KR0147888B1 - 3-pyrrolidone derivatives - Google Patents

Abstract

The present invention relates to novel 3- (1-aminocycloalkyl) pyrrolidine derivatives which can be used as useful intermediates for the preparation of pyridone carboxylic acid antimicrobials (aka quinolone antimicrobials) or beta-lactam antibiotics and methods for their preparation. .

The novel 3- (1-aminocycloalkyl) pyrrolidine derivatives provided according to the invention are represented by general formula (I).

In which R ₁ , R ₂ or R ₃ are the same as or different from each other, hydrogen, methyl or ethyl; R ₄ is hydrogen, methyl, ethyl, propyl or allyl; R ₅ is hydrogen, methyl, ethyl, propyl, allyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbon Carbonyl, substituted or unsubstituted benzyl, or substituted or unsubstituted benzenesulfonyl; R ₆ is hydrogen, methyl, ethyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, trityl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, or substituted Or unsubstituted benzenesulfonyl; n is 1, 2, 3 or 4.

Description

3- (1-aminocycloalkyl) pyrrolidine derivatives and preparation method thereof

The present invention relates to a novel 3- (1-aminocycloalkyl) pyrrolidine derivative which can be used as an effective intermediate for the preparation of pyridone carboxylic acid antimicrobial agents (also known as quinolone antimicrobials) or beta-lactam antibiotics and a method for preparing the same. .

EP-0208210 and 0191451 disclose that pyridone carboxylic acids prepared using various 3-aminopyrrolidine or 3-aminomethylpyrrolidine derivatives are useful as antimicrobial agents, and JMDomagala (J. Med. Chem., 1992, 35, 4745; 1993, 36, 871; 1993, 36, 4139) and D. Bouzard (J. Med. Chem., 1992, 35, 518) and others prepared from pyrrolidine derivatives. Many pyridine carboxylic acids have been published and investigated.

Pyridone carboxylic acid antimicrobials prepared from pyrrolidine derivatives are known to be much more effective against Gram-negative bacteria as well as Gram-positive bacteria in the treatment of bacterial infections than pyridine carboxylic acid antimicrobials prepared from piperazine derivatives represented by ciprofloxacin, Solubility problems and toxicity problems of drugs are sometimes caused. The present inventors have extensively researched to solve this problem, and provide a compound of the present invention, an intermediate thereof, and a method for preparing the same, wherein the 1-aminocycloalkyl group is substituted at the 3 position of pyrrolidine.

The novel 3- (1-aminocycloalkyl) pyrrolidine derivatives provided according to the invention are represented by general formula (I).

Wherein R _1, R ₂ or R ₃ are the same or different from each other and are hydrogen, methyl or ethyl; R ₄ is hydrogen, methyl, ethyl, propyl or allyl; R ₅ is hydrogen, methyl, ethyl, propyl, allyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxy Carbonyl, substituted or unsubstituted benzyl, or substituted or unsubstituted benzenesulfonyl; R ₆ is hydrogen, methyl, ethyl, C ₁ -C ₆ acyl, C ₂ -C ₆ isyl, C ₂ -C ₆ alcoholcicarbonyl, trityl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxycarbonyl , Aryloxycarbonyl, or substituted or unsubstituted benzenesulfonyl; n is 1, 2, 3, or 4.

R ₅ or R ₆ in the compounds represented by formula (I) in most cases comprise aminoprotecting groups which can be removed by, for example, catalytic reduction, chemical reduction or other commonly known conditions.

The present invention includes salts formed in the amino group of the compound represented by the general formula (I), for example salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid; Salts with organic carboxylic acids such as tartaric acid, formic acid, oxalic acid, citric acid, formic acid, maleic acid, acetic acid, trifluoroacetic acid and the like; These include salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, naphthalenesulfonic acid and the like.

If the compound represented by formula (I) and salts thereof have optical isomers, the present invention includes all of its isomers, crystalline forms, solvates and hydrates.

Compounds of the present invention can be prepared, for example, according to the following routes of production.

R _1, R _2, R _3, R _4, R _5, R ₆ , and n in the formula of the above pathway have the same meaning as defined above; R ₇ represents methyl or ethyl. Formulas (VII) and (VIII) may form salts and salts thereof include salts having the same meaning as salts of compounds of formula (I).

Each step of the generation path is described below.

1) The compound of formula (III) is a Wittig reaction or horner, which is a conventional method for preparing a double bond using an appropriate in-lide from an aldehyde or keto group of formula (II). It can be obtained by performing the Homer-Emmons reaction. For example, triethylphosphonoacetate is reacted with sodium hydride to prepare phosphorus-yl, and then reacted with an aldehyde of formula (II) (R ₂ is hydrogen), where the double bond is a trans isomer. R ₂ , R ₃ is hydrogen, R ₇ is ethyl) and the reaction solvent is suitable with ethers such as tetrahydrofuran, dioxane, diglyme or ether and the reaction temperature is from 0 ℃ to reflux of the solvent Temperature, preferably from room temperature to 40 ° C.

2) The compound of general formula (IV) can be obtained by carrying out the compound of general formula (III) with a compound such as nitromethane, nitroethane or nitropropane and the Michael addition reaction commonly known in the reaction. The nitroalkane compound used is used as a reaction solvent and reagent. To promote the reaction, tetramethylguanidine or piperidine may be added as a catalyst and the reaction temperature may be performed at a boiling temperature of 0 ° C. to a solvent, preferably at 40 ° C. to 60 ° C. for several hours.

3) The compound of formula (V) can be obtained by reducing the nitro group to an amino group by carrying out a catalytic reduction reaction of the compound of formula (IV), and ring closing by a warming reaction. The catalytic reduction reaction of the nitro group can be carried out in an alcoholic solvent which does not adversely affect the reaction such as methanol or ethanol using Raney-Nickel, and hydrogen gas can be supplied at atmospheric pressure or under pressure. Hydrogen gas supply under pressure is suitable if the pressure up to 100psi, the reaction can be carried out at a boiling point temperature of 0 ℃ to the solvent, preferably from room temperature to 60 ℃. In addition, the ring closure reaction can be carried out in a few minutes to several ten minutes while heating to the boiling point temperature of the solvent using ethanol or toluene.

4) The compound of formula (VI) can be obtained by reacting the compound of formula (V) with sodium hydride and again with an alkyl halide such as benzyl bromide or benzyl chloride. The solvent used may include ethers such as tetrahydrofuran, dioxane or anisole and N, N-dimethylformamide (DMF) or N, N-dimethylacetamide, and the reaction temperature is from 0 ° C. to solvent. The reaction can be completed within 24 hours at a boiling point temperature of, preferably from room temperature to 40 ° C.

5) Compounds of formula (VII) are applicable when the aminoprotecting group (R ₅ ) of the compound of formula (VI) is a group such as acyl, alkoxycarbonyl, benzyloxycarbonyl, alkoxycarbonyl or trityl It can be obtained by carrying out the known catalytic reduction, chemical reduction and hydrolytic deprotection under acidic or basic conditions. For example, it is carried out in hydrochloric acid, bromic acid, sulfuric acid, acetic acid, trifluoroacetic acid or a mixed solvent thereof when the protecting group R ₅ is t-butoxycarbonyl, and palladium- when R ₅ is benzyloxycarbonyl. It is carried out by hydrogen reduction using a carbon catalyst.

6) The compound of general formula (VIII) can be obtained by reducing the compound of general formula (VII) with an amide group by using a reducing agent such as lithium aluminum hydride. The solvent is ether or tetrahydrofuran. The reducing agent used may use at least 1 mol to 3 mol per mol of compound (VII) and the reaction temperature may be carried out at -10 ° C to the boiling point temperature of the solvent, preferably 0 ° C to 15 ° C.

7) The compound of general formula (I) may be prepared from a compound of general formula (VIII) or a compound of general formula (VI), for example in each case as follows.

i) Compounds of formula (VIII) in the presence of any base, using reagents such as acid halides such as acetyl chloride or chloroacetyl chloride, benzyloxycarbonyl halides, benzenesulfonic acid halides and dialkyldicarbonates, etc. In a solvent which does not adversely affect the reaction, by protecting the amino group according to methods commonly known in the reaction, or ii) reducing the compound of formula (VI) in the same manner as mentioned in step 6 Compounds of can be obtained.

In contrast, when R ₄ in the compound of formula (I) is hydrogen, a reagent such as iodine methane, iodine ethane, iodine propane or allyl bromide is used from the compound, and the reaction is performed in a solvent which does not adversely affect the reaction in the presence of any base. The compound of formula (I) wherein R ₄ is methyl, ethyl, propyl, or allyl can be obtained, and formaldehyde and formic acid when R ₄ and R ₅ in the compound of formula (I) are both hydrogen Can be used to obtain compounds of formula (I) wherein both R ₄ and R ₅ are methyl.

Any of the bases mentioned above include metal bases such as sodium, potassium, potassium tert-butoxide, sodium hydride, organic bases such as triethylamine, diethylamine, pyridine, quinoline and the like, sodium bicarbonate, sodium carbonate, carbonate It means an inorganic base such as potassium.

8) Compounds of the general formula (I, R ₆ is hydrogen) are subject to catalytic reduction, chemical reduction, or the amino protecting group R ₆ of the compound of the general formula (I, R ₆ It is obtained by removal by hydrolysis under acidic and basic conditions. Palladium-carbon is suitable as a catalyst for the catalytic reduction reaction, and a hydrogen gas of normal pressure or pressure should be supplied. Methanol, ethanol or propanol and mixed solvents thereof or aqueous solvents thereof which do not adversely affect the reaction may be used, and the reaction temperature is carried out in a few hours at a boiling point temperature of the solvent, preferably from room temperature to 50 ° C. Can be. Alternatively, hydrolysis under acidic or basic conditions may be carried out under acidic conditions such as hydrochloric acid, bromic acid, sulfuric acid, trifluoroacetic acid or a mixed solvent thereof and basic conditions such as sodium hydroxide, potassium hydroxide and the like. In addition, compounds of the general formula (I, R ₆ is hydrogen) include acid halides such as acetyl chloride and chloroacetyl chloride, organic anhydrides such as acetic anhydride or trifluoroacetic acid, alkoxycarbonyl halide, benzyloxycarbonyl halide, Reagents such as benzenesulfonic acid halides and dialkyl dicarbonates can be converted back to compounds of the general formula (I, R ₆ as aminoprotecting groups mentioned on page 4) according to methods commonly known in the reaction. .

Compounds of general formula (I) can be separated and purified according to conventional methods such as column chromatography, crystallization, distillation or extraction, depending on the properties of the amino substituted groups R _4, R ₅ .

Compound (I) of the present invention may function as an intermediate useful for preparing quinolone antibacterial or betalactam antibiotics. For example _, the following general formulas Xa and Xb prepared using the compound of the present invention (I; R _1, R ₂ , R _3, R _4, R ₅ and R are all hydrogen) are Gram-negative bacteria as shown in Table 1. Of course, it shows excellent antimicrobial effect against Gram-positive bacteria. This proves that compound (I) of the present invention is a useful intermediate for the preparation of various antibacterial agents.

The content of the present invention will be described in detail by describing the following Examples. However, the present invention is not limited only to these embodiments.

Example 1

Ethyl (E) -3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-propenate

Sodium hydride (60%, 0.44 g) was suspended in tetrahydrofuran (25 ml), cooled to 0 ° C., and triethyl phosphphotoacetate (2.35 g) was added dropwise and stirred at room temperature for 1 hour. To this solution was added [1- (t-butoxycarbonyl) amino] cyclopropane carboxyaldehyde (1.85 g) dissolved in tetrahydrofuran (5 ml) and stirred at room temperature for 16 hours. Acetic acid (0.7 ml) was added and water was added again, followed by extraction three times with ether, and the ether layer was washed sequentially with dilute sodium hydrogen carbonate solution and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and silica gel column separation (eluent, hexane: ethyl acetate = 4: 1) gave a colorless crystalline title compound (2.2 g).

Example 2

Ethyl 3- [1- (t-butoxycarbonyl) amino] cyclopropyl-4-nitrobutannoate

Ethyl (E) -3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-propennoate (2.20 g) is dissolved in nitromethane (15 ml) and tetramethylguanidine (0.3 ml) Addition was followed by stirring at 45-50 ° C. for two days. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 10% citric acid and water, and dried over magnesium sulfate to obtain an oily title compound (2.54 g).

Example 3

3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-pyrrolidone

Ethyl 3- [1- (t-butoxycarbonyl) amino] cyclopropyl-4-nitrobutannoate (2.50 g) is dissolved in ethanol (40 ml), and Raney-nickel (1.5 ml) is added, followed by hydrogen. The reaction was performed at room temperature for 24 hours while injecting gas. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, toluene (20 ml) was added and the mixture was heated to reflux for 40 minutes. Toluene was concentrated under reduced pressure, crystallized by adding ether, and the resulting crystals were filtered to give a white title compound (1.36 g).

Example 4

1-benzyl-3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-pyrrolidone

Dissolve 3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-pyrrolidone (1.20 g) in N, N-dimethylformamide (5 ml) and sodium hydride (55%, 240 mg) Was added in small portions and stirred at room temperature for 40 minutes. Benzyl bromide (941 mg) was added and stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. Water was added to the residue, followed by extraction three times with ethyl acetate. The extract was washed twice with water and once with brine, and then dried over magnesium sulfate. After removing the solvent under reduced pressure, the obtained oily residue was crystallized by adding isopropyl ether and filtered to give the title compound (1.24 g) as white crystals.

Example 5

3- (1-amino) cyclopropyl-1-benzyl-2-pyrrolidone

1-benzyl-3- [1- (t-butoxycarbonyl) amino] cyclopropyl-2-pyrrolidone (27.7 g) was added little to trifluoroacetic acid (150 ml) cooled to 0 degreeC, and it was normal temperature. Stir for 1 and a half hours. The reaction was concentrated under reduced pressure and dissolved by adding water to the residue. Neutralize to pH9 with 2N caustic soda solution, extract three times with chloroform, and extracts are washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a yellow oily residue, which was subjected to silica gel column chromatography (eluent, chloroform: methanol: ammonia water = 120: 10: 1) to give a pale yellow oily title compound (18.0 g).

Example 6

3- (1-amino) cyclopropyl-1-benzylpyrrolidine

3- (10-amino) cyclopropyl-1 dissolved in lithium aluminum hydride (95%, 1.72 g) suspended in tetrahydrofuran (100 ml), cooled to -10 ° C or below, and dissolved in tetrahydrofutane (30 ml) Benzyl-2-pyrrolidone (6.9 g) was added dropwise. The mixture was stirred at 5-10 ° C. for 2 hours, cooled to 0 ° C., and then water (1.71 ml), 20% caustic soda (1.3 ml) and water (6 ml) were added in turn, and the resulting solid was filtered and tetra Washed sufficiently with hydrofuran. The filtrate was concentrated under reduced pressure to give the title compound (5.2 g) as a yellow oil.

Example 7

1-benzyl-3- [1-trifluoroacetyl) amino] cyclopropylpyrrolidine

3- (1-amino) cyclopropyl-1-benzylpyrrolidine (1.05 g) and triethylamine (1.05 ml) were dissolved in dichloromethane (10 ml), cooled to 0 ° C. and diluted with ditlolomethane (5 ml). The dissolved trifluoroacetic anhydride (0.37 g) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction was washed with water and sodium bicarbonate solution, dried over magnesium sulfate, the solvent was concentrated under reduced pressure to give a yellow oil which was purified by silica gel column chromatography (eluent, ethyl acetate) to give the pale yellow crystalline title compound (1.17 g). Got it.

Example 8

3- [1- (trifluoroacetyl) amino] cyclopropylpyrrolidine

Dissolve 1-benzyl-3- [1- (trifluoroacetyl) amino] cyclopropylpyrrolidine (1.38 g) in ethanol (30 ml), add 10% palladium-carbon (0.61 g) and then hydrogen gas. It was reacted overnight at room temperature while injecting. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the yellow oily title compound (1.0 g).

Example 9

3- (1-acetylamino) cyclopropyl-1-benzylpyrrolidine

3- (1-amino) cyclopropyl-1-benzylpyrrolidine (4.46g) and triethylamine (5.7ml) were dissolved in dichloromethane (100ml), cooled to 0 ° C, and acetic anhydride (3.15g) Was added dropwise, stirred for 30 minutes at 0 to 5 ℃ and stirred for 1.5 hours at room temperature. Water was added and the organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain an oily residue. (3.3 g) was obtained.

Example 10

3- (1-acetylamino) cyclopropyl pyrrolidine

The reaction was carried out in the same manner as in Example 8 using 3- (1-acetylamino) cyclopropyl-1-benzylpyrrolidine (1.75 g) to obtain a colorless oily title compound (1.06 g).

Example 11

3- (1-acetylamino) cyclopropyl-1- (t-butoxycarbonyl) pyrrolidine

Dissolve 3- (1-acetylamino) cyclopropyl pyrrolidine (0.95 g) and triethylamine (0.86 g) in dichloromethane (25 ml), cool to 10 ° C or less, and di-t-butyl-dicarbonate ( 1.48 g) was added and stirred at room temperature for 1 hour. Water was added, extraction was performed three times with dichloromethane, and the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained oily residue was purified by a silica gel column (eluent, chloroform: methanol: ammonia water = 120: 10: 1) to give a pale yellow oily title compound (1.45 g).

Example 12

3- [1- (N-acetyl-N-ethyl) amino] cyclopropyl-1- (t-butoxycarbonyl) pyrrolidine

3- (1-acetylamino) cyclopropyl-1- (t-butoxycarbonyl) pyrrolidine (1.40 g) was dissolved in tetrahydrofuran (40 ml) and sodium hydride (60%, 0.25 or less) at or below 10 ° C. g) was added followed by stirring for at least 10 minutes and ethyl iodide (1.22 g) was added. After refluxing for 3 hours, ethyl iodide (1.0 g) was added again, and the mixture was further refluxed for 1 hour. The solvent was evaporated under reduced pressure, water was added to the residue, followed by extraction three times with chloroform and the organic layer was washed with salt fire. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to obtain an oily residue, which was purified by a silica gel column (eluent, hexane: ethyl acetate = 1: 1) to give a pale yellow oily title compound (0.85 g).

Example 13

3- [1- (N-ethyl) amino] cyclopropyl pyrrolidine. 2 bromate

To a solution containing about 30% bromic acid in acetic acid (7 ml), 3- [1-N-acetyl-N-ethyl) amino] cyclopropyl-1- (t-butoxycarbonyl) pyrrolidine (0.85 g) was added. Then, the mixture was warmed to reflux for 1.5 hours, and the residue obtained by evaporating the solvent under reduced pressure was dissolved in ethanol. After decolorizing with carbon, the solvent was evaporated under reduced pressure to give a red crystalline title compound (0.79 mg).

Example 14

3- [1- (N, N-dimethyl) amino] cyclopropyl-1-benzylpyrrolidine

3- (1-amino) cyclopropyl-1-benzyl pyrrolidine (1.30 g) was dissolved in a mixed solution of 35% formaldehyde (4 ml) and formic acid (10 ml) and warmed to reflux for 2 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in water, neutralized with potassium carbonate solution, and extracted three times with chloroform. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give a brown oily residue which was purified by silica gel column chromatography (eluent, chloroform: methanol: ammonia water = 120: 10: 1) to give an oily title compound (1.0 g). Got.

Example 15

3- [1-N, N-dimethyl) amino] cyclopropylpyrrolidine

Reaction was carried out in the same manner as in Example 8 using 3- [1- (N, N-dimethyl) amino] cyclopropyl-1-benzylpyrrolidine (1.0 g) to give a pale yellow oily title compound (0.58 g). Obtained.

Example 16

3- [1- (t-butoxycarbonyl) amino] cyclopropyl-1-benzylpyrrolidine

3- (1-amino) cyclopropyl-1-benzylpyrrolidine (6.7 g) and triethylamine (6.5 ml) were dissolved in dichloromethane (120 ml), cooled to 5 ° C. or lower, and diluted with dichloromethane (10 ml). The dissolved di-t-butyldicarbonide (8.12 g) was added dropwise and allowed to react overnight at room temperature. Water was added to the reaction, the organic layer was separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with dilute sodium bicarbonate solution and dried over magnesium sulfate. The residue obtained by evaporation of the solvent was subjected to silica gel column chromatography (eluent, chloroform: tetrahydrofuran: methanol = 100: 5: 3) to give a pale yellow crystalline title compound (8.2 g).

Example 17

3- [1- (t-butoxycarbonyl) amino] cyclopropylpyrrolidine

Dissolve 3- [1- (t-butoxycarbonyl) amino] cyclopropyl 1-benzylpyrrolidine (5.2 g) in ethanol (50 ml), add 10% palladium-carbon (2.3 g), and then hydrogen gas. The reaction was carried out at 40 ° C. for 5 hours while being injected. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the residue was crystallized by adding ether, followed by filtration to give the title compound (2.2 g) as a white crystal.

Claims (5)

3- (1-aminocycloalkyl) pyrrolidine derivative represented by the following general formula (I) and salts thereof Wherein R _1, R ₂ or R ₃ are the same or different from each other and are hydrogen, methyl or ethyl; R ₄ is hydrogen, methyl, ethyl, propyl or allyl; R ₅ is hydrogen, methyl, ethyl, propyl, allyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbon Carbonyl substituted or unsubstituted benzyl, or substituted or unsubstituted benzenesulfonyl; R _6S is hydrogen, methyl, ethyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, trityl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, Or substituted or unsubstituted benzenesulfonyl; n is 1,2,3 or 4. The compound according to claim ₁ , wherein R ₁ , R ₂ , R ₃ , R ₆ is hydrogen, R ₅ is acetyl, lifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl or trityl and R ₄ is hydrogen, Methyl or ethyl; 3- (1-aminocycloalkyl) pyrrolidine derivatives and salts thereof, wherein R _4D and R ₅ are both methyl. The compound and salt thereof according to claim 2, wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₆ are hydrogen and R ₅ is hydrogen or t-butoxycarbonyl. According to the following production route, a Wittig reaction or a Homer-Emmons reaction was performed from compound (II) to obtain compound (III), and Michael addition reaction from compound (III). To give compound (IV), followed by catalytic reduction to reduce the nitro group to an amino group, and ring-closed by warming to obtain compound (V), followed by reaction with sodium hydride and benzyl halide Or reacted with an alkyl halide to afford compound (VI), and the aminoprotecting group (R ₅ ) is subjected to catalytic reduction, chemical reduction and hydrolytic deprotection under acidic or basic conditions to give compound (VII) , By reducing at least 1 to 3 moles of a lithium aluminum hydride reducing agent per mole of the obtained compound (VII) to obtain the compound (VIII), and then according to a commonly known method. A method for preparing compounds and salts represented by formula (I) by reacting an aminoprotecting group. R _1, R ₂ or R ₃ in the above formula are the same or different from each other and are hydrogen, methyl or ethyl; R ₄ is hydrogen, methyl, ethyl, propyl or allyl; R ₅ is hydrogen, methyl ethyl, propyl, allyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbonyl , Substituted or unsubstituted benzyl, or substituted or unsubstituted benzenesulfonyl; R ₆ is hydrogen, methyl, ethyl, C ₁ -C ₆ acyl, C ₂ -C ₆ alkoxycarbonyl, trityl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyl oxycarbonyl, aryloxycarbonyl, or substituted Or unsubstituted benzenesulfonyl; n is 1, 2, 3 or 4; R ₇ is methyl or ethyl. A compound of formula (VI) is prepared from the compound of formula (II) according to the route of claim 4, and then at least 1 to 3 moles of lithium aluminum hydride reducing agent is used per mole of compound (VI) obtained. A process for preparing a compound represented by formula (I) and salts thereof by carrying out a reduction reaction. Wherein n, R ₁ , R ₂ , R ₃ , R ₄ and R ₆ and R ₇ are as defined in claim 4.