JPS5931493B2 - Catechol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of the general formula (I)-(OC) which are useful as pharmaceuticals.
H/N(l) [In the formula, R_3 and R_4 represent a hydrogen atom or a benzyl group.

One of R_1 and R_2 represents a hydrogen atom or a methyl group, and the other represents a phenyl lower alkyl group substituted with a hydroxyl group or a methoxy group at the 4-position, or they are bonded to each other to form an adjacent carbon R_, elementary atom The present invention relates to a catechol derivative represented by -CH<representing a cyclobutyl group] which forms a ring with -CH.

Compound (I) of the present invention has the general formula (■) = Engineering □.

. (■) [In the formula, R_'3 and R_2 represent a hydrogen atom or a benzyl group] is produced by alkylating [this step is referred to as step (A)].

Further, in general formula (I), a compound in which R_3 and R_4 are both hydrogen atoms, that is, a catechol derivative represented by general formula (■) [wherein R1 and R2 have the same meanings as above], is a compound represented by general formula (■) [wherein R1 and R2 have the same meanings as above]. It can also be produced by subjecting a compound represented by the formula (in which R1 and R2 have the same meanings as above) to a benzyl group elimination reaction [this step is referred to as (B)].

In the above formula, examples of the lower alkyl moiety of the phenyl lower alkyl group in which the 4-position represented by R1 or R2 is substituted with a hydroxyl group or a methoxy group include 1 to 3 alkyl groups. Specific examples of these include 4-hydroxybenzyl, 4-methoxybenzyl, 4-methoxyphenethyl, and the like. Each of R3 and R4 is preferably a hydrogen atom.

The alkylation in step (A) of the present invention is carried out by subjecting the compound of general formula () to an alkylation reaction.

The alkylation reaction of compound () is performed by combining compound () and general formula (
V) Reductively reacting the compound represented by [wherein R1 and R2 have the same meanings as above] (reductive alkylation)
Alternatively, the compound () and the formula [wherein R,, R.

is carried out by reacting an alkyl group represented by the same definition as above with a corresponding alkylating agent. 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) with, for example, an alkali metal. The reaction is carried out in the presence of a reducing agent such as 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 typically involves alcohols (e.g., methanol, ethanol), water, organic carboxylic acids (e.g., acetic acid), esters (e.g., ethyl acetate), ethers (e.g.,
dioxane, tetrahydrofuran) under reaction conditions of about 1 to 100 atmospheres and about 20 to 100 °C,
This is carried out using platinum, palladium, nickel catalysts (eg, Raney nickel), etc. In the general formula (), when R3O and/or R4O are benzyloxy groups, this benzyloxy group simultaneously undergoes debenzylation during catalytic reduction and becomes a free hydroxyl group. In addition, in the case of catalytic hydrogen reduction, if platinum oxide Raney nickel or the like is used as a catalyst and mild reaction conditions (catalytic reduction at room temperature and pressure) are used, the benzyloxy group of the raw material compound () can be debenzylated. In some cases, reductive alkylation can be carried out without causing 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). An alkyl group represented by the following formula (wherein RhR has the same meaning as above) is introduced to produce compound (I). Compound () and formula −
The reaction with the alkylating agent corresponding to the alkyl group represented by C<: is usually carried out by bringing the two into contact at a temperature of about 0 to 150°C in a solvent.

Examples of the alkylating agent include alkyl halides and dialkyl sulfates corresponding to the alkyl group, and the halogen atoms of the alkyl halides include chlorine, bromine,
Examples include iodine. The amount of these halogenating agents used varies depending on the halogenating agent used, but when compound ()l
It is usually about 1 to 1.2 moles per mole. In addition,
In order to capture the acid produced in the reaction, it may be advantageous 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. Examples of the reaction solvent 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, in order to produce a compound () into which one alkyl group is introduced,
Before carrying out the alkylation reaction, it is preferable to introduce one protecting group into the amino group of the compound () in advance, and to remove the protecting group after the main alkylation reaction. Examples of protecting groups for amino groups include benzyl, carbobenzyloxy, and trifluoroacetyl. These protecting groups can be introduced into the amino group using, for example, benzaldehyde, carbobenzyloxychloride, trifluoroacetic anhydride or its chloride in a manner similar to the alkylation method described above. In addition, as a method for removing this protecting group, for example, compound (I) with a protected amino group may be subjected to a reaction similar to the reaction for removing the protecting group for the hydroxyl group in step (B) described below. Removal can occur simultaneously with or before or after removal of the protecting group. In addition, R-0. of compound (). k
．． When 0 is an unprotected hydroxyl group, a protecting group such as carbobenzyloxy or trifluoroacetyl group is simultaneously introduced into the hydroxyl group when a protecting group for the amino group is introduced. These hydroxyl-protecting groups are removed at the same time as the amino-protecting group is removed. Process (B) of the present invention
The reaction for removing the protecting group from the hydroxyl group is carried out by subjecting the compound of general formula () to an ether bond cleavage reaction.

Any reaction conditions may be used as long as they remove the benzyl group, which is a protecting group for the hydroxyl group, and do not cleave the methoxy group on the phenyl ring. 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., 5 to 10% by weight hydrochloric acid, 5 to 10% by weight]
Hydrohalic acid such as hydrobromic acid] may be used. In this case, the solvent may be water, organic carboxylic acid (e.g.
acetic acid), alcohols (e.g. methanol, ethanol)
, ethers (e.g., tetrahydrofuran, dioxane)
etc. The amount of mineral acid used is usually about 5 to 30 moles per 1 mole of the compound (). In addition, the process (A
) The compound () can be obtained by debenzylation by catalytic reduction similar to the catalytic hydrogen reduction described in (). The compounds of general formulas () and (I) thus obtained can be separated from their respective reaction mixtures by conventional separation and purification methods (e.g., crystallization,
Easily isolated by column chromatography. Compound (I) contains at least one asymmetric carbon in its molecule and is usually obtained in a racemic form.

These racemates exhibit potency as they are, but 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 (1) is converted into a salt of an optically active organic carboxylic acid (e.g., tartaric acid, malic acid, mandelic acid), This can be divided by fractional crystallization or column chromatography. The compound () obtained in this way can 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, maleic acid, tartaric acid). , fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid) by a method known per se. For example, R3 obtained in this way
and Compound (1) in which R4 is a hydrogen atom, that is, Compound () and acid addition salts thereof, exhibit stimulatory action on β2 receptors in tracheal muscles without stimulating β1 receptors in the heart, and are effective for example in asthma and It is useful as a medicine for treating other obstructive airway diseases. For example, when the above-mentioned compound (1) and compound () or their pharmaceutically acceptable acid addition salts are used as the above-mentioned medicine, the dosage thereof varies depending on the pathology of the target disease, but
The daily dose per kg is usually 50 to 150 μ7,
By itself or mixed with appropriate pharmaceutically acceptable carriers, excipients, diluents, powders, granules, tablets, capsules,
It can be administered orally in the form of an injection, an inhalation, a spray, or the like. The compound of general formula () can be synthesized by the method shown below.

[In each of the above formulas, K3 and has the same meaning as defined above], compounds (a) and (b) are generally produced using methods similar to those for producing known compounds included in general formulas (a) and (b). It can be produced by a method similar to this. Furthermore, a compound in which K3 and Rt are hydrogen atoms in the general formula () can be produced by a method similar to the above process (2). It can be produced by subjecting it to the same hydroxyl-protecting group removal reaction as described in B).

The compound of general formula () can be produced by using as a starting material a compound () in which R and R'4 are benzyl groups in the reaction of step (A) described above. Reference example 1 Metallic potassium (2.357) and ethanol (20m
1) Dry ether of potassium ethoxide (
Dissolve 3,4-dibenzyloxyphenylacetonitrile (19.87) in methyl nitrate (11 ml) and add dropwise to the solution while stirring.

Stir at room temperature for 3 hours and leave at -30°C overnight. Collect a lot of the pale yellow powder that precipitates. Wash with ether and dry with air.
- Obtain 4-dipencyloxyphenylannitroacetonitrile potassium salt 237. Add this product to a 5% aqueous sodium hydroxide solution (1.51) and heat under reflux for 28 hours.

After cooling, concentrated hydrochloric acid (200 ml) was added to the reaction mixture while stirring at -10-0°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.
-dibenzyloxyphenylnitromethane was obtained as pale yellow needle crystals. Melting point: 65-67°C Reference example 2 3,4-dibenzyloxybenzaldehyde oxime (
3.37), sodium hydrogen phosphate (7.87) and urea (0.27) in acetonitrile (20 m0) was heated to reflux and added with stirring to trifluoroacetic anhydride (3.4 m0 and 90% hydrogen peroxide). A solution of pertrifluoroacetic acid in acetonitrile (5 ml) is 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℃ o This product is reference example 1
It was consistent with what was obtained. Reference example 3 3,4-dibenzyloxyphenyl nitromethane (7t
), 3,4,5-trimethoxybenzaldehyde (47
), ammonium acetate (17), 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-3ζ4ζ5'-trimethoxy-1α-nitrostilbene as a yellow oil. N.M.
R(CDCl3): 6.54 (20CH3, s), 6.
17 (0CH3, s), 4,90, 4.80 (0CH2
, s), 3.70 (2ar0mat.H,.s), 3.
06 (3ar0mat.H.m), 2,70 (10ar
0mat. H. m), 1.95 (=CH, s) reference example
4 Lithium aluminum hydride (8f) was dissolved in dry ether (
200ml) and heated under reflux for 1 hour.

After most of the lithium aluminum hydride has dissolved, this is added to a solution of 3,4-dibenzyloxy-3ζ4',5'-trimethoxy-alpha-nitrostilbene (4.27) in dry dioxane-ether (1:4). (50ml) was added dropwise at -10 to -5°C while stirring. The mixture is further stirred at room temperature for 3 hours. Next, water (8 ml) was added to the reaction solution to decompose excess lithium aluminum hydride, and then a 20% aqueous sodium hydroxide solution (16 ml) was added. 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 carried out with chloroform, and when the chloroform in the eluate was distilled off, α-(3,4-
Dibenzyloxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine was obtained. NMR (CD
Cl3): 8.37 (NH2, b), 7.00-7.4
0 (CH2, m), 6.24 (20CH3, s), 6.
20 (0CH3, s), 6.24-6.20 (CH.m
), 4.88 (0CH2, S) 13.70 (2ar0m
at. H1s), 3・14(1ar0mat.H,.s
), 3.07 (2ar0mat.H.d), 2.63 (10ar0mat.H..m) This oil was treated with a small excess of oxalic acid in a conventional manner, and the resulting oxalate was dissolved in methanol and ethyl monoacetate (9 :1) recrystallized from α-
(3,4-dibenzyloxyphenyl)-β-(3,4
-Oxalate of 5-trimethoxyphenyl)ethylamine was obtained as colorless silky crystals.

Melting point: 155-158°C. Reference example 5α-(3,4-dibenzyloxyphenyl)β-(3,4,5-trimethoxyphenyl)ethylamine (200rf19) was dissolved in methanol (10ml) and hydrogenated in the presence of 5% palladium on carbon. Stir at room temperature under a gas stream.

After hydrogen absorption has stopped, the catalyst is removed and the solution 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:
1), d-(3,4-dihydroxyphenyl)-β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needle crystals. Melting point: 175
-184℃ Example 1 (1) α-(3,4-dibenzyloxyphenyl)-β
-(3,4,5-trimethoxyphenyl)ethylamine (1.81) and p-hydroxyphenylacetone (
Dissolve 0.65f) in methanol (25ml) and add sodium cyanoborohydride (0.65f) to this while stirring.
237) 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-d-
(3,4-dibenzyloxyphenyl)-β-(3,4
- 5-Trimethoxyphenyl)ethylamine was obtained as a colorless oil. NMR (CDCl3): 9.24 (CH
3, d), 7.60-7.00 (2CH2, m), 6.
33 (20CH3, s), 6.20 (0CH3, s),
6.20-5.90 (CHN.m), 4.90 (20C
H3, s), 3.80 (2ar0mat.H,.s),
3.40 (4ar0mat.H1s), 3.20 (Ar
Omat. H,. s), 3.12 (2ar0mat.H,.d), 2.70 (1
0ar0mat. H. m) Treat this oil with dry hydrochloric acid saturated ether in a conventional manner, and dissolve the resulting hydrochloride in ethanol-ether (20:1).
Recrystallized from N-(β-4-hydroxyphenyl)
-Methyl)ethyl-d(3,4-dibenzyloxyphenyl)-β(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles.

Melting point: 103-105°C. 2) Chloroform was distilled off from the third fraction of the eluate to obtain 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 (20
CH3, s), 6.27 (0CH3, s), 6.20-
5.80 (CHN..m), 5.50, 4.98 (0C
H2, s), 4.00 (2ar0mat.H.s), 3.60-3.00 (3ar0mat.H,.m), 3
．． 10 (4ar0mat.H,.s), 2.70 (10
ar0mat. 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-(β4-
Hydroxyphenyl-α-methyl)ethyl d-(3.4
-dibenzyloxyphenyl)β-(3,4,5-trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles.

Melting point: 175-180°C. Example 2 N-(β4-
Hydroxyphenyl-α-methyl)ethyl-α-(3
・4-dibenzyloxyphenyl)-β-(3
・4・5-Trimethoxyphenyl)ethylamine hydrochloride (364~) in methanol (10ml)
Stir at room temperature in a stream of hydrogen gas in the presence of % Pd-c.

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-(β-4-hydroxyphenyl-α-methyl)ethyl-d-(3.4-dihydroxyphenyl)-β-(3. 4,5-trimethoxyphenyl)ethylamine hydrochloride is obtained as a light brown powder. Melting point: 2149-150°C. Example 3 N-(β-4-hydroxyphenyl-α-methyl)ethyl-α-(3,4-dibenzyloxyphenyl)-β-(3. 4,5-trimethoxyphenyl)ethylamine hydrochloride [Example IHI]
The isomer obtained in the first fraction] (378~) 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- 4-hydroxyphenyl-d-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. Example 4 α-(3.4-dibenzyloxyphenyl)-β-(3.4.5-trimethoxyphenyl)ethylamine (500TI!9) and cyclobutanone (105~) were dissolved in ethanol (10ml). , add lithium cyanoborohydride (
500~) and stir at room temperature for 18 hours.

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-1(3.4-dibenzyloxyphenyl)-β-1(3.4.5). -Trimethoxyphenyl)ethylamine hydrochloride was obtained as colorless needles. Melting point 179-185°C. Example 5 N-cyclobutyl-d obtained in Example 4 (3.
4-dibenzyloxyphenyl)-β-(3,4,5-
trimethoxyphenyl)ethylamine hydrochloride (160T
n9) in the presence of 10% Pd-c in methanol (10 ml) in a stream of hydrogen gas at room temperature.

After hydrogen absorption has stopped, the catalyst is removed and the filtrate 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. Recrystallization from acetone gave colorless crystals. Melting point 144-148℃
. NMR (D2O) τ 2 8.50- 7.60 (
3CH2, m), 7.00-6.40(CH2,N
CHm), 6.30 (30CH3, s), 6.00-
5.60 (CHN, m), 3.66 (2ar0mat.
H. ．． s), 3.40-3.00 (3ar0mat
．． H,. m) Example 6 α=(3.4-dibenzyloxyphenyl)-
β-(3.4.5-trimethoxyphenyl)ethylamine (500 m9) and p-methoxyphenethyl bromide (250 W19) are heated on an oil bath at 120° C. for 30 minutes.

The crystals precipitated after cooling were recrystallized from ethanol-ether to give N-p-methoxyphenethyl-α-(3.
4-dibenzyloxyphenyl)-β-(3 ・
4.5-trimethoxyphenyl)ethylamine hydrobromide was obtained as colorless needles. Melting point 170-1
73℃.

Example 7 N-p-methoxyphenethyl-α-(3.4-dibenzyloxyphenyl) obtained in Example 6
-β-(3.4.5-trimethoxyphenyl)ethelamine hydrobromide (160~) is stirred in methanol (10 ml) in the presence of 10% Pd-c in a stream of hydrogen gas at room temperature.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_3 and R_4 represent a hydrogen atom or a benzyl group. One of R_1 and R_2 represents a hydrogen atom or a methyl group, and the other represents a phenyl lower alkyl group substituted with a hydroxyl group or a methoxy group at the 4-position, or they are bonded to each other to form a ring with the adjacent carbon atom. A catechol derivative formed by ▲, which has mathematical formulas, chemical formulas, tables, etc. ▼ indicates a cyclobutyl group].