 ml of methanol and subjected to catalytic hydrogenation with 10 % palladium carbon (250 mg) until the stoichio-metric amount of hydrogen was absorbed. The reaction mixture was treated in the same manner as described in Example 3 - (3), whereby a-(3,4-dimethoxyphenethylamino-methyl)-4-hydroxybenzyl alcohol hydrochloride (180 mg) was obtained as colorless needles, m.p. 164 - 167C.
The product was identified with the standard specimen by thin layer chromatography and a mixed melting point test.
, '
Claims (4)
1. A process for the preparation of benzyl alcohol derivatives of the formula:
[I]
which comprises subjecting an .alpha.-halogenoacetophenone derivative of the formula:
[II]
wherein R1 is a hydroxy group-protecting group which is removable by catalytic hydrogenation, and X is a halogen atom, and a 3,4-dimethoxyphenethylamine derivative of the formula:
[I I I]
wherein R2 is an amino group-protecting group which is removable by catalytic hydrogenation, to a condensation reaction to give an .alpha.-(3,4-dimethoxyphenethylamino)aceto-phenone derivative of the formula:
[IV]
wherein R1 and R2 are as defined above, and subjecting the resulting compound to catalytic hydro-genation directly or after converting the compound to an .alpha.-(3,4-dimethoxyphenethylaminomethyl)benzyl alcohol derivative of the formula:
[V]
wherein R1 and R2 are as defined above, by treating it with a reducing agent.
[I]
which comprises subjecting an .alpha.-halogenoacetophenone derivative of the formula:
[II]
wherein R1 is a hydroxy group-protecting group which is removable by catalytic hydrogenation, and X is a halogen atom, and a 3,4-dimethoxyphenethylamine derivative of the formula:
[I I I]
wherein R2 is an amino group-protecting group which is removable by catalytic hydrogenation, to a condensation reaction to give an .alpha.-(3,4-dimethoxyphenethylamino)aceto-phenone derivative of the formula:
[IV]
wherein R1 and R2 are as defined above, and subjecting the resulting compound to catalytic hydro-genation directly or after converting the compound to an .alpha.-(3,4-dimethoxyphenethylaminomethyl)benzyl alcohol derivative of the formula:
[V]
wherein R1 and R2 are as defined above, by treating it with a reducing agent.
2. A process according to claim 1, wherein the groups R1 and R2 are both benzyl group.
3. A process according to claim 1, wherein the catalytic hydrogenation is carried out with palladium-carbon in a lower alkanol.
4. A process according to any one of claims 1, 2 or 3, wherein sodium borohydride is used as the re-ducing agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55021927A JPS609740B2 (en) | 1980-02-22 | 1980-02-22 | Production method of benzyl alcohol derivative |
| JP21927/1980 | 1980-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1150316A true CA1150316A (en) | 1983-07-19 |
Family
ID=12068692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000371226A Expired CA1150316A (en) | 1980-02-22 | 1981-02-18 | Process for the preparation of benzyl alcohol derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS609740B2 (en) |
| CA (1) | CA1150316A (en) |
| CH (1) | CH645339A5 (en) |
| ES (1) | ES8202534A1 (en) |
| NL (1) | NL8100857A (en) |
| SE (1) | SE454172B (en) |
-
1980
- 1980-02-22 JP JP55021927A patent/JPS609740B2/en not_active Expired
-
1981
- 1981-02-06 SE SE8100853A patent/SE454172B/en not_active IP Right Cessation
- 1981-02-18 CA CA000371226A patent/CA1150316A/en not_active Expired
- 1981-02-20 ES ES499673A patent/ES8202534A1/en not_active Expired
- 1981-02-20 NL NL8100857A patent/NL8100857A/en not_active Application Discontinuation
- 1981-02-20 CH CH115181A patent/CH645339A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS609740B2 (en) | 1985-03-12 |
| ES499673A0 (en) | 1982-02-01 |
| JPS56118045A (en) | 1981-09-16 |
| SE454172B (en) | 1988-04-11 |
| NL8100857A (en) | 1981-09-16 |
| ES8202534A1 (en) | 1982-02-01 |
| CH645339A5 (en) | 1984-09-28 |
| SE8100853L (en) | 1981-08-23 |
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