JPS6018648B2 - Tetrahydronaphthylamine derivative - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel tetrahydronaphthylamine derivatives useful as pharmaceuticals. More specifically, the present invention relates to the general formula [where RI is a hydrogen atom or a lower alkyl group, R2
represents a lower alkyl group, and n represents an integer of 0 to 3] and salts thereof. The compound of the above-mentioned formula [1] is, for example, a compound of the general formula [wherein,
R1, R2 and n are as defined above, and R3 and R4 each represent a hydroxyl-protecting group.] It can be easily obtained by subjecting a compound represented by the following formula to a reaction for eliminating the hydroxyl-protecting group. The general formula [1],

Regarding [0], examples of the lower alkyl group represented by RI and R2 include those having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and i-propyl groups.
R2 is preferably a methyl group. The protecting group for the hydroxyl group represented by R3 and R4 may be any group as long as it is a protecting group that can be removed by the method of the present invention, such as lower alkoxymethyl (where the alkyl moiety is an alkyl group having about 1 to 3 carbon atoms). Examples, methoxymethyl, ethoxymethyl,
(propoxymethyl), benzyloxymethyl, benzyl, Q-substituted penzyl (eg, Q-methylbenzyl), and lower alkoxymethyl groups and benzyl groups are particularly preferred. n is an integer from 0 to 3,
Particularly preferred is 3. The removal reaction of the hydroxyl protecting group in the present invention is carried out by the general formula

This is carried out by subjecting the compound [0] to a hydroxyl-protecting group reaction. Such elimination reaction may be any reaction as long as it eliminates the protective groups of the hydroxyl groups represented by R3 and R4 and does not cleave the lower alkoxy group represented by the formula 1OR2, such as hydrolysis, catalytic hydrogen reduction, etc. can be given. The hydrolysis reaction is carried out, for example, by reacting a compound in an appropriate solvent at a temperature selected from a range of approximately 180 to 70 qo.

[0] with a mineral acid (eg, a hydrohalic acid such as about 5-1% by weight hydrochloric acid, about 5-1% by weight hydrobromic acid). In this case, the solvent is
For example, water, organic carboxylic acids (e.g. acetic acid), alcohols (e.g. methanol, ethanol), ethers (e.g.
Examples include tetrahydrofuran, dioxane), etc.
The amount of mineral acid used is the compound

[0] Usually 5 to 3 per mole
It is selected from a range of about 0 mol. Also, R3 and R
When the protecting group represented by 4 is a penzyl group, a Q-substituted penzyl group, etc., dependylation can be performed by catalytic hydrogen reduction to obtain compound [1]. Catalytic hydrogen reduction is usually
In an inert solvent such as alcohols (e.g., methanol, ethanol), water, organic carboxylic acids (e.g., acetic acid), esters (e.g., ethyl acetate), ethers (e.g., dioxane, tetrahydrofuran), about 1 to 10 Hydrophobic pressure level, approximately 2
Under reaction conditions selected from the range of about 0 to 100 qo,
It is carried out using a catalyst such as platinum oxide or palladium. The compound of general formula [1] thus obtained can be easily isolated from the reaction mixture by conventional separation and purification methods (eg, crystallization, column chromatography). Compound [1] contains two asymmetric carbon atoms in its molecule, and exists in four types of stereoisomers (eg, geometric isomers, optical isomers). When compound [1] is obtained as a mixture of these isomers, it can be separated into each isomer by using an appropriate separation means. For example, as a method for resolving a racemate, a resolution method that is usually used for resolving optical isomers is used. ), which can be separated by fractional crystallization or column chromatography. Also, geometric isomers (shi, trans, cis)
A mixture of these can also be separated by means such as fractional crystallization and column chromatography. Furthermore, if necessary, compound [1] can be obtained in the form of a single isomer by using a single isomer as the starting compound [n]. It goes without saying that these isomers and mixtures thereof are included within the scope of the present invention. Compound [1] thus obtained 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, fumaric acid). acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, tayaic acid) by a method known per se. The thus produced compound [1] and its salts exhibit a relaxing effect on tracheal muscles in animals, especially mammals (e.g., humans, cows, rabbits, guinea pigs), and are useful in the treatment of, for example, acute breathing and other obstructive airway diseases. It is useful as a medicine such as medicine. For example, when the above-mentioned compound [1] or a pharmaceutically acceptable salt thereof is used as the above-mentioned medicament, it may be mixed with itself or with an appropriate pharmaceutically acceptable carrier, excipient, diluent, powder, It can be administered orally or parenterally in the form of parent granules, tablets, capsules, injections, inhalants, sprays, and the like. The dosage depends on the target, the symptoms of the target disease,
Although it varies depending on the route of administration, for example, when administering to an adult's end of breath, the daily dose is usually about 1 to 9 of 100 for oral administration, and about 0.1 to 5 for static administration.
Approximately 1 to 5 per dose for local administration due to female level, fraud, etc.
Each is appropriately selected from a range of about 0 to o. general formula

The compound [0] can be synthesized, for example, by the following method. [In the formula, R1, R2, R3, R4 and n have the same meanings as above, R3' and R4' are R3, R4
represents a hydroxyl-protecting group or a lower alkyl group represented by , Ms represents a methanesulfonyl group, and Py represents pyridine] The phenethyl alcohol derivative represented by the general formula [a] is obtained by adding 2,3-dihydroxybenzaldehyde to 2,3-dihydroxybenzaldehyde using a known method. By introducing an appropriate protecting group into the catechol, condensing it with nitromethane to obtain a nitrostyrene derivative, and then treating the resulting phenethylamine derivative with sodium nitrite, or by introducing an appropriate protecting group into catechol, n - It is obtained by reacting with an alkyl lithium such as butyl lithium to form a lithio form and reacting with ethylene oxide. This protecting group can be substituted with another protecting group at an appropriate step in each of the above reactions. The hydroxyl group of the phenethyl alcohol derivative [a] thus obtained is substituted with a halogen to form [b], and then reacted with a phenylacetonitrile derivative in the presence of a base catalyst to obtain a butyronitrile derivative represented by the general formula [c]. As the base catalyst used in this reaction, a strong base such as potassium t-butoxide, sodium amide, potassium amide, sodium hydride, lithium hydride or n-butyl lithium is used. The reaction is generally carried out in the presence of a suitable solvent,
Such solvents vary depending on the type of base catalyst used, but include, for example, t-butyl alcohol, dimethylsulfoxide, dimethylformamide, ethers (e.g., diethyl ether, 1,2-dimethoxyethane, terahydrofuran), benzene, Toluene, liquid ammonia, etc. are used. The reaction temperature is generally selected from a range of approximately ÷80 to 100°C. The amount of base catalyst is halogen [
b] and the phenylacetonitrile derivative, respectively, in an amount of about 1 to 3 mol per mol. The compound [c] thus obtained is subjected to a hydrolysis reaction of sia/group to form 2,4-
A diphenylbutyric acid derivative [d] is obtained. Then, the ring is opened by an acid halide and an IJ-Delcrafts reaction to obtain a tetralone derivative [e]. Catalysts used in general Friedel-Crach reactions are used in such ring-closing reactions. For example, Lewis compounds such as aluminum chloride, stannic chloride, and zinc chloride are used. The reaction is preferably carried out in an appropriate solvent, and examples of such solvents include benzene, nitrobenzene, and carbon disulfide. The reaction temperature is selected from a range of about -20 to 30°C. Such a ring-closing reaction can also be carried out using a catalyst such as hydrogen fluoride without converting compound [d] into an acid halide. The thus obtained compound [e] is reacted with a primary alkylamine to obtain an imino compound [f]. This reaction is advantageously carried out in a solvent such as toluene or benzene, with water removed azeotropically. Further, the reaction can also be carried out in the presence of a dehydrating agent such as a molecular sieve or zincrohexylcarbodiimide, or in the presence of an acidic catalyst such as p-toluenesulfonic acid or titanium tetrachloride. The reaction temperature varies depending on the type of catalyst used, but is usually about 2
It is selected from a range of about 0 to 180oo. The thus obtained imino compound [f] can be purified and isolated, or subjected to the next reduction reaction without being subjected to a single reaction to obtain a compound of the general formula [b]. Reduction reactions include catalytic reduction using platinum oxide, palladium, Raney nickel, etc., methods using reducing agents such as alkali metal borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, reduction with diporane, and acetic acid. , Reduction with organic acids such as propylene or hydrochloric acid, hydrogenated acids such as sulfuric acid, and metals such as zinc and iron, Reduction with alkali metals such as sodium and lithium and alcohols such as methanol, ethanol, and isopropanol, Reduction with magnesium and alcohols , and conventional reduction methods such as electrolytic reduction. In the reduction reaction step, depending on the combination of the types of protecting groups represented by R3 and RP and the reaction conditions, the protecting groups may be removed at the same time and compound [1] may be obtained all at once. For example, an imino compound in which R3 and R4 are pendyl groups [
f] using catalytic reduction, or R3 and R4
An example of this is the case where an imino compound [f] in which is a methoxymethyl group is reduced with a mineral acid and a metal. Moreover, the compound of general formula [b] can also be obtained by directly subjecting compound [e] to a reductive amination reaction. Such amination is carried out by reacting the primary amine with compound [e] under reducing conditions. The reduction conditions used for this purpose include the above-mentioned imino compound [f]
Although the means used for the reduction reaction may be conveniently employed,
In the case of an alkali metal borohydride such as sodium borohydride, it is necessary to use a reducing agent with weak reducing power such as sodium cyanoborohydride to reduce the carbonyl group. Good results may be obtained by reacting in the presence of a condensing agent such as sodium acetate or acetic acid.
In this reaction, as in the case of the reduction reaction of compound [f], the protecting group is removed during the reaction, and the compound [f] is removed at once.
1] may be obtained. general formula

RI at [0]
A compound in which is a hydrogen atom (denoted as [0']) can be obtained by converting compound [e] into an oxime conductor by a conventional method, and then reducing it by the same means as the reduction of compound [f]. . The general formula thus obtained

A compound [0'] in which RI is a hydrogen atom in [0] is subjected to an alkylation reaction to form a compound [n] in which RI is a lower alkyl group.
It can also lead to Such an alkylation reaction can be carried out under the same reaction conditions as the reductive amination reaction of [e] using an appropriate carbonyl compound ○:CR'R'' [in the formula, R', R
'' is carried out by reacting with a hydrogen atom or a lower alkyl group]. This reduced alkyl reaction can be carried out by selecting the reaction conditions, for example by using catalytic reduction, to form an oxime derivative [
g] can also be applied directly. Also, the compound (0')
A compound in which RI is a lower alkyl group even if it is reacted with an appropriate active carboxylic acid derivative to form an acid amide derivative and reduced with lithium aluminum hydride etc.

[0] can be obtained. Furthermore, it can be obtained by formylating the compound [0'] in which RI is a hydrogen atom in the compound represented by the general formula [B] or converting it into a carbamate ester derivative, and then reducing it with lithium aluminum hydride or the like. . In the reduction or reductive alkylation reaction of the oxime derivative [Y] and the reductive alkylation reaction of the compound [0'], as in the case of the reduction reaction of the compound [f] described above, by combining the protecting group and the reducing conditions, During the reaction, the protecting group may be removed and the target compound [1] may be obtained all at once. The thus obtained compound of the general formula [b] (including [b']) is often preferentially given as either a cis or trans isomer with respect to the amino group and the alkoxyphenyl group, depending on the reduction conditions used. Further, in the case of a mixture of cis and trans isomers, each isomer can be isolated by conventional separation means such as recrystallization and chromatography, if desired. The present invention will be explained in more detail below with reference to Reference Examples and Examples, but the present invention is not limited to these in any way. Reference example 1 2,3-dibenzyloxyphenethyl alcohol (17
Methanesulfonyl chloride (8 hl) was gradually added dropwise to the pyridine (35 ml) solution prepared in the evening above while stirring under ice cooling. After stirring for 1 hour, the reaction mixture was extracted with ether mixed with ice water. The extract is washed with water, carp hydrochloric acid, and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate hexane to obtain 2,3-dibenzyloxyphenethyl alcohol methanesulfonate as colorless powder crystals. Melting point: 80-81℃ Reference Example 2 To a solution of 2,3-dibenzyloxyphenethyl alcohol methanesulfonate (19.4 hours in acetone (20 hours)) was added sodium iodide (40 minutes) and heated under reflux for 8 hours. Precipitation. was removed from the oven, and the solution was added to ice water and extracted with ether.The extract was washed with water, dried over anhydrous sodium sulfate, and the solution was distilled off under reduced pressure.The residue was recrystallized from ethyl to give the chloride 2, 3-Dibenzyloxyphenethyl is obtained as colorless needles. Melting point 52-55 qo. Reference Example 3 n-Butyllithium (15% hexane solution) (5 ml) is added to toluene (15% hexane solution) with stirring at -70 qo in a nitrogen stream.
A solution of 3,4,5-trimethoxyphenylacetonitrile (15 ml) in toluene (5 ml) was added dropwise. 1. After stirring for an hour, add dropwise a solution of 2,3-dibenzyloxyphenethyl iodide (20 parts of toluene (10 parts: 1 part). After stirring for 3 hours at room temperature, add ice water to the reaction solution and dilute with ether. Extract. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.The residue is subjected to silica gel column chromatography to obtain 4-(2',3'-dibenzyloxyphenyl)- 1-(3',4,5'-trimethoxyphenyl)butyronitrile (16) is obtained as a colorless oil.Infrared absorption spectrum:
1:2250 (CN). Reference example 44-(2',3'-dibenzyloxyphenyl)-1-(3',4',5'
monotrimethoxyphenyl)butyronitrile (8.0 evening)
Potassium hydroxide (4.5 hours) was added to a solution of ethylene glycol (10 hours) and heated under reflux for 2 hours. After cooling, add water and extract with ether, acidify the aqueous layer with hydrochloric acid and extract with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
'-dibenzyloxyphenyl)-2-(3',4',
6-Trimethoxyphenyl)butyric acid is obtained as a colorless oil. Infrared Absorption Svector Les Mizobukuro-1:1705 (C〇〇H). Reference example 5 '1) 4-(2',3'-dibenzyloxyphenyl)
- To a solution of 3-(3,4',5'-trimethoxyphenyl)butyric acid (10 min) in benzene (10 ml) was added phosphorus pentachloride (5 min) while stirring under ice for 1 hour at room temperature. Stir. The solvent was removed under reduced pressure, the residue was dissolved in carbon disulfide, and a solution of stannic chloride (4.2 ml) in carbon disulfide (30 ml of carbon disulfide) was added.
) while stirring while cooling on ice. After stirring for 30 minutes, ice water was added to the reaction mixture, acidified with hydrochloric acid, and extracted with chloroform. The extract is washed with carp hydrochloric acid, water, saturated sodium bicarbonate solution, and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to give 5,6-dibenzyloxy-3,4-dihydro 2-(3',4'
,5'-trimethoxyphenyl)-1(2H)naphthalenone (4.6 hours) is obtained. Melting point 162-164qo.
■ 4-(2',3'-dibenzyloxyphenyl)-2-(3',4',5-trimethoxyphenyl)butyric acid (
Add phosphorus pentachloride (3.9 hours) to a solution of benzene (2 hours) of 6.8 hours) while stirring under ice cooling, and stir at room temperature for 1 hour. Add stannic chloride (2.2
Add a benzene (2 ml) solution of hl) and stir for 30 minutes. Add carp hydrochloric acid to the reaction solution and extract with chloroform. Prepare the extract with hydrochloric acid, water, saturated sodium bicarbonate solution,
Wash with water and dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using carbon tetrachloride-acetone-ethanol (20:4
:1) and recrystallized from ethanol to give 3,4-dihydro-5,6-dihydroxy-2-(3',4',5
'-Trimethoxyphenyl)-1(pan)-naphthalenone monobenzyl ether (1.6 t) is obtained as colorless needles. Melting point 153-159 qo. Reference example 63,4-dihydro-5,6-dihydroxy-2-(3',4,5-trimethoxyphenyl)-1(2H) naphthalenone monobenzyl ether (p of 226) was dissolved in methanol (1 hl) , dissolved in tetrahydrofuran (2 ml), 5
% palladium on carbon (2 gruel base) and subjected to catalytic reduction. The catalyst is removed from the furnace, the furnace liquid is removed under reduced pressure, and the residue is subjected to silica gel column chromatography. Elution with chloroform acetone gives 3,4-dihydro-5,6-dihydroxy-2-(3',4',5'-trimethoxyphenyl)-1(ga)-naphthalenone (3 of 56). Melting point: 194-20 (decomposition). Reference example 7 3,4-dihydro 5,6-dihydroxy-2-(3'
,4',5-trimethoxyphenyl)-1(pan)-naphthalenone (1.9 nights) and anhydrous potassium carbonate (5 nights)
Chloromethyl methyl ether (8 hl) was added dropwise to a solution of N,N-dimethylformamide (25 hl). After stirring for 30 minutes, water was added to the reaction mixture and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 3,4-dihydro-5,6-bis-methoxymethoxy-2-( 3,4',5-trimethoxyphenyl)-
1(outer m)-naphthalenone (1.6 m) is obtained as colorless needles. Melting point 106-10900. Reference example 85,6
-dibenzyloxy-3.4-dihydro-2-(3,
4',5-trimethoxyphenyl)-1(ga)-naphthalenone (52 compound 9) and methylamine (ear hl) are heated in a sealed tube at 180°C for 1 hour in the presence of molecular sieves. Excess methylaminoisomer was removed, the residue was dissolved in acetic acid (1), zinc dust (1 night) was added, and the mixture was heated at 65-7000 for 1 hour. Add water to the reaction solution, make alkaline with sodium hydroxide, and extract with benzene. The extract is washed with water and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure, and the residue was recrystallized from methanol to give trans-5,6-dibenzyloxy-1,2,3,4-tetrahydro-2-(3
,4',5-trimethoxyphenyl)-1N-methyl-1
- Naphthylamiso (170 double 9) is obtained as colorless crystals. Melting point 138-141°C. Trans-5 was recrystallized from i-propanol-ethyl acetate as a hydrochloride by a conventional method.
, 6-dibenzyloxy-1,2,3,4-tetrahydro-2-(3',4',5-trimethoxyphenyl)-1N-methyl-1-naphthylamine hydrochloride is obtained as colorless needles. Melting point: 174-176°C. The mother liquor of methanol recrystallization was concentrated and subjected to silica gel column chromatography and eluted with chloroform to obtain cis-5,6-dibenzyloxy-1,2,3,4-tetrahydro-2-(3
',4',5-trimethoxyphenyl)-1N-methyl-1-naphthylamine is obtained. Nuclear magnetic resonance spectrum (7 values in deuterated chloroform): 8
．． 30-7.80 (CH2), 7.78 (NCH3),
7.50-6.60 (CQ, C2-H), 6.30 (C
, one day), 6.14 (OCH3), 4. Group, 4.85 (
〇CH2), 3.44 (C2-aromat.H), 3
．． 05 (CM-aromat.H), 2.60 (aromat.
mat. H). Reference example 95,6 dibenzyloxy-3
, 4-dihydro-2-(3',4',5-trimethoxyphenyl)-1(ga)-naphthalenone (2.7 days) and methylamine (2) were added to a benzene solution of titanium tetrachloride while stirring under ice-cooling. (0.3 ml) was added dropwise. Stir at room temperature for 2 hours, and then heat under reflux for 2 hours. After mixing, the precipitate was removed from the oven, and the oven liquid was distilled off under reduced pressure. The residue was treated in the same manner as in Reference Example 8. 5,6-dibenzyloxy-1,2,3,4-tetrahydro-2-(3,4'
, 5'-trimethoxyphenyl)-1N-methyl-1-naphthylamine is obtained as colorless crystals. Melting point 138-141℃
. Reference example 10 3,4-dihydro 5,6-bis-methoxymethoxy-
2-(3,4,5'-trimethoxyphenyl)-1(2
H)-naphthalenone (1.6 ml) was dissolved in pyridine (3 ml)
), add hydroxylamine hydrochloride (1.5 hours), and heat under reflux for 4 hours. The solvent is distilled off under reduced pressure, water is added to the residue, and the precipitated crystals are collected in a furnace. Recrystallized from ethyl acetate-hexane to give 3,4-dihydro-5,6-bismethoxymethoxy 2-(3
,4',5-trimethoxyphenyl)-1(2H)-naphthalenone oxime is obtained as colorless needles. Melting point 13
8-140oo. Reference example 115,6-dibenzyloxy-3,4-dihydro-2-1. (3',4',5-trimethoxyphenyl)-1(pan)-naphthalenone was treated in the same manner as in Reference Example 10 to obtain 5,6-dibenzyloxy-3
, 4-dihydro-3-(3',4',5-trimethoxyphenyl)-1(2H)-naphthalenone oxime is obtained as colorless needles. Melting point 141-143q0. Reference example
12 3,4-dihydro 5,6-bismethoxymethoxy-2
1(3',4',5'-trimethoxyphenyl)1(pan)-naphthalenone oxime (9 of 925) was dissolved in tetrahydrofuran (5 hl) and isopropanol (15 h).
1) and add metallic sodium (1.1 min.) little by little. After stirring at room temperature for 9 hours, water was added to the reaction mixture and extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography.
,3,4-tetrahydro-5,6-bis-methoxymethoxy2-(3,4',5'-trimethoxyphenyl)
-1-Naphthylamine is obtained as a colorless oil. Nuclear magnetic resonance spectrum (in deuterated chloroform): 5.88 (cis form C, 1 day, d, J = 3.9 Hz), 5.86 (trans form C, 1 day, d, J = 7. Beat Z), 2.94 (cis CM-day, S), 2.97 (trans C7-day, d
), 2.60 (trans form C8-day, d), 3.45 (
Cis form C2-ammat. day, S) 3.50 (trans form C2-aromat. day, S). Reference Example 13 Sodium amide (1.2 hours) is suspended in benzene (3 plates), cyanobenzene (3.6 hours) is added, and the mixture is heated under reflux for 1 hour in a nitrogen stream. After washing, add 2,3-dimethoxyphenethyl (6.2 evening) dropwise under ice-cooling. After stirring at room temperature for 3 hours, add 2 more
Heat to reflux for an hour. After cooling, add hydrochloric acid and extract with ether. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 5.5 g of 4-(2',3'-dimethoxyphenyl)-1-phenylbutyronitrile as a pale yellow oil. boiling point 160-16
6qC (0.01 day/day). This product was hydrolyzed in the same manner as in Reference Example 4, then treated in the same manner as in Reference Example 5-1, and recrystallized from methanol. 5
Obtained as colorless plate crystals. Melting point: 147-149°C. Reference Example 14 To a solution of 3,4-dihydro-5,6-dimethoxy-2-phenyl-1(spot)-naphthalenone (5.6 ml) in benzene (20 ml) was added aluminum chloride (13 ml) and heated under reflux for 2 hours. After lining, add carp hydrochloric acid to the reaction mixture and dilute with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethanol-water to give 3,4
-dihydro-5,6-dihydroxy-2-phenyl-1
(ga) - Naphthalene/n (4.9 evenings) was obtained. Melting point 192
11 writing 0 (disassembly). Reference Example 15 (1'3,4-dihydro-5,6-dihydroxy-2-phenyl-1.(2H)-naphthalenone (2.5 ml) in acetone solution (10 ml), pendyl chloride (3 ml), potassium carbonate (3.3 ml) Poly), potassium chloride (3.9 evenings)
and heated under reflux for 2 hours. The precipitate is removed from the furnace, and the furnace liquid is distilled off under reduced pressure. The residue was recrystallized from ethanol to give 5,6-dibenzyloxy-3,4
-dihydro-2-phenyl-1(pan)-naphthalenone (
4 evenings). Melting point: 132-13400. (2' 3,
To a methanol solution of 4-dihydro-5,6-dihydroxy-2-phenyl-1(2H) naphthalenone (2.54 hours) were added sodium methoxide (0.92 hours) and chloromethyl methyl ether (3.2 hours) and cooled on ice. Stir for 1 hour. The reaction solution was diluted with water and extracted with ether. The extract is washed with dilute sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from petroleum ether to give 3,4-dihydro-5,6-
Pismethoxymethoxy-2-phenyl-1(2H)naphthalenone (2.3 min) is obtained. Melting point: 71.5-72.
500. Reference example 16 {1} 5,6-dibenzyloxy-3,4-dihydro
-2-phenyl-1(pan)-naphthalenone (0.434
of isopropylamine (2 hl) and molecular sieves are heated in a sealed tube at 180 pm for 1 hour. Excess isopropylamine was distilled off, the residue was dissolved in methanol, and sodium borohydride (0.5 mL) was added.
Warm for an hour. The solvent was removed under reduced pressure, diluted sodium hydroxide solution was added to the residue, and the mixture was extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ether as a hydrochloride in a conventional manner to give cis-5,6-dibenzyloxy-1,2,3,4-tetrahydro-N-isopropyl-2.
-Phenyl-1-naphthylamine hydrochloride is obtained as colorless needles. Melting point 165-185°C. ■3,4-dihydro-5,6-bismethoxymethoxy-2-phenyl-1 (
2H)-naphthalenone (9 of 570) in Reference Example 16-{
It reacts in the same manner as 1' and recrystallizes it from acetone as a hakamate salt in a conventional manner to give cis-1,2,3,4-tetrahydro-N-isopropyl-5,6-bismethoxymethoxy-2-phenyl-1- Naphthylamine hakamate is obtained as colorless needles. Melting point: 124-12600. Reference example 17 {1) 3,4-dihydro-5,6-bismethoxymethoxy-2-phenyl-1(pan)-naphthalenone (Satoshi 4 imitation)
was treated in the same manner as in Reference Example 10 and recrystallized from ether-water to obtain 3,4-dihydro-5,6-bismethoxymethoxy-2-phenyl-1(ga)-naphthalenone oxime as colorless needle crystals. Melting point 141-143°C. ■ 5,6-Dibenzyloxy-3,4-dihydro-0-2-phenyl-1(ga)-naphthalenone was treated in the same manner as in Reference Example 10 and recrystallized from ethanol to give 5,6-dibenzyloxy-3. , 4-dihydro-2-phenyl-1(2H)-naphthalenone oxime is obtained as colorless needles. Melting point: 157-160q0. Reference example 18 3,4-dihydro-5,6-pismethoxymethoxy 2
-Phenyl-1(2H)-naphthalenone oxime (54
Dissolve 9) in methanol (1) and stir in a hydrogen stream in the presence of 10% palladium-carbon. After hydrogen absorption has stopped, the catalyst is removed from the furnace and the furnace liquid is concentrated under reduced pressure. The product is converted into a tate salt by a conventional method and recrystallized from acetone to obtain cis-1,2,3,4-tetrahydro-5,6-bismethoxymethoxy-2-phenyl-1-naphthylamine tate salt. Melting point 144-14 is ○. Reference example 19 5,6-dibenzyloxy-3,4-dihydro-2-phenyl-1 (2H)-naphthalenone oxime (100
Dissolve mc) in ether, add aluminum malgam and 2-3 drops of methanol, and stir at room temperature. The precipitate is removed from the furnace, and the furnace liquid is concentrated under reduced pressure. It is converted into a hydrochloride by a conventional method and recrystallized from ethanol to obtain cis-5,6-dibenzyloxy-1,2,3,4-tetrahydro-2-phenyl-1-naphthylamine hydrochloride. Melting point 187
-205℃. Reference example 203,4-dihydro 5,6-
Bismethoxymethoxy-12-phenyl-1(2H)-naphthalenone oxime (spot 0 female) ethanol (Arashi HL)
Add metallic sodium (60°C) little by little to the solution and heat for 1 hour. Dilute the reaction group skin with water and extract with ether. The extract is washed with water and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure, and the oxalate salt was recrystallized from acetone using a conventional method to obtain cis-1,2,3,4-tetrahydro-5,6-bismethoxymethoxy-12-phenyl-1-naphthylamine hakamate. get. Melting point 144-14900. Trans-1,2,3,4-tetrahydro-5,6-bismethoxymethoxy-2-phenyl-1-naphthylamine salt is obtained from the recrystallized mother liquor. Melting point 92-9500. Reference example 21 transformer-1, 2,
Dissolve 3,4-tetrahydro-5,6-bismethoxymethoxy-2-phenyl-1-naphthylamine nitric acid salt (9 of 216) in ethanol (1 hl) and add acetone (0
．． 1ml) Lithium cyanoborohydride (9 of 200)
Add and stir at room temperature for 18 hours. Add water to the reaction solution and extract with ether. The extract is washed with water and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure,
The residue was converted into a tate salt by a conventional method and recrystallized from acetone ether to give trans-1,2,3,4-tetrahydro-
N-isopropyl-5,6-bismethoxymethoxy 2
-Phenyl-1-naphthylamine travolate is obtained. Melting point 1
38-140q○. Example 1 Trans-5,6-dibenzyloxy-1,2,3,4
-Tetrahydro-2-(3',4',5'-trimethoxyphenyl)-N-methyl-1-naphthylamine hydrochloride (450 o) was dissolved in ethanol (5 hl),
Stir in a stream of hydrogen in the presence of % palladium-carbon (9 of 400). After absorbing 2 molar equivalents of hydrogen, the catalyst is removed from the furnace, and the furnace liquid is concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate to give trans-1,2,3,4-tetrahydro-5,6-dihydroxy-2-(3',4',5'-trimethoxyphenyl)-N-methyl- 1-Naphthylamine hydrochloride is obtained as colorless crystals. Melting point: 129-132°C. Example 2 Cis-1,2,3,4-tetrahydro-5,6-bis-methoxymethoxy-2-(3',4',5'-trimethoxyphenyl)-1-naphthylamine postacid acid salt (9 c)
Dissolve in methanol (2 ml), add dry hydrochloric acid gas-saturated methanol (3 drops), and heat at 70°C for 30 minutes. Methanol was removed under reduced pressure, and the residue was recrystallized from methanol to give cis-1,2,3,4-tetrahydro-5,
6-Dihydroxy-2-(3',4',5'trimethoxyphenyl)-1-naphthylamine hydrochloride is obtained as colorless crystals. Melting point 164-17000. Example 3 Cis-5,6-dibenzyloxy-1,2.3,4-tetrahydro-N-isopropyl-2-phenyl-1-naphthylamine hydrochloride (100 females) was dissolved in 20% methanolic hydrochloric acid at 70 to 80 qo. Heat for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol ether to give cis-1,2,3,4-tetrahydro-5,
6-dihydroxy-N-isobropy-2-phenyl-
1-Naphthylamine hydrochloride is obtained. Melting point 106-109
qo. Example 4 (1) Cis-1,2,3,4-tetrahydro-N-isopropyl-5,6-bismethoxymethoxy-2-phenyl-1-naphthylamine hakamate (12
0-9) was treated in the same manner as in Example 3 to obtain cis-1,2,3
, 4-tetrahydro-5,6-dihydroxy-N-isopropyl-2-phenyl-1-naphthylamine hydrochloride is obtained. Melting point 106-10900. '2} Transformer 1, 2,
3,4-tetrahydro-N-isopropyl-5,6-bismethoxymethoxy-2-phenyl-1-naphthylamine oxalate was treated in the same manner as in Example 3 to obtain trans-1,2
,3,4-tetrahydro-5,6-dihydroxy-N-
Isof. Lopyru-2-phenyl-1-naphthylamine hydrochloride is obtained. Melting point 139-1420○. Example 5 {1) Cis-1,2,3,4-tetrahydro-5,6-
Bismethoxymethoxy-12-phenyl-1-naphthylamine tathrate was treated in the same manner as in Example 3, and recrystallized from ethanol and ethyl acetate to give cis-1,2,3,4-tetrahydro-5,6-dihydroxy-2-phenyl. -1 naphthylamine hydrochloride is obtained.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom or a lower alkyl group,
R^2 represents a lower alkyl group, n represents an integer of 0 to 3]
A tetrahydronaphthylamine derivative or a salt thereof.