KR810001299B1 - Process for producing of 2-amino tetralin derivatives - Google Patents

Abstract

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Description

Method for preparing 2-aminotetrarin derivative

The present invention relates to a process for the preparation of 2-aminotetrarin derivatives of the following formula (1) having excellent hardening action.

In the above structural formula

R ¹ and R ² are the same or different hydrogen atoms, lower alkoxy groups or two bonded together to represent a lower alkylenedioxy group,

R ³ represents a hydrogen atom, a lower alkyl group or a cycloalkyl group,

R ⁴ , R ⁵ , R ⁶ represent the same or different hydrogen atom, lower alkoxy group, lower alkyl group, halogen group, investigating group or two together to form a lower alkylenedioxy group,

A represents a linear or branched alkylene group having 2 to 10 carbon atoms or an alkylene group having an ether bond as an oxygen atom in the middle.

Examples of the 2-aminotetrarin derivative of the present invention include the following compounds, and other acid addition salts below the free form of each compound are also included in the present invention.

(1) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyr] -1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as compound A) Technology).

(2) N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as "Compound B" ).

(3) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -5-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(4) N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(5) N-ethyl-N- [2- (3,4-dimethoxybenzoyloxy) ethyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(6) N-methyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(7) N-ethyl-N- [3- (3,4-dimethoxybenzoyloxy) propyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(8) N-ethyl-N- [3- (3,4-dimethoxybenzoyloxy) -2,2-dimethylpropyl] -6-methoxy-1,2,3,4-tetrahydro-2-naph Thiaminel Hydrochloride

(9) N-ethyl-N- [2- (2- (3,4-dimethoxybenzoyloxy) ethoxy] ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl Amine hydrochloride

(10) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter ＂ As compound CVII).

(11) N-ethyl-N- [4- (benzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(12) N-ethyl-N- [4- (3,4-dihydroxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(13) N-salt-N- (4- (4-ethylmethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(14) N-ethyl-N- [4- (3-methoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(15) N-ethyl-N- [4- (4-ethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(16) N-ethyl-N- [4- (4-propoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(17) N-ethyl-N- [4- (4-methylbenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(18) N-ethyl-N- [4- (3-methoxy-4-ethoxy-benzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine Hydrochloride

(19) N-ethyl-N- [4- (3,4-dichlorobenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(20) N-ethyl-N- [4- (3,4-methyleneoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(21) N-ethyl-N- [4- (2,6-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(22) N-ethyl-N- [4- (3,4,5-trimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylaminesulfone Acid

(23) N-ethyl-N- [4- (3,4,5-triethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(24) N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as As compound D ').

(25) N-ethyl-N- [8- (3,4-dimethoxybenzoyloxy) octyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(26) N-ethyl-N- [10- (3,4-dimethoxybenzoyloxy) decyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(27) N-benzoyloxy-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as Described as "Compound E").

(28) N-isopropyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as 기술 Compound L ＂).

(29) N-cyclohexyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(30) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-ethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(31) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-propoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(32) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -5,8-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(33) N-ethyl-N-4- (3,4-dimethoxybenzoyloxy) butyl] -6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter referred to as Described as "Compound F").

(34) N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride ( Hereinafter referred to as 'Compound G').

(35) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(36) N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (hereinafter As compound H ′).

(37) N-ethyl-N- [4- (4- (3,4-dimethoxybenzoyloxy) butyl] -8-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (Hereinafter referred to as compound K).

(38) N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -8-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(39) N-ethyl-N- [4- (4-methylbenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

(40) N-ethyl-N- [4- (3,4-dichlorobenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride

The 2-aminotetrarin derivatives of the present invention described above can be prepared by various methods, but representative methods include compounds of the following formula (II) and compounds of the following formula (III) in the presence of a base such as sodium carbonate or anhydrous calcium carbonate. 2-aminotetrazine derivatives of formula (I) can be obtained by heating in conventional organic solvents that do not react with formulas (II) and (III) such as acetone, methyl ethyl ketone, acetonitrile benzene.

In the above structural formula

R ¹ , R ² and R ³ are as defined above,

R ⁴ , R ⁵ , R ⁶ are as defined above except for hydroxyl groups,

A is as defined above, and

X represents a halogen atom.

In this case, when X is a halogen atom other than iodine, the reaction can proceed smoothly by adding sodium iodide.

In addition, the compound of formula (II) and the following formula (IV) do not react with the formulas (II) and (IV) such as benzene, toluene, xylene, chloroform, and the like as bases such as triethylamine and trimethylamine. After reacting in a conventional organic solvent, the compound of formula (V) is synthesized, and then the compound of formula (V) is reacted with lithium hydride aluminum in an organic solvent such as ether, tetrahydrofuran, dioxane, and the like. To synthesize a compound. The compound of formula (VI) is represented by the following formulas (VI) and (VII), such as benzene, toluene, xylene, chloroform, in the presence or absence of a base of the compound of formula (VII) and triethylamine, trimethylamine, etc. The reaction can be carried out in a conventional organic solvent which does not react to obtain 2-aminotetrarin derivative of formula (I).

In the above structural formula

R ⁷ represents a lower alkylene group,

B represents an alkylene group having two carbon atoms less than A.

In the above structural formula

R ¹ , R ² , R ³ , R ⁷ and B are as defined above.

In the above structural formula

R ¹ , R ² and R ³ are as defined above.

In the above structural formula

X and R ⁴ , R ⁵ and R ⁶ are as defined above except that they are hydroxyl groups.

In the case of obtaining a compound of formula (I) wherein R ⁴ , R ⁵ and R ⁶ are hydroxyl groups, the hydroxyl group of the starting compound (III) or (VII) is protected with a protecting group such as benzyl group, and then What is necessary is just to carry out manufacture, and finally, a protecting group is isolate | separated by the method which does not involve cutting | disconnection of ester group in contact reduction etc.

In addition, the structural formula (I) can form acid addition salts, and as diacids, inorganic acids such as hydrochloric acid, hydrous acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, citric acid, methanesulfonic acid, P-toluenesulfonic acid, hydroxyl acid, tartaric acid, citric acid, methanesulfonic acid And organic acids such as organic acids such as -toluenesulfonic acid, fisheries, lactic acid, nitric acid and maleic acid.

Next, the usefulness of the compound of this invention is explained in full detail.

The 2-aminotetrarin derivative of the present invention exhibits excellent mycelial action against smooth muscle organs such as stomach and intestinal tract, and especially exhibits significant mycelial action against the lower digestive tract. It is a very useful compound as a medicine. Table 1 below shows the results of studies on the representative compounds of the present invention on the effects of colon movement by pelvic nerve stimulation on the dog's biological stomach. Also known compound N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -3- (4-methoxyphenyl) -2-propylamine hydrochloride, known as an antifungal for the lower digestive tract. (Hereinafter, referred to as “mebeberine”).

TABLE 1

In addition, in the experiment of Table 1, a ballon method is generally used, but the method is called as follows.

Experimental method of colonic motion due to bone nerve stimulation on dog body (Balloon method). Mongrel dogs weighing 8-15 kg were used without distinction between females and males.

Belt Valbital Hair 30mg / kg Intravenous anesthesia, anesthetized, fixed to the stomach, and open to the lower abdomen central line and water-filled rubber ball from hongmun to descending colon and fixed and fixed 100 Μg / kg was administered by intravenous injection, and the change in the internal pressure was recorded in a graphagram through a low pressure transducer. The stimulation conditions of the pelvic nerve were electrical stimulation with a short wave of frequency: 50 cps, duration: 1 msec, and voltage: 4 V for 5 seconds.

Inhibition rate was calculated by the following equation.

In addition, Table 2 shows the results of studies on the toxicity of the representative compounds of the present invention to the colon movement by neo-tigmin stimulation of rats in rats and the mesothelioma in contrast to mebeberin.

TABLE 2

The details of the experimental operation of Table 2 are as follows.

Experimental method of colonic movement by neostigmine stimulation on rat living body (Balloon method).

Mice of male STD-wistar species weighing 300-400 g were used. Rats were anesthetized with 1 g / kgip of urethane and fixed to the stomach, and a rubber ball filled with water was inserted and fixed from the hongmun to the descending colon, and the change in internal pressure was recorded in a polygraph through a low pressure transducer.

Neostigmine was continuously injected subcutaneously at a rate of 90 µg / kg / hr to maintain constant colon exercise for a long time. In addition, the drug was dissolved in oral distilled water and injected into the stomach at the rate of 0.2ml / 100g through oral cathetel. ED ₅₀ was expressed as the dose which expresses the action in 50% of the animals in use.

In the above Table 1 and Table 2, the compound of the present invention has excellent antifungal action, is also low toxicity, and it is already clear that it is useful as a medicament.

Conventional anticholinergic antifungal drugs act without distinction of the upper and lower part for the gastrointestinal tract, but the compounds of the present invention exhibit selective selective myocardial action for the lower digestive tract. Table 3 below shows the 50% inhibition of gastric contraction (S, ID ₅₀ ) and ₅₀ colonic contractile movements of the dog's pelvic nerve stimulation for dog vagus nerve stimulation. The percent inhibition required (C, ID ₅₀ ) was obtained and the selectivity of mycelial action was studied according to the ratio. In addition, Mebeberin used in comparison with the lower digestive tract is a drug that exhibits a selective mycelial action.

As is apparent from the following Table 3, the representative compound of the present invention has superior selectivity to mebeberine.

TABLE 3

Further experiments to obtain the above Table 3, S, ID ₅₀ is obtained from the following Instruction of.

Mongrel dogs weighing 8-15 kg were used without discrimination between the male and the male.

After anesthesia by pentobarbitalum 30mg / kg intravenous administration, fixation to stomach, incision along central epigastric line, incision of upper gastrointestinal axial axis, insertion of rubber ball filled with water and change of internal pressure for low pressure Transducers were recorded and recorded as polygraphs. As a stimulating condition of the vagus nerve, a short wave of frequency: 20 cps, duration: 1 m sec, and voltage: 8 V was electrically stimulated for 10 seconds and repeated every 3 minutes.

Inhibition rate (%) was calculated by the following formula, and S, ID 50 was the dose when the 50% inhibition rate was indicated.

In addition, and at a dose of time to display a 50% inhibition in the experimental data obtained by the experimental manipulations (which can change the drug dose), such as in the case of Table 1, values of C, ID _50.

In addition, the experimental method with respect to Table 1 and Table 3 is based on the known method (recorded in pages 1 to 14 of the European Journal of Pharmacology 18 (1972)).

The invention is illustrated by the following examples.

Example 1

1.85 g of N-ethyl-1,2,3,4-tetrahydro-2-naphthylamine, 3.9 g of 3,4-dimethoxybenzoic acid-4- iodide butyl ester, 1.1 g of sodium carbonate, and 40 ml of methyl ethyl ketone Are mixed and heated to reflux for 60 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining oil is purified by silica gel chromatography. Hydrogen chloride and ethanol solution were added thereto, and it concentrated under reduced pressure. Crystallized crystallized from acetone ether mixture and filtered and recrystallized from alcohol and ether, N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -1,2,3,4-tetra Colorless powder of hydro-2-naphthylamine hydrochloride 2. 3 g was obtained.

Example 2

(A) 28.0 g of 6-methoxy-2-tetraron, 200 ml of 19% ethylamine ethanol solution, 2, 2 g of platinum oxide, and 10 ml of anhydrous ethanol are mixed and irradiated with an infrared lamp from the outside to carry out contact reduction. After absorbing hydrogen, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was flowed into chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Hydrogen chloride solution was added to the residue and concentrated under reduced pressure. Acetone was added to the residue, and the precipitated crystals were filtered and recrystallized from alcohol and ether to give 9.7 g of colorless crystals of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride. Get

(B) 2.0 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride is mixed with 20 ml of 2N-sodium hydroxide and extracted with chloroform. The chloroform layer was dried and concentrated under reduced pressure, and 3.1 g of 3,4-dimethoxybenzoic acid 4-octabutyl ester, 0.9 g of sodium carbonate, and 40 ml of methyl ethyl tetone were mixed and heated to reflux for 60 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the remaining oily substance was purified by silica gel chromatography, and purified with N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl. ] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine solution is added and concentrated under reduced pressure. The residue was dissolved in acetone, ethyl was added, left at low temperature, the precipitated crystals were collected by filtration, and recrystallized from acetone and an ether mixture, which was then recrystallized from N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl]. 2.65 g of colorless crystals of -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride were obtained.

Example 3

(A) 4.7 g of hydrogen hydride aluminum and 200 ml of anhydrous tetrahydrofuran are mixed and 10 g of anhydrous tetrahydro of 10 g of N-acetyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine is added thereto. A mixture of 100 ml of furan is added dropwise. After stirring for 0.5 hour to room temperature, the mixture was heated to reflux for 4 hours, and a mixture of 4.7 ml of water and 50 ml of tetrahydrofuran was added dropwise under ice-cooling. Then add 4.7 ml of 15% sodium hydroxide and 14 ml of water dropwise. The precipitated insolubles are collected by filtration, and the filtrate is concentrated under reduced pressure. The residue was extracted with chloroform, washed with chloroform and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure by adding hydrogen ethanol solution to the remaining oil. Acetone was added, and the precipitated crystals were filtered and recrystallized from alcohol and ether to obtain 8.9 g of colorless needles of N-ethyl-6-methoxy-1,2,3,4, tetrahydro-2-naphthylamine hydrochloride. All.

All physical data, such as melting | fusing point 231-232 degreeC, melting | fusing point and an infrared absorption spectrum, are consistent with what was obtained by Example 2 (a).

(B) 3,4-dimethoxyanic acid 6-chloro as a free base obtained by a conventional method from 2.0 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 3.1 g of hexyl ester, 1.4 g of sodium dehydrate, 2.0 g of sodium carbonate and 80 ml of methyl ethyl ketone are added and heated to reflux for 90 hours. The reaction solution is concentrated under reduced pressure and the residue is extracted with chloroform.

The chloroform layer was dried over anhydrous sodium sulfate anhydrous and concentrated under reduced pressure. The oily substance was purified by silica gel column chromatography, and purified by N-ethyl-N- (6- (3,4-dimethoxybenzoyloxy) hexyl] -6-meth. Obtain a pale yellow oily substance of oxy-1,2,3,4-tetrahydro-2-naphthylamine, dissolve in hydrogen chloride and ethanol solution, concentrate under reduced pressure, dissolve the residue in acetone, add ether and leave at low temperature. The precipitated crystals were collected by filtration and recrystallized from a mixture of acetone and ether to give N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -6-methoxy-1,2,3,4- Colorless crystal 119 of tetrahydro-3-naphthylamine hydrochloride is obtained.

Example 4

(A) A mixture of 7.4 g of aluminum anhydride and 100 ml of anhydrous methylene chloride is cooled at 50 ° C, and a solution of 5.9 g of 3,4-dimethoxyphenyl acetate chloride and 30 ml of anhydrous methylene chloride is added dropwise thereto. The ethylene is then heavily injected over 15 minutes with vigorous stirring. Then, the mixture was stirred for 3 hours and a half at room temperature, cooled with ice water from the outside, and 40 ml of water was added dropwise.

The ethylene chloride layer was washed with 2N hydrochloric acid, water, saturated sodium bicarbonate water and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily substance. 25 ml of 19% ethylamine ethanol solution, 10 ml of anhydrous ethanol and 0.25 g of platinum oxide were added thereto to carry out catalytic reduction. After hydrogen absorption is completed, the catalyst is filtered off, the filtrate is concentrated under reduced pressure, hydrogen chloride and ethanol solution are added to the residue and concentrated under reduced pressure. Acetone was added, and the precipitated crystals were collected by filtration, 2N aqueous sodium hydroxide solution was added, extracted with chloroform, washed with water, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. The residue is purified by alumina column chromatography. Hydrogen chloride and ethanol solution were added, and the crystal | crystallization obtained by concentrating under reduced pressure was recrystallized from the mixture of anhydrous ethanol and isopropanol, and it was N-Emeth-6,7-dimethoxy- 1,2,3,4- tetrahydro-2-naphth. 1.12 g of colorless needles of butyl hydrochloride were obtained.

(B) N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl amine 390 ml, 3,4-dimethoxy benzoic acid 4-chloro butyl ester 500 mg, sodium iodide N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6,7-dimethoxy was carried out in accordance with Example 3 (b) using 270 mg, 200 mg of anhydrous sodium carbonate, and 30 mg of methylethylkenone. 400 ml of colorless crystals of -1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 5

6.0 g of N-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydronaph-2-tylamine hydrochloride, 9.2 g of 3,4-dimethoxybenzoic acid 6-chlorohexyl ester, sodium iodine 4.6 g 3.3 g sodium carbonate and 150 ml of methyl ethyl ketone, were prepared according to Example 3 (b), followed by N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -6,7-dimethoxy- 7.0 g of colorless needles of 1,2,3,4-tetrahydro-2-naphthylamine hydrochloride were obtained.

Example 6

1.86 g of N-ethyl-1,2,3,4-tetrahydro-2-naphthylamine salt, 2.9 g of 3,4-acid dimethoxybenzoic acid 6-chlorohexyl ester, 1.45 g of sodium iodide, 1.02 g of sodium carbonate, and The procedure was carried out in accordance with Example 3 (b), using 30 ml of methyl ethyl kenone, and N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -1,2,3,4-tetrahydro-2 1.0 g of a colorless oil of naphthylamine hydrochloride was obtained.

Example 7

1.91 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 2.96 g of 3,4-dimethoxybenzoyl (2-dichlorochloroethoxy) ethyl ester, 1.54 g of sodium iodide, 1.07 g of sodium carbonate and 30 ml of methyl ethyl ketone were carried out according to the method shown in Example 3 (b), followed by N-ethyl-N- [2- (2- (3,4-dimethoxybenzoyl). Oxy) ethyl]]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 1.6g was obtained.

Example 8

1.1 g of 6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 1.1 g of 3,4-dimethoxybenzoic acid 4-chlorobutyl ester, 1.0 g of sodium iodide, 1.0 g of sodium carbonate, and [00 (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4- was carried out according to the method shown in Example 3 (b) using 30 ml of methyl ethyl kenone. 0.3 g of colorless tablets of tetrahydro-2-naphthyl hydrochloride are obtained.

Example 9

(A) 5.0 g of P-ethoxyphenyl acetate, 7.0 g of phosphorus pentachloride and 10 ml of anhydrous benzene are mixed and heated at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 20 ml of anhydrous dichloromethane, and the used solution was added dropwise to a mixed solution of 7.3 g of anhydrous aluminum chloride and 80 ml of anhydrous dichloromethane cooled at -50 ° C, and ethylene gas was vigorously added thereto for 20 minutes. Inject. Then stir for 4 hours at room temperature. The reaction solution was added dropwise to 30 ml of water under ice cooling. The dichloromethane layer is separated out and washed with 8% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then water. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, it is obtained as a pale yellow oil of 6-ethoxy-2-tetraron. Thus-reduced 6-ethoxy-2-tetraron was subjected to catalytic reduction with 40 ml of 20% ethylamine ethanol solution and 0.4 g of platinum oxide as it was roughly produced. After the absorption of hydrogen is over, the catalyst is removed by filtration, and the filtrate is depressurized and concentrated. The residue was extracted with chloroform, washed with 2N-sodium hydroxide and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hydrogen chloride and ethanol solution were added to the residue, and concentrated under reduced pressure. The precipitated crystals are recrystallized from a mixture of ethanol and ether to obtain 1.4 g of colorless needles of N-ethyl-6-ethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride.

(B) 1.0 g of N-ethyl-6-ethoxy-1,2,3,4-tetrahydro-2-naphthylamine acid salt, 1.2 g of 3,4-dimethoxybenzoic acid 4-chlorobutyl ester, sodium iodide N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6 was carried out according to the method shown in Example 3 (b) with 1.0 g, 1.0 g of sodium carbonate and 40 ml of methyl ethyl ketone. 0.6 g of colorless crystals of -ethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloric acid were obtained.

Example 10

(A) N-ethyl-6-n-propoxy-1,2,3,4-tetrahydro-2 was carried out according to the method shown in Example 9 (A) using 5.0 g of Pn-propoxyphenylacetic acid. 1.1 g of colorless crystals of naphthylamine hydrochloride are obtained.

(B) 1.0 g of N-ethyl-6-n-propoxy-1,2,3,4-tetrahydro-2-naphthylamine acid salt, 1.2 g of 3,4-dimethoxybenzoic acid 4-chloro butyl ester, iodine N-ethyl-N- [4- (3,4-ditylmethoxybenzoyloxy) butyl]-according to the method shown in Example 3 (b) using 1.0 g of sodium sulfate, 1.0 g of sodium carbonate and 40 ml of methyl ethyl ketone. 0.7 g of colorless needles of 6-n-propoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 11

(A) 20 g of 6-methoxy-2-tetraron, 22 g of isopropylamine, 0.5 g of platinum oxide, and 20 ml of anhydrous ethanol were used in the same manner as described in Example 2 (a), and N-isopropyl-6- 13.9g of colorless needles of methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

(B) N-isopropyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine salt 1.6g, 3,4-dimethoxy 4-benzoic acid iodide butyl ester 2.5g, sodium carbonate N-isopropyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy- was carried out according to the method shown in Example 2 (b) using 0.65 g and 40 ml of methyl ketone. 0.95 g of colorless crystals of 1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

[12]

(A) N-propyl-6 was carried out according to the method shown in Example 2 (a) using 21.0 g of 6-methoxy-2-tetraron, 22 g of n-propylamine, 0.5 g of platinum oxide, and 25 ml of anhydrous ethanol. 25.0 g of colorless crystals of -methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

(B) Nn-propyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine acid salt 2.0g, 3,4-dimethoxybenzoic acid 4-iodide ester 3.15g, sodium carbonate 1.9 g and 50 ml of methyl ethyl ketone according to the method shown in Example 2 (b), Nn-propyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1, 2.35 g of a colorless oil of 2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 13

N-methyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl amine salt 2.0g, 3,4-dimethoxybenzoic acid 4-iod butyl ester 3.3g, sodium carbonate 2.1g and methyl N-methyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3 was carried out by the method shown in Example 2 (b) using 50 ml of ethyl ketone. 1.9 g of colorless oils of, 4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 14

2.0 g of N-ethyl-1,2,3,4-methoxytetrahydro-2-naphthylamine acid salt, 3.3 g of 3,4,5-trimethoxybenzoic acid 4-iodine butyl ester, 0.9 g of sodium carbonate and methyl N-ethyl-N- [4- (3,4,5-trimethoxybenzoyloxy) butyl] -6-methoxy-1, obtained by the method shown in Example 2 (b) using 40 ml of ethyl ketone, The organic base of 2,3,4-tetrahydro-2-naphthylamine is treated with methanesulfonic acid to obtain 1.5 g of a pale yellow lactate of methanesulfonic acid salt.

Example 15

N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl amine salt 2.5g, 3,4-dimethoxybenzoic acid-2- iodide ethyl ester 3.6g, sodium carbonate 1, 2g And N-ethyl-N- [2- (3,4-dimethoxybenzoyloxy) ethyl] -6-methoxy-1,2 according to the method shown in Example 2 (b) using 40 ml of methyl ethyl ketone. 2.9 g of colorless crystals of, 3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 16

N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 2.0 g, 3,4-dimethoxybenzoic acid-3-iodide propyl ester 3.4 g, sodium carbonate 1.2 g and methyl N-ethyl-N- [3- (3,4-dimethoxybenzoyloxy) propyl] -6-methoxy-1,2,3 according to the method shown in Example 2 (b) using 60 ml of ethyl ketone. 2.4 g of colorless crystals of, 4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 17

2.1 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 3.2 g of P-methoxy-benzoic acid 4-chlorobutyl ester, 3.0 g of sodium iodide, sodium carbonate N-ethyl-N- [4- (4-methoxybenzoyloxy) butyl] -6-methoxy-1, carrying out the procedure as described in Example 2 (b) using 3.0 g and 60 ml of methyl ethyl ketone. 1.34 g of colorless crystals of 2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 18

1.3 g of N-ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 1.8 g of 3,4-dimethoxybenzoic acid 4-chlorobutyl ester, 0.9 g of sodium iodide g, 0.8 g sodium carbonate and 80 ml of methyl ethyl ketone according to the method shown in Example 3 (b), N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -5,8 0.8 g of an oil of dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride is obtained.

In addition, the synthesis method of the raw material compound N-ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl amine salt is as follows. 5,8-dimethoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylamine 0.7g, 15% paradium 0.3g, 78% perchloric acid 0.5ml, acetic acid 30ml mixed incandescent lamp It is irradiated and reduced by irradiation. After absorbing the calculated amount of hydrogen, the catalyst was filtered off, potassium acetate was added to the filtrate at 0, 5 g. After stirring, the insolubles were filtered out, the filtrate was concentrated under reduced pressure, and 10 ml of acetic acid and 2 ml of acetic anhydride were added to the remaining 0.7 g of reddish brown syrup. After warming in water for 2 hours, concentrated under reduced pressure, extracted with dichloromethane, washed dichloromethane layer with water, dried and dried under reduced pressure, and the residue was recrystallized from acetone-ether and N-acetyl-5,8-dimethoxy-1,2,3,4 0.3 g of tetrahydro-2-naphthyl amine salt is obtained.

1 g of hydrogenated lithium almenium was suspended in 20 ml of tetrahydrofuran, and 2.0 g of N-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine was dissolved in 7 ml of tetrahydrofuran. The solution is added dropwise. After the addition, the mixture was heated to reflux for 2 hours 30 minutes. A mixture of 1.0 ml of tetrahydrofuran and 10 ml of ice-cold water is added dropwise. Then 1 ml of 15% sodium hydroxide and 3 ml of water are added dropwise. The precipitate was filtered, the filtrate was concentrated under reduced pressure, extracted with chloroformium, and the chloroform layer was washed with water, and concentrated under reduced pressure. Hydrogen chloride and ethanol solution were added to the residue. 1.3 g of 5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained. Melting point 240-242 ° C

Example 19

N-ethyl-5-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 2.1 g, 3,4-dimethoxybenzoic acid-4-chlorobutyl ester 3.2 g, sodium iodide 3.0 g N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -5-methism was carried out in accordance with the method shown in Example 3 (b) using 3.0 g of sodium carbonate and 90 ml of methyl ethyl ketone. 2.2 g of colorless crystals of oxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 20

N-ethyl-8-methoxy-1,2,3,4-tetrahydro-2-naphthyl amine salt 2.4g, 3,4-dimethoxybenzoic acid-4-chlorobutyl ester 3.7g, sodium iodide 3.7g , N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -8-methoxy using 100 ml of anhydrous sodium carbonate and methyl ethyl ketone according to the method shown in Example 3 (b) 1.5 g of colorless crystals of -1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 21

3.5 g of N-ethyl-8-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 6.2 g of 3,4-dimethoxybenzoic acid-6chlorohexyl ester, 3.1 g of sodium iodide, sodium carbonate 2.2 g, 100 ml of methyl ethyl ketone was carried out according to the method shown in Example 3 (b), followed by N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -8-methoxy- 4.8 g of pale yellow oil of 1,2,3,4-tetrahydro-2-naphthylamine hydrochloride is obtained.

Example 22

(A) 12.4 g of 7-methoxy-2-tetraron, 60 ml of 19% ethylamine ethanol solution and 0.4 g of platinum oxide were used in the same manner as described in Example 2 (A), and N-ethyl-7-meth 10.7 g of colorless crystals of oxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

(B) N-ethyl-7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 2.0g, 3,4-dimethoxybenzoic acid 4-iodide ester 3.2g, sodium carbonate 3.0 g and 50 ml of methyl ethyl ketone were carried out according to the method shown in Example 2 (b), and N-ethyl-NN- [4- (3,4-dimethoxybenzoyloxy) butyl] -7-methoxy-1 1.2 g of colorless crystals of, 2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 23

(A) Using 17.0 g of 6,7-methylenedioxy-2-tetraron, 120 ml of 19% ethylamine ethanol solution, 0.4 g of platinum oxide, and 100 ml of anhydrous ethanol, according to the method shown in Example 2 (A) 7.2 g of colorless needles of N-ethyl-6,7-methyleneoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

(B) 2.0 g of N-ethyl-6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 3.3 g of 3,4-dimethoxybenzoic acid 4-chlorobutyl ester, N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] was carried out in accordance with the method shown in Example 3 (b) using 3.0 g of sodium oxide, 3.0 g of sodium carbonate, and 40 g of methyl ethyl ketone. 1.2 g of colorless needles of -6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 24

(A) 3- (methoxycarbonyl) into a mixture of 8.8 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 6.1 g of triethylamine, and 80 ml of anhydrous benzene A solution of 7.1 g propionyl chloride dissolved in 10 ml of anhydrous benzene is added dropwise. After heating for 2 hours and 30 minutes, the reaction solution left at room temperature under reflux is washed in the order of 2N hydrochloric acid, water, 2N-sodium hydroxide and water, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give 12.5 g of pale yellow color of N-ethyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine. Get

(B) 8.3 g of lithium aluminum hydride is suspended in 200 ml of anhydrous tetrahydrofuran. Here, 14.5 g of N-ethyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and anhydrous tetrahydrofuran 100 ml of the mixture is added dropwise. After refluxing for 4.5 hours, a mixture of 8.3 ml of water and 50 ml of tetrahydrofuran was added dropwise under ice-cooling. Then, 8.3 ml of 15% sodium hydroxide is added dropwise, and finally 25 ml of water is added dropwise. The precipitated insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue was extracted with benzene, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2- 10.8 g of colorless oil (naphthylamine) was obtained. The organic base obtained in this manner is treated with hydrogen chloride and ethanol solution to obtain hydrochloride as colorless crystals.

(C) 2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride are heated and refluxed for 4 hours. N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro was dissolved in 10 ml of anhydrous benzene with 3,4-dimethoxybenzoic acid chloride obtained by concentration under reduced pressure. It is added dropwise in a mixture of 4.0 g of 2-naphthylamine, 2.2 g of triethylamine and 50 ml of anhydrous benzene. After dropping, the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 3 hours 30 minutes. The reaction solution is washed with water, 2N-sodium hydroxide and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naph. A colorless oily product of tilamine was obtained. A hydrogen chloride ethanol solution is added to this oily substance, concentrated under reduced pressure, and the residue is left at a low temperature with a mixture of acetone ether to precipitate crystals. After filtration and collection, the mixture is left at low temperature with a mixture of acetone and ether to precipitate crystals. Filtration and collection recrystallized from a mixture of acetone and ether, and then N-ethyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2 3.0 g of colorless crystals of naphthylamine hydrochloride are obtained. Melting point 139 to 140

This melting point, infrared spectrum, and the like were consistent with those of the compound obtained in Example 2 (b).

Example 25

(A) N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride 7.5 g of free base and 5- (ethoxycarbonyl) which can be carried out as usual. N-ethyl-N- [5- (ethoxycarbonyl) pentanoyl] -6-methoxy-1,2,3 was carried out according to the method shown in Example 24 (A) using 6.7 g of pentanoyl chloride. 10.8 g of a colorless oil of, 4-tetrahydro-2-naphthylamine were obtained.

(B) 10.8 g of N-ethyl-N- [5- (ethoxycarbonyl) pentanoyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and lithium aluminum hydride 4.5 g was used according to the method shown in Example 24 (b) to prepare N-ethyl-N- [6-hydroxyhexyl] -6-methoxy-1,2,3,4-tetrahydro-2- 8.2 g of pale yellow oil of naphthylamine is obtained.

(C) 3,4-dimethoxybenzoic acid chloride obtained from 5.2 g of 3,4-dimethoxybenzoic acid and N-ethyl-N- (6-hydroxyhexyl) -6-methoxy-1,2,3,4 N-ethyl-N- [6- (3,4-dimethoxybenzoyloxy) hexyl] -6 was carried out according to the method shown in Example 24 (C) using 8.2 g of tetrahydro-2-naphthylamine. 7.3 g of colorless crystals of -methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained. Melting point 119 to 120 ° C. This melting point and infrared spectrum are the same as those obtained in Example 3 (b).

[Example 26]

(A) Example using 3 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride and 2.9 g of tanoyl chloride in 7- (ethoxycarbonyl) It carried out according to the method shown to 24 (a), N-ethyl-N- [7- (ethoxycarbonyl) heptanoyl] -6-methoxy-1,2,3,4-tetrahydro-2-naph 4.6 g of a reddish brown oil of tilamine is obtained.

(B) N-ethyl-N- [7- (ethoxycarbonyl) heptanoyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine acid 4.6 g, lithium aluminum hydride It carries out according to the method shown in Example 24 (b) using 2.0g. 3.4 g of a colorless oil of N-ethyl-N- (8-hydroxyoctyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine are obtained.

(C) 3.4 g of N-ethyl-N- (8-hydroxyoctyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 2.05 g of 3,4-dimethoxybenzoic acid Using the method of Example 24 (C). 3.5 g pale yellow oil of N-ethyl-N- (8- (3,4-dimethoxybenzoyloxy) octyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride Get

Example 27

(A) using 6.11 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride and 7.1 g of 9- (ethoxycarbonyl) nonisoyl chloride N-ethyl-N- [9- (ethoxycarbonyl) nodinoyl] -6-methoxy-1,2,3,4-tetrahydro-2- was carried out according to the method shown in Example 24 (A). 11.4 g of a pale yellow oil of naphthylamine is obtained.

(B) 11.4 g of N-ethyl-N- [9- (ethoxycarbonyl) nonanoyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine acid and hydrophobicity Was carried out according to the method shown in Example 24 (A) using 5.2 g of dium aluminum, and N-ethyl-N- (10-hydroxydecyl) -6-methoxy-1,2,3,4-tetrahydro- 9.3 g of oil of 2-naphthylamine are obtained.

(C) 9.3 g of N-ethyl-N- (10-hydroxydecyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 5.17 g of 3,4-dimethoxybenzoic acid N-ethyl-N- [10- (3,4-dimethoxybenzoyloxy) decyl) -6-methoxy-1,2,3,4 according to the method shown in Example 24 (C) using 8.8 g of an oil of tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 28

(A) 0.6 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl-amine hydrochloride and 0.5 g of 2- (ethoxycarbonyl) -2-methylpropionyl chloride N-ethyl-N- [2- (ethoxycarbonyl) -2-methylpropionyl] -6-methoxy-1,2,3, which was prepared according to the method shown in Example 24 (a) using 0.68 g of an oil of 4-tetrahydro-2-naphthylamine is obtained.

(B) N-ethyl-N- [2- (ethoxycarbonyl) -2-methylpropionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine 0.66 g, It was carried out according to the method shown in Example 24 (b) using 0.55 g of hydrium aluminum hydride, and N-ethoxy-N- (3-hydroxy-2,2-dimethylpropyl-6-methoxy-1, 0.5 g of a colorless oil of 2,3,4-tetrahydro-2-naphthylamine is obtained.

(C) N-ethyl-N- (3-hydroxy-2,2-dimethylpropyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthyl 0.45 g and 3, N-ethyl-N- [3- (3,4-dimethoxybenzoyloxy) -2,2-dimethyl-propyl was carried out according to the method shown in Example 24 (C) using 0.3 g of 4-dimethoxybenzoic acid. 0.2 g of colorless crystals of] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 29

(A) 13.8 g of N-isopropyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride and 9.1 g of 3- (methoxycarbonyl) propionyl chloride N-isopropyl-N- [3-methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphth, carried out according to the method shown in Example 24 (a). 17.5 g of oil of tilamine is obtained.

(B) 17.5 g of N-isopropyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and lithium hydride Performing according to the method shown in Example 24 (b) using 7.2 g of aluminum, and followed by N-isopropyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro- 12.85 g of an oil of 2-naphthylamine are obtained.

(C) 12.85 g of N-isopropyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthyl-amine hydrochloride and 3,4-dimethoxy N-isopropyl-N- [4- (3,4-dimethoxy-1,2,3,4-tetrahydro-2- was carried out according to the method shown in Example 24 (C) using 8.12 g of benzoic acid. Obtained 16.2 g of colorless needles of naphthylamine hydrochloride Melting point 172-174 DEG C. The melting point and infrared spectrum of this obtained were consistent with those obtained in Example 11 (b).

Example 30

Example 24 using 15 g of (n) Nn-propyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride and 9.7 g of 3- (methoxycarbonyl) propionyl chloride Nn-propyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine was carried out according to the method (a). 19.9 g of oil is obtained.

(B) 19.8 g of Nn-propyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 10 g of lithium hydride Nn-propyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthyl was carried out according to the method shown in Example 24 (b) using 13.5 g of an oil of amine is obtained.

(C) 13.45 g of Nn-propyl-N- (4- (hydroxybutyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 8.5 g of 3,4-dimethoxybenzoic acid Colorless syrup of Nn-propyl-N- [4- (3,4-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride using 19.0 g of the product is obtained, which is consistent with the infrared spectrum obtained in Example 12 (b).

Example 31

5.3 g of (a) 6-methoxy-2-tetraron, 3 g of cyclohexylamine, and 70 ml of anhydrous ethanol were heated to reflux for 7 hours. 0.3 g of platinum oxide is added thereto, catalytic reduction is carried out. After the absorption of hydrogen gas is completed, the catalyst is filtered off, the filtrate is concentrated under reduced pressure, and a saturated hydrogen chloride ethanol solution is added and concentrated under reduced pressure. Acetone was added to the residue, followed by stirring. The precipitated crystals were collected and recrystallized from a mixture of ethanol and ether. 5.0 g of colorless needles are obtained.

(B) 5.0 g of N-cyclohexyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride and 2.8 g of 3- (methoxycarbonyl) propionyl chloride N-cyclohexyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2- was carried out according to the method shown in Example 24 (A). 3.5 g of reddish brown oil of naphthylamine is obtained.

(C) N-cyclohexyl-N- [3- (methoxycarbonyl) propionyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine 1.87 g lithium aluminum hydride N-cyclohexyl-N- (4- (hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro- was carried out according to the method shown in Example 24 (b) using 0.95 g. 1.45 g of a yellow oil of 2-naphthylamine is obtained.

(D) N-cyclohexyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine 2.8 g and 3,4-dimethoxybenzoic acid 2.0 N-cyclohexyl-N-4- (3,4-dimethoxybenzoyloxy) -butyl-6-methoxy-1,2,3, which was prepared according to the method shown in Example 24 (C) using g. 2.6 g of pale yellow oil of 4-tetrahydro-2-naphthylamine hydrochloride are obtained.

Example 32

Example 24 (C) using 0.2 g of N-ethyl-N- (4-hydroxybutyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 0.16 g of benzoic acid chloride 0.07 g of colorless crystals of N-ethyl-N- (4-benzoyloxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride are obtained by following the method shown in .

Example 33

Example 24 (using 1.4 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 1.0 g of piperonic acid) C) N-ethyl-N- [4- (3,4-methyleneoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naph 0.82 g of colorless crystals of tilamine hydrochloride are obtained.

Example 34

1.5 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetra-hydro-2-naphthylamine and 1.0 g of 2,6-dimethoxybenzoic acid are used N-ethyl-N- [4-2,6-dimethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro was carried out according to the method shown in Example 24 (C). 0.55 g of an oil of 2-naphthylamine hydrochloride is obtained.

Example 35

Example using 0.2 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 0.132 g of P-ethoxybenzoic acid N-ethyl-N- [4- (ethoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine was carried out according to the method shown in 24 (C). 0.18 g of colorless crystals of hydrochloride are obtained.

Example 36

Example using 0.2 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 0.15 g of Pn-propoxycyanic acid N-ethyl-N- [4- (4-n-propoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2 was carried out according to the method shown in 24 (C). 0.23 g of colorless crystals of naphthylamine hydrochloride were obtained.

Example 37

0.2 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 0.2 g of 3,4,5-triethoxy aromatic acid N-ethyl-N- [4- (3,4,5-triethoxybenzoyloxy) butyl] -6-methoxy-1,2, which was prepared according to the method shown in Example 24 (C) using 0.2 g of an oily product of 3,4-tetrahydro-2-naphthylamine hydrochloride was obtained.

Example 38

0.28 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 0.22 g of 3-methoxy-4-ethoxybenzoic acid N-ethyl-N- [4- (3-methoxy-4-ethoxybenzoyloxy) butyl] -6-methoxy-1,2, which was prepared according to the method shown in Example 24 (C) using 0.2 g of colorless oils of 3,4-tetrahydro-2-naphthylamine hydrochloride were obtained.

Example 39

Example using 0.9 g of m-methoxybenzoic acid and 1.5 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine N-ethyl-N- [4- (3-methoxybenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naph was carried out according to the method shown in 24 (C). 0.85 g of a colorless powder of tilamine hydrochloride is obtained.

Example 40

Example 24 using 0.8 g of P-toluic acid and 1.5 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine N-ethyl-N- [4- (4-methylbenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine was carried out according to the method described in (C). 1.15 g of colorless powder of hydrochloride are obtained.

Example 41

Using 2.0 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 1.7 g of 3,4-dichlorobenzoic acid chloride N-ethyl-N- [4- (3,4-dichlorobenzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro- was carried out according to the method shown in Example 24 (C). 1.5 g of colorless needles of 2-naphthylamine hydrochloride are obtained.

Example 42

2.0 g of N-ethyl-N- (4-hydroxybutyl) -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 2.5 g of 3,4-bis (benzyloxy) benzoic acid N-ethyl-N- [4- (3,4-bis (benzyloxy) benzoyloxybutyl] -6-methoxy-1,2,3 using the method shown in Example 24 (C) using 3.0 g of a colorless powder of, 4-tetrahydro-2-naphthylamine hydrochloride are obtained.

2.5 g of N-ethyl-N- [4- (3,4-bis (benzyloxy) benzoyloxy) butyl] -6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 70 ml of water, 70 ml of ethanol, and 0.5 g of 5% palladium carbon were mixed with magenta in a reduced phase under normal pressure.

After absorbing the calculated amount of hydrogen, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. N-ethyl-N- [4- (3,4-dihydroxybenzoyloxy) butyl] -6-methoxy-1,2, 1.5 g of 3,4-tetrahydro-2-naphthylamine hydrochloride is obtained as a colorless syrup.

Claims (1)

A method for preparing the 2-aminotetrarin derivative of the following formula (I) by reacting a compound of the following formula (II) with a compound of the following formula (III).

In the above structural formula R ¹ and R ² represent the same or different hydrogen atoms, lower alkoxy groups or two together to represent a lower alkylene dioxy group, R ³ represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, and R ⁴ , R ⁵ , R ⁶ represents the same or different hydrogen atom, lower alkoxy group, lower alkyl group, halogen group, hydroxyl group or two together to represent a lower alkylene dioxy group, A is an alkylene group having 2 to 10 carbon atoms or straight or branched chain or intermediate Represents an alkylene group having an ether bond as an oxygen atom, and X represents a halogen atom (however, in the formula (III), the hydroxyl groups of R ⁴ , R ⁵ , and R ⁶ are protected by a protecting group, and then a protecting group is advantageous after the reaction).