JPS5939419B2 - Method for producing catechol derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (■) [wherein R1 is a lower alkyl group, R,, R3 and R
4 represents at least one lower alkyl group or a phenyl alkyl group substituted with hydroxy or lower alkoxy, any two of these may be bonded to each other to form a ring, and the remainder is hydrogen. It is an atom.

] is subjected to a benzyl group elimination reaction [
This step is referred to as step (B)].The present invention relates to a method for producing a catechol derivative useful as a medicine, which is represented by the general formula () [wherein R1, R2, R3 and R4 have the same meanings as above].

In the above formula, examples of the lower alkyl group represented by R1, R2, R3 and R4 include alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl groups.

The alkyl moiety of the phenyl alkyl group represented by R2, R3 and R4 includes the same alkyl group having 1 to 3 carbon atoms as the lower alkyl group represented by R1 to R4,
The phenyl ring of the phenyl alkyl group can be inserted at any position thereof,
Preferably 1 to 3 hydroxyl groups or/and lower alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc. having 1 to 1 carbon atoms) at the 3, 4, and 5 positions.
3 lower alkoxy groups) as a substituent. Specific examples of these phenylalkyl groups include 4-
Examples include hydroxybenzyl and 4-methoxybenzyl. When any two of R2, R3 and R4 are bonded to each other to form a ring with adjacent carbon atoms, the ring is, for example, a cycloalkyl group having 4 to 6 carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl group, etc. Here are the rings corresponding to . The general formula ()
The compound represented by and () can be produced by the following method.

That is, the general formula () [wherein RIO and R6'O represent a hydroxyl group which may be protected with a benzyl group, and R1
has the same meaning as above.

] By alkylating a compound represented by the general formula [where R1, R2, R3 and R4 have the same meanings as above, R5O and R6O represent a hydroxyl group which may be protected with a benzyl group.

] can be obtained [This process is called process (self).
] o The alkylation in step (5) above is carried out by subjecting the compound of general formula () to an alkylation reaction. The alkylation reaction of compound () is the reaction between compound () and monodisperse formula (V).
[In the formula, k and w each represent a lower alkyl group or a phenyl alkyl group substituted with hydroxy or lower alkoxy as shown in R2 to R4, and one of them may be a hydrogen atom.

In addition, these may be bonded to each other to form a ring similar to the ring formed by bonding any two of R2 to R4 to each other. Alkylation) or by reacting the compound/compound () with an alkylating agent corresponding to the alkyl group represented by the formula -C-R3 [wherein R2 to R4 have the same meanings as above]. It will be done.

Reductive alkylation of compound () with compound (V) can be carried out by reacting compound () and compound (V) under conditions of catalytic hydrogen reduction, or by reacting compound () and compound (V),
For example, the reaction is carried out in the presence of a reducing agent such as an alkali metal cyanoborohydride (eg, sodium cyanoborohydride, lithium cyanoborohydride). The amount of compound (V) to be used is usually about 1 to 5 mol per 1 mol of compound (), both when the reaction is carried out under catalytic hydrogen reduction conditions and when the above-mentioned reducing agent is used. Catalytic hydrogen reduction usually involves alcohols (e.g.
methanol, ethanol), water, organic carboxylic acids (e.g.
acetic acid), esters (e.g. ethyl acetate), ethers (
The reaction is carried out in an inert solvent such as dioxane, tetrahydrofuran) under reaction conditions of about 1 to 100 atmospheres and about 20 to 100°C using a platinum, palladium, nickel catalyst (eg Raney nickel) or the like. In the general formula (), RIO
When and/or RJO is a hydroxyl group protected by a benzyl group, that is, a benzyloxy group, this benzyloxy group simultaneously undergoes debenzylation during catalytic reduction to become a free hydroxyl group. In addition, in the case of catalytic hydrogen reduction, for example, platinum oxide, Raney nickel, etc. are used as a catalyst,
If mild reaction conditions (catalytic reduction at room temperature and pressure) are used, reductive alkylation may be carried out without debenzylation of the benzyloxy group of the starting compound (). When performing reductive alkylation using a reducing agent such as alkali metal cyanoborohydride, the amount of these reducing agents used is usually about 1 to 5 mol per 1 mol of compound () or (V). .

The reaction is generally carried out in a solvent such as methanol or ethanol.
Preferably in the presence of hydrochloric acid, hydrobromic acid, etc.
It is carried out at a temperature of °C. In either case of catalytic hydrogen reduction or reduction using a reducing agent such as alkali metal cyanoborohydride, by reductive alkylation, the amino group of the compound of general formula () is converted to the formula -CH corresponding to compound (V). (In the formula,
Phenyl alkyl into which an alkyl group represented by (R7, w has the same meaning as above) is introduced, and in the general formula (1), at least one of R2 to R4 is substituted with a lower alkyl group or/and hydroxy or lower alkoxy. A compound that is a group or a compound () in which these groups are bonded to each other to form a ring is produced. / The reaction between the compound () and an alkylating agent corresponding to the alkyl group represented by the formula -C-R is usually carried out in a solvent,
This is carried out by bringing the two into contact at a temperature of about 0 to 150°C.

Examples of the alkylating agent include alkyl halides and dialkyl sulfates corresponding to the alkyl group, and examples of the halogen atom of the alkyl halides include chlorine, bromine, and iodine. The amount of these halogenating agents used varies depending on the halogenating agent used, but is usually about 1 to 1.2 mol per mol of the compound (). In addition, in order to capture the acid produced in the reaction, it may be preferable to carry out the reaction in the presence of a tertiary amine such as triethylamine, or a base such as sodium bicarbonate, potassium carbonate, or sodium carbonate. As a reaction solvent, for example,
Examples include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and inert solvents such as benzene. In addition, in this alkylation reaction, two or more alkyl groups may be introduced into the amino group of the compound () depending on the alkylating agent used and reaction conditions. In this case, the alkyl group is 1
In order to produce a compound () into which a number of amino acids have been introduced, one protecting group is introduced into the amino group of the compound () before the alkylation reaction, and after the main alkylation reaction, the protecting group is It is better to let go. Examples of protecting groups for amino groups include benzyl. These protecting groups can be introduced into the amino group using, for example, benzaldehyde in a manner similar to the alkylation method described above. In addition, as a method for removing this protecting group, for example, compound (1) with an amino group protected may be removed using the following scheme B.
) can be removed at the same time as the hydroxyl-protecting group is removed, or either before or after the removal of the hydroxyl-protecting group. The elimination reaction of the benzyl group, which is a protecting group for the hydroxyl group in step (B) according to the present invention, is carried out by subjecting the compound of general formula () to an ether bond cleavage reaction.

The reaction conditions are such that the benzyl group is removed and the formula -0R1
Any material may be used as long as it does not cleave the lower alkoxy group represented by. For example, in an appropriate solvent at a temperature of about -80 to 70°C, the compound () is mixed with a mineral acid [e.g.
~10% by weight of hydrochloric acid, 5 to 10% by weight of hydrobromic acid, etc.]. in this case,
Examples of the solvent include water, organic carboxylic acids (eg, acetic acid), alcohols (eg, methanol, ethanol), and ethers (eg, tetrahydrofuran, dioxane). The amount of mineral acid used is usually about 5 to 30 moles per 1 mole of the compound (). In addition, the compound () can be obtained by debenzylation by catalytic reduction similar to the catalytic hydrogen reduction described in step (8).The compounds of the general formulas () and (1) thus obtained are Compound (1) is easily isolated from the reaction mixture by conventional separation and purification methods (e.g., crystallization, column chromatography).
and () contain at least one asymmetric carbon in the molecule and are usually obtained in racemic form. Although these racemates exhibit pharmacological activity as they are, they can be further divided into their respective enantiomers if desired. As a resolution method, a resolution method commonly used for the resolution of optical isomers is used. For example, the racemic form of compound () or () is converted into a salt of an optically active organic carboxylic acid (e.g., tartaric acid, malic acid, mandelic acid). This can be separated by fractional crystallization or column chromatography. Compounds (1) and () obtained in this manner may be optionally prepared with pharmaceutically acceptable salts, such as inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid), organic acids (e.g., citric acid, malonic acid, Acid addition salts can be obtained by methods known per se. The compounds () and their acid addition salts obtained in this way exhibit stimulatory action on β2-receptors in tracheal muscles without stimulating β1-receptors in the heart, and are useful for example in asthma and other obstructive airway diseases. It is useful as a medicine such as a treatment for. When using the compound () or a pharmaceutically acceptable acid addition salt thereof as the above-mentioned medicament,
The dosage varies depending on the pathology of the target disease, but is usually 50 to 150μ7 per 1k9 of adult body weight per day, either as such or in an appropriate pharmaceutically acceptable carrier.
It can be mixed with excipients and diluents and administered orally or parenterally in the form of powder, granules, tablets, capsules, injections, inhalants, sprays, and the like. The compound of general formula () can be synthesized by the method shown below.

[In each of the above formulas, R1, R5'0 and RtO have the same meanings as above] Furthermore, in the general formula (■), a compound in which R5'O and R6'0 are unprotected hydroxyl groups is a compound represented by the general formula (■). ) can be produced by subjecting a compound in which R, 'O and RJO are protected hydroxyl groups to the same hydroxyl-protecting group removal reaction as described in step (B) above.

The compound of general formula (■) can be produced by using RJO and a compound (■) in which RJO is a hydroxyl group protected by a benzyl group as starting materials in the reaction of step (4) described above. . Reference example 1 Metallic potassium (2.35y) and ethanol (207y)
A solution of 3,4-dibenzyloxyphenylacetonitrile (19.87) dissolved in methyl nitrate (11 ml) was added dropwise to a 100 mO solution of dried potassium ethoxide (100 mO) prepared by fLl.

Stir at room temperature for 3 hours and leave at -30°C overnight. Also collect a lot of the pale yellow powder that precipitates. Wash with ether and dry with air.
- Obtain 23t of 4-dibenzyloxyphenylacinitroacetonitrile potassium salt. This product was added to a 5% aqueous sodium hydroxide solution (1.5 L) and heated under reflux for 28 hours.

After cooling, concentrated hydrochloric acid (200 wLl) was added to the reaction mixture while stirring at -10 to 0°C, and the mixture was extracted with ether. The ether insoluble matter is removed, the ether layer is washed with water, and after drying, the ether is distilled off. The residue was subjected to silicic acid column chromatography, and the eluate was recrystallized from ether-hexane.
4-dibenzyloxyphenylnitromethane was obtained as pale yellow needles. Melting point: 65-67°C. Reference example 2 3,4-dibenzyloxybenzaldehyde oxime (
3.37), sodium hydrogen phosphate (7.8y) and urea (0,27) in acetonitrile (20m0) was heated to reflux and added with stirring from trifluoroacetic anhydride (3.4ml) and 90% hydrogen peroxide. A solution of pertrifluoroacetic acid prepared in acetonitrile (5 ml) was added dropwise.

After the addition, the mixture was further heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether extract was washed successively with water, a 10% aqueous sodium bicarbonate solution, and water, and dried over magnesium sulfate. The ether was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography.
After eluting with chloroform and distilling off the chloroform in the eluate, the resulting residue was recrystallized from ether to give 3.
4-dibenzyloxyphenylnitromethane was obtained as pale yellow needles. Melting point: 65-67°C. This product is reference example 1
It was consistent with what was obtained. Reference example 3 3,4-dibenzyloxyphenyl nitromethane (77
), 3,4,5-trimethoxybenzaldehyde (47
), ammonium acetate (1f7), and acetic acid (25 ml) in benzene (100 ml) by heating to reflux while removing water.

After 3 hours, ammonium acetate (2y) was added and the mixture was further heated under reflux for 25 hours.

Then, water was added to the reaction solution and extracted with ether. Wash the ether extract with water and dry. The ether was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The eluate was eluted with chloroform and the chloroform was distilled off to give 3,4-dibenzyloxy-3',4',5-trimethoxyα-nitrostilbene as a yellow oil. N
MR (CDCl3): 6.54 (20CH3, s), 6
．． 17 (0CH3, s), 4.90, 4.80 (0CH
2, s), 3.70 (2ar0mat.H..s), 3
．． 06 (3ar0mat.H1m), 2.70 (10a
r0mat. H. ．． m), 1.95 (-CH..s) Reference Example 4 Lithium aluminum hydride (87) was dissolved in dry ether (
200 mO and heated under reflux for 1 hour.

After most of the lithium aluminum hydride has dissolved, it is added to a solution of 3,4-dibenzyloxy-31,4ζ5'-trimethoxy-α-nitrostilbene (4.27) in dry dioxane-ether (1:4). Add 50 ml dropwise at -10 to -5°C with stirring.The mixture is further stirred at room temperature for 3 hours.Water (8 ml) is then added to the reaction mixture to decompose excess lithium aluminum hydride, and then 20% aqueous sodium hydroxide solution is added. (16ml).
Additional water (8 ml) is added to this, the organic layer is decanted and the resulting precipitate is washed with ether. The organic layer and ether washings are combined and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to silicic acid column chromatography. Elution was performed with chloroform, and the chloroform in the eluate was distilled off to obtain α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine as a colorless oil. . NMR (CDC
l3); 8.37 (NH2, b), 7.00-7.40
(CH2, m), 6.24 (20CH3, s), 6.2
0(0CH3,s), 6.24-6.20(CH..m
), 4488 (0CH2, s), 3.70 (2ar0m
at. H. ．． s), 3.14 (1ar0mat.H1s
), 307 (2ar0mat.H..d), 2.63(
10ar0mat. H1m) This oil was treated with a small excess of oxalic acid in a conventional manner, and the resulting oxalate was recrystallized from methanol-ethyl acetate (9:1) to give α-(3,4-dibenzyloxyphenyl). Oxalate of monoβ-(3,4,5-trimethoxyphenyl)ethylamine was obtained as colorless silky crystals.

Melting point: 155-158℃ o Reference example 5α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine (200η) was dissolved in methanol (10m0, 5% Stir at room temperature in a hydrogen gas stream in the presence of palladium on carbon.

After hydrogen absorption has stopped, the catalyst is removed, and the r liquid is evaporated to dryness under reduced pressure. The residue was treated with dry hydrochloric acid saturated ether in a conventional manner, and the resulting hydrochloride was diluted with ethanol monoethyl acetate (10:
Recrystallization from 1) gave α-(3,4-dihydroxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride as colorless needles. Melting point: 175
-184℃. Reference example 6 α-(3,4-dibenzyloxyphenyl)-β-(3
- Dissolve 4,5-trimethoxyphenyl)ethylamine oxalate (220~) in ethanol (30m0), add acetone (0.1m01 sodium cyanoborohydride (24~) to this, and stir at room temperature for 20 hours.

Add water to the reaction solution and extract with ether. The ether extract was washed with water and dried over anhydrous potassium carbonate. Distill the solvent,
The residue was subjected to silicic acid column chromatography.
Elution was carried out with chloroform, and when the chloroform in the eluate was distilled off, N-isopropyl-α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine was obtained as a colorless oil. Obtained as 1.
NMR (CDCl3); 9.07 (2CH3, d), 7
．． 48 (CH, d), 7.22 (CH2, d), 6.
25 (20CH3, s), 6,17 (0CH3, s),
6.00-6.30 (CHN..m), 4.93 (20
CH2, 1s), 3,73 (2ar0mat.H..s
), 3.25 (ArOmat.Hls), 3.23 (A
rOmat. H,. d), 3.13 (ArOmat.H
、． d), 2.62 (10ar0mat.Hsm) Reference Example 7 (1) α-(3,4-dibenzyloxyphenyl) β-(3,4,5-trimethoxyphenyl)ethylamine (
1.87) and p-hydroxyphenylacetone (0
．． Dissolve 657) in methanol (25m0) and add water while stirring to the solution.
Add 23y) and stir at room temperature for 62 hours.

Add water to the reaction solution and extract with ether. The ether extract was washed with water and dried, and the ether was distilled off under reduced pressure. The residue was subjected to silicic acid column chromatography. Elution was performed with CHCl3 and the eluate was divided into three fractions.

After chloroform was distilled off, N-(
β-4-hydroxyphenyl-α-methyl)ethyl-α
-(3,4-dibenzyloxyphenyl)-β-(3,
4,5-tri3methoxyphenyl)ethylamine was obtained as a colorless oil. NMR (CDCl3): 9.24
(CH3, d), 7.60-7.00 (2CH2, CH
、． m), 6.33 (20CH3, s), 6.20 (0
CH3,s), 46.20-5.90(CHN.m
), 4.90 (20CH3, s), 3.80 (2ar0
mat. H. s), 3.40 (4ar0mat.H.s
), 3.20 (ArOmat.H..s), 3.12 (
2ar0matH. d), 2.70 (10ar0mat
．． H,. m) This oil was treated with dry hydrochloric acid saturated ether in a conventional manner, and the resulting hydrochloride was recrystallized from ethanol-ether (20:1) to give N-(β-4-hydroxyphenyl-α-methyl). Ethyl-α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles.

Melting point: 103-105°C. (4) Distill chloroform from the third fraction of the eluate and remove N-(β-4-hydroxyphenyl-α-methyl)ethyl-α-(3,4-dibenzyloxyphenyl)-β- (3,4,5-trimethoxyphenyl)ethylamine was obtained as a colorless oil.

NMR (CDCl3): 8.99 (CH3, b), 7.
6-7.0 (2CH2, CH.m), 6.40 (20C
H3, s), 6.27 (0CH3, s), 6.20-5
,80(CHN..m),5,50,4.98(0CHN..m)
2, s), 4.00 (2ar0mat.H.s), 3.
60-3.00 (3ar0mat.H..m), 3,1
0(4ar0mat.H,.s), 2.70(10ar
0mat. H. m) This oil was treated with dry hydrochloric acid saturated ether in a conventional manner, and the resulting hydrochloride was recrystallized from ethanol-ether (20:1) to give N-(β-4-hydroxyphenyl-α-methyl). Ethyl α-(3,4-dibenzyloxyphenyl)β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles.

Melting point: 175-180°C. Example 1 N-isopropyl-α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)
Ethylamine (176 η) is stirred in the presence of 5% Seki-e in ethanol (10 ml) under a stream of hydrogen gas at room temperature.

After hydrogen absorption has stopped, the catalyst is stripped off and the slurry is evaporated to dryness under reduced pressure. The residue was treated with dry hydrochloric acid and saturated ether to give the hydrochloride in a conventional manner, giving isopropyl alcohol-acetone (
20:1) to give N-isopropyl α-(3.
4-dihydroxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles. Melting point: 157-159°C. Example 2 N-(β-4 obtained from the first fraction of Reference Example 7-(1)
-Hydroxyphenyl-α-methyl)ethyl-α-(3
・4-dibenzyloxyphenyl)-β-(3.4.5
-trimethoxyphenyl)ethylamine hydrochloride (364
(W) is stirred at room temperature in a stream of hydrogen gas in the presence of 5% Pde in methanol (10 mO).

After hydrogen absorption has stopped, the catalyst is stripped off and the slurry is evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol ether (10:1) to give N-(β4-hydroxyphenyl-α-methyl)ethyl α-(3,4-dihydroxyphenyl)-β-(3,4,5- Trimethoxyphenyl)ethylamine hydrochloride is obtained as a light brown powder. Melting point: 149-150℃
. Example 3 N-(β-4-hydroxyphenyl-α-methyl)ethyl-α-(3,4-dibenzyloxyphenyl)-β-(3. 4,5-Trimethoxyphenyl)ethylamine hydrochloride [Reference Example 71 (:)
The isomer obtained in the first fraction] (378η) was subjected to catalytic reduction similar to the catalytic reduction in Example 2, and the resulting crystals were recrystallized from ethanol-ether (10:1) to give N
-(β-4hydroxyphenyl-α-methyl)ethyl-
α(3,4-dihydroxyphenyl)-β-(3,4-
5-Trimethoxyphenyl)ethylamine hydrochloride [isomer of the compound obtained in Example 2] was obtained as a colorless powder.

Melting point 125-126°C. Reference example 8 α-(3,4-dihydroxyphenyl)-β(3,4-dihydroxyphenyl)
5-trimethoxyphenyl)ethylamine hydrochloride (70
Dissolve η) in ethanol (10m0) and acetone (0.
05m1), sodium cyanoborohydride (10m0
Add and stir at room temperature for 15 hours.

Add water to the reaction solution and extract with ether. The ether was distilled off under reduced pressure, and the residue was treated with dry hydrochloric acid saturated ether in a conventional manner. The resulting hydrochloride was diluted with isopropyl alcohol.
Recrystallized from acetone (20:1) to give N-isopropyl-α-(3,4-dihydroxyphenyl)-β-(3.
4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles. Melting point 157-159°C. This product was consistent with that obtained in Example 1. Reference example 9α1 (
3,4-dibenzyloxyphenyl)β-(3,4,5
-trimethoxyphenyl)ethylamine oxalate (120
Tf9) in ethanol (30 mO and acetone (5 mO)
Dissolve in the mixture of 1) and stir at room temperature in a hydrogen stream in the presence of 5% palladium on carbon.

After stopping the absorption of hydrogen gas, the catalyst is stripped off and the slurry is concentrated under reduced pressure. The residue was treated with dry hydrochloric acid saturated ether in a conventional manner, and the resulting hydrochloride was recrystallized from isopropyl alcohol-acetone (20:1) to give N-isopropyl-α-(3,4-dihydroxyphenyl)-β. -(3・4・5
-Trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles. Melting point 157-159°C. This product was consistent with that obtained in Example 1. Reference example 10 α-(3,4-dibenzyloxyphenyl) β-(3,
4,5-trimethoxyphenyl)ethylamine (500
~) and cyclobutanone (105TI19) were dissolved in ethanol (10ml), and while stirring, lithium cyanoborohydride (500~) was added to the mixture and the mixture was heated to 18% at room temperature.
Stir the time.

Add water to the reaction solution and extract with ether. The ether extract was washed with water, dried, and the ether was distilled off under reduced pressure. The residue was treated with dry hydrochloric acid saturated ether to give the hydrochloride salt in a conventional manner, and recrystallized from ethanol to give N-cyclobutyl-α-(
3,4-dibenzyloxyphenyl)-β-(3,4-
5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles. Melting point 179-185°C o Example 4 N-cyclobutyl-α-(3.4
-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride (160η)
are stirred at room temperature in a stream of hydrogen gas in the presence of methanol (10% Seki-c in 10 mO).

After hydrogen absorption has stopped, the catalyst is stripped off and the slurry is evaporated to dryness under reduced pressure. The residue was crystallized from ether to give N-cyclobutyl-α-(3,4-dihydroxyphenyl)-β-(3
- 4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as a colorless powder. NMR(D2O)τ; 8.50
-7.60 (3CH2, m), 7.00-6.40 (C
H2, NCH. ．． m), 6.30 (30CH3, s),
6.00-5.60 (CllN..m), 3466 (2
ar0mat. H. s), 3,40-3.00 (3ar
0mat. H,. m) Reference example 11α-(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine (500 instant) and p bromide
-Methoxyphenethyl (250 η) is heated on an oil bath at 120° C. for 30 minutes.

After cooling, the precipitated crystals were recrystallized from ethanol-ether to give N-p-methoxyphenethyl-α-1(3,4-dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl). ) Ethylamine hydrobromide was obtained as colorless needles. Melting point 170-173°C. Example 5 N-p-methoxyphenethyl-α obtained in Reference Example 11
-(3,4-dibenzyloxyphenyl)-β-(3,
4,5-Trimethoxyphenyl)ethylamine hydrobromide (160 mg) was dissolved in methanol (10% P in 10 mO
Stir at room temperature in a stream of hydrogen gas in the presence of d-c.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. Substituted phenylalkyl group, any two of which may be bonded to each other to form a ring, and the remainder is a hydrogen atom] is subjected to a benzyl group elimination reaction. A method for producing a catechol derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3 and R_4 have the same meanings as above].