CN1273452C - 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation - Google Patents

Abstract

The present invention relates to new quinoline carboxylic acid derivatives substituted by 7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl) of structure such as formula (I) and a preparation method thereof, and these compounds can be Used as an antibacterial agent and feed additive, where: A represents CH, CF, CCl, COCH ₃ , CCH ₃ or NZ represents H, halogen, NH ₂ , CH ₃ ; R ₁ represents C ₁ -C ₃ -alkyl, FCH ₂ CH ₂ -, cyclopropyl, fluorocyclopropyl or phenyl which may be monosubstituted to trisubstituted by halogen, or A and R ₁ together represent a bridge with the structure CO-CH ₂ -CH(CH ₃ )-; Y represents H, C ₁ -C ₆ -alkyl with or without hydroxyl, halogen or amino substitution, or 5-methyl-2-oxo-1,3-dioxol-4-enylmethyl, or Alkyl acyloxymethyl; R ₂ , R ₃ may be the same or different, each representing H, C ₁ -C ₆ -alkyl, amino protecting group.

Description

7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl) substituted novel quinoline carboxylic acid derivative and its preparation method

Technical field:

The present invention relates to new fluoroquinolones and naphthyridone formic acid derivatives with excellent antibacterial activity and their preparation methods; and to antibacterial agents and feed additives containing them.

Background technique:

Quinolones have developed from nalidixic acid (nalidixic acid, J.Med.Chem.1962, 5, 1063) in 1962 to now a class of broad-spectrum, high-efficiency, low-toxic synthetic drugs. Early quinolones have stronger antibacterial activity to Gram-negative bacteria, but lower activity to Gram-positive bacteria, although newly listed quinolones such as gatifloxacin (Drug, 1999,58 (4) : 683) etc. have improved antibacterial activity, but generally speaking, the activity against Gram-positive bacteria needs to be further enhanced, and it is necessary to enhance the antibacterial activity to some specific bacteria such as Streptococcus pneumoniae, Enterococcus etc. simultaneously.

It has been reported (JP05,345,777; Chem.Pharm.Bull.44(7)1376-1386(1996)), quinolones with (4,4-dimethyl-3-amino-pyrrolyl) substitution at the 7th position Compounds have certain antibacterial activity.

The 7-aminomethyl-5-azaspiro[2,4]heptane substituent (CN.1400209, 2003-03-05) is introduced into the 7-position of the quinolone parent ring, and has broad-spectrum antibacterial activity. The activity against Gram-positive bacteria was significantly enhanced.

We introduced an aminomethyl group at the 3-position of pyrrolidine and a dimethyl group at the 4-position to obtain new quinoline carboxylic acid compounds, which are different from the compounds known in the previous literature. After measuring the pharmacological activity of these compounds, it was found that they have unexpected effects. They are effective against Gram-positive bacteria, especially drug-resistant bacteria (two strains of MRSA-Methicillin-resistant Staphylococcus aureus, two strains of MRSE-Methicillin-resistant epidermidis) showed strong antibacterial activity, thus completing the present invention.

Invention content:

The present invention provides the compound of formula (I) or pharmaceutically acceptable salts, esters, amides, hydrates, optical isomers and crystals thereof.

The compound of the present invention is a quinolone compound having a (4,4-dimethyl-3-aminomethyl-pyrrolidine) substituent at the 7-position of the quinolone nucleus. Compared with the quinolone antibacterial drugs known to have weak activity against Gram-positive bacteria, the compound of the present invention has superior activity against Gram-positive bacteria, especially anti-MRSA and MRSE bacteria. Formula (I) compound structure of the present invention is as follows:

in:

A represents CH, CF, CCl, COCH ₃ , CCH ₃ or N

Z represents H, halogen, NH ₂ , CH ₃ ;

R ₁ represents C ₁ -C ₃ -alkyl, FCH ₂ CH ₂ -, cyclopropyl, fluorocyclopropyl or phenyl which may be monosubstituted to trisubstituted by halogen, or A and R ₁ together represent ₂ -CH(CH ₃ )-structure bridge;

Y represents H, C ₁ -C ₆ -alkyl with or without hydroxyl, halogen or amino substitution, or 5-methyl-2-oxo-1,3-dioxol-4-enylmethyl , or alkylacyloxymethyl;

R ₂ and R ₃ can be the same or different, each representing H, C ₁ -C ₆ -alkyl, amino protecting group, etc. These amino protecting groups include: formyl, acetyl, trifluoroacetyl , substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxy or ethoxy or tert-butoxy or isobutoxy or trichloroethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, alkylacyloxymethyl, substituted Or unsubstituted benzyl, trityl, tetrahydrofuryl, 5-methyl-2-oxo-1,3-oxol-4-enylmethyl, α-aminoalkylacyl.

The present invention also relates to a process for preparing the compound of formula (I) as defined above, and an antibacterial pharmaceutical composition containing the compound of formula (I) as an active ingredient.

The compound of formula (I) that the present invention relates to, in the pyrrolidine part of the compound of formula (I), wherein the carbon atom substituting the aminomethyl group is an asymmetric carbon atom, so it can exist in the form of R or S or a mixture of R and S, The present invention includes all such isomers and mixtures.

The compounds of formula (I) of the present invention may form pharmaceutically acceptable non-toxic salts. These salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, etc. , mandelic acid, ascorbic acid or malate, and amino acid salts such as alanine, aspartic acid, lysine, etc. or salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, etc. Their alkali metal salts, alkaline earth metal salts, silver salts, barium salts, etc. can also be prepared by conventional conversion methods.

The esters of the formula (I) compound of the present invention not only include substituted or unsubstituted fatty esters, especially 1-6 carbon atoms, such as lower alkyl esters such as methyl esters, but also include chemical hydrolysis or enzymatic hydrolysis in vivo, Esters that can be at least partially converted into compounds of formula (I), such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxyformyloxyethyl ester, choline ester, aminoethyl ester (such as: dimethylaminoethyl ester or 1-piperazinyl ethyl ester), 5-2,3-indanyl ester, 2-benzo[c]furanone ester and hydroxyalkyl ester (such as: 2-hydroxyethyl ester or 2,3 -dihydroxypropyl ester), 5-methyl-2-oxo-1,3-dioxol-4-enyl methyl ester.

The compounds of formula (I) of the present invention may also exist in the form of solvates (such as hydrates), and therefore, these solvates are also included in the compounds of the present invention.

The present invention also relates to the preparation method of the compound of formula (I), the compound of the present invention can be prepared by the method shown in the following reaction scheme 1.

Reaction route 1:

In the above scheme, Y, R ₁ , R ₂ , R ₃ , Z and A are as defined above; and X represents a halogen atom, preferably fluorine and chlorine.

According to the reaction route, in the presence of a solvent and adding a suitable base, or without a solvent, use an excess of the compound of the formula (III) to meet the needs, and stir the compound of the formula (II) at room temperature to 200 ° C with or without pressure and the compound of formula (III) for 0.5-10 hours to prepare the compound of formula (I). The compound of formula (III) or its salts with eg hydrochloric acid, hydrobromic acid or trifluoroacetic acid can be used in this reaction as a free mixture.

As the solvent for the above reaction, any solvent that does not adversely affect the reaction can be used. Preference is given to using acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine or hexamethylphosphoric acid amide.

The reaction is generally carried out in the presence of an acid acceptor. In this case, in order to improve the reaction efficiency of the more expensive starting material formula (II) compound, use an excess of reactant formula (III) compound, such as relative starting material is equimolar to 10 times the molar amount, superior etc. Molar weight to 5 times the molar weight. When excess reactant compound of formula (III) is used, the unreacted mixture remaining after the reaction can be recovered and reused in the reaction. Acid acceptors superior for this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride, etc., organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N -Dimethylaminopyridine, N,N-dimethylaminoaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,4-diazabicyclo[ 2,2,2]octane (DABCO), etc.

Any protecting group conventionally used in the field of organic chemistry and which is easily removed after the reaction without decomposing the structure of the target compound can be used as a suitable amino protecting group in the compound of formula (III). Specific examples of protecting groups useful for this purpose include formyl, acetyl, trifluoroacetyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted benzyl, trityl, tetrahydropyranyl, 5-methyl-2-oxo-1,3-oxolane- 4-enmethyl, alkanoyloxymethyl, α-aminoalkylacyl, etc.

After the reaction is completed, the amino protecting group present in the formed compound of formula (I) can be removed by hydrolysis, solvolysis or reduction according to the relevant properties of the protecting group. For example, the compound of formula (I) is deprotected by treatment in a solvent in the presence or presence of a mineral acid or base at a temperature of 0-150°C. Acids that can be used for this purpose include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, etc. Or Lewis acid such as: boron tribromide, aluminum oxide, etc. As the base used for this purpose, hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide, barium hydroxide, etc., alkali metal carbonates such as sodium carbonate, calcium carbonate, etc., alkali metal alkoxides such as: Sodium methoxide, sodium ethoxide, etc., or sodium acetate, etc. Reaction can be carried out in solvent, for example water or organic solvent such as: ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid etc., or the mixture of this organic solvent and water, if desired, this reaction also can be without any solvent in progress.

In addition, when the protecting group is p-toluenesulfonyl, benzyl, trityl, p-methoxybenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, β-iodoethoxy When carbonyl etc. are present, these groups can be efficiently removed by reduction. Although the reduction reaction conditions for removing the protecting group vary with the nature of the relevant protecting group, the reduction is generally carried out with hydrogen flow, in an inert solvent, in the presence of a catalyst such as platinum, palladium, Raney nickel, etc. at a temperature of 10-150 ° C , or use metal sodium or metal lithium in ammonia water at a temperature of -50°C to -10°C.

The compound of formula (I) of the present invention can also be prepared by the method shown in Scheme 2 below.

Reaction route 2:

In the above compounds, R represents an aliphatic carboxyl group of 2-6 carbon atoms with or without heteroatom substitution, or an aromatic carboxyl group of 7-11 carbon atoms, Y, R ₁ , R ₂ , R ₃ , Z and A as defined above; and X represents a halogen atom, preferably fluorine and chlorine.

In the present invention, the compound of formula (II) is first converted to the compound of formula (IV) as a known method, and the conversion can be easily realized according to the existing disclosed method (see CN 1059527A).

Compounds of general formula (V) can be prepared as follows:

The compound represented by the general formula (IV) and the compound represented by the general formula (III) are condensed.

According to the reaction route, by adding a suitable base in the presence of a solvent, or without a solvent, using an excess of the compound of the formula (III) to meet the needs, stirring the compound of the formula (IV) at room temperature to 200 ° C with or without pressure and the compound of formula (III) for 0.5-10 hours to prepare the compound of formula (V).

As the solvent for the above reaction, any solvent that does not adversely affect the reaction can be used. Preference is given to using acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine or hexamethylphosphoric acid amide.

The reaction is generally carried out in the presence of an acid acceptor. In this case, in order to improve the reaction efficiency of the more expensive starting material formula (IV) compound, use an excess of reactant formula (III) compound, such as relative starting material is equimolar to 10 times the molar amount, superior etc. Molar weight to 5 times the molar weight. When excess reactant compound of formula (III) is used, the unreacted mixture remaining after the reaction can be recovered and reused in the reaction. Acid acceptors superior for this reaction include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride, etc., organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N -Dimethylaminopyridine, N,N-dimethylaminoaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,4-diazabicyclo[ 2,2,2]octane (DABCO), etc.

The hydrolysis of general formula (V) compound is in basic solvent (for example: triethylamine, ammoniacal liquor, sodium bicarbonate, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide etc. in methanol, ethanol, tetrahydrofuran, dioxane Solution in ring or water, or in acidic solution (for example: trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, etc. in water, alcohol, tetrahydrofuran, dioxane, chloroform, dichloromethane solution) in React at 0-150°C for 0.5-10 hours.

Any protecting group conventionally used in the field of organic chemistry and which is easily removed after the reaction without decomposing the structure of the target compound can be used as a suitable amino protecting group in the compound of formula (III). Specific examples of protecting groups useful for this purpose include formyl, acetyl, trifluoroacetyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted benzyl, trityl, tetrahydropyranyl, 5-methyl-2-oxo-1,3-oxolane- 4-enmethyl, alkanoyloxymethyl, α-aminoalkylacyl, etc.

After the reaction is completed, if there is an amino protecting group in the formed compound of formula (I), it can be removed by hydrolysis, solvolysis or reduction according to the relevant properties of the protecting group. For example, the compound of formula (V) is deprotected by treatment in a solvent in the presence of an organic or inorganic acid or base at a temperature of 0-150°C. Acids that can be used for this purpose include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, etc. Or Lewis acid such as: boron tribromide, aluminum oxide, etc. As the base used for this purpose, hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide, barium hydroxide, etc., alkali metal carbonates such as sodium carbonate, calcium carbonate, etc., alkali metal alkoxides such as: Sodium methoxide, sodium ethoxide, etc., or sodium acetate, etc. Reaction can be carried out in solvent, for example water or organic solvent such as: ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid etc., or the mixture of this organic solvent and water, if desired, this reaction also can be without any solvent in progress.

In addition, when the protecting group is p-toluenesulfonyl, benzyl, trityl, p-methoxybenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, β-iodo When substituting ethoxycarbonyl and the like, these groups can be efficiently removed by reduction. Although the reduction reaction conditions for removing the protecting group vary with the nature of the relevant protecting group, the reduction is generally carried out at a temperature of 10-150° C. in the presence of a catalyst such as platinum, palladium, Raney nickel, etc., in an inert solvent with a stream of hydrogen. Or use metal sodium or metal lithium in ammonia water at a temperature of -50°C to -10°C.

The compounds of formula (II) used as starting materials in the present invention are known compounds and can be easily prepared by methods known in prior publications (for example: L.A.Mitscher et al., J.Med.Chem.30 , 2283 (1987); J.M.Domagala et al., J.Med.Chem.31, 503 (1988); D.T.W.Chu et al., J.Med.Chem.29, 2633 (1986); J.M.Domagala et al., J.Med.Chem. 34, 1142 (1991); D. Bouzard et al., J. Med. Chem. 35, 518 (1992); J. M. Domagala et al., J. Med. Chem. 31, 991 (1988)).

According to the method shown in the following reaction scheme 3, the compound of formula (III) which is another starting material of the present invention can be prepared.

Reaction route 3:

P represents an amino protecting group. The definition of its protecting group is as above.

The present invention also provides antibacterial compositions containing the compound of formula (I), or pharmaceutically acceptable salts, esters, amides, hydrates, optical isomers, and crystals thereof as active ingredients. When the antibacterial composition is used for clinical purposes, it can be formulated into solid, semi-solid or liquid pharmaceutical preparations for oral, parenteral or local use by combining it with a pharmaceutically acceptable inert carrier. Pharmaceutically acceptable inert carriers which can be used for this purpose can be either solid or liquid. Solid or semisolid pharmaceutical preparations can be prepared in the form of powders, tablets, dispersible powders, capsules, suppositories, and pastes, in which case solid carriers are usually employed. The solid carrier that can be used is preferably one or more of diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, swelling agents, etc., or can be encapsulated substances. In powder formulations, the carrier contains from 5% to 70% of the micronized active ingredient. Specific examples of suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, xanthan gum, methylcellulose, sodium carboxymethylcellulose, low Boiling point waxes, cocoa butter, etc., because of their ease of administration, tablets, powders, capsules represent the most favorable oral solid preparations for absorption.

Liquid formulations include solutions, suspensions and emulsions. For example, injectable preparations for parenteral administration can be in the form of water or water and propylene glycol solution, and its isotonicity, pH and other physiological conditions are adjusted to suit the living body. Liquid preparations can also be prepared in aqueous polyethylene glycol solution. Oral aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents. Aqueous suspensions for oral administration can be prepared by dispersing the micronized active ingredient in viscous material, such as natural or synthetic gums, methylcellulose, sodium acid methylcellulose, and other known suspending agents.

It is especially advantageous to formulate the aforementioned pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit form may be in packaged form, such as a tablet, capsule, or powder in a vial or vial, or as an ointment, gel, or cream in a tube or bottle.

While the amount of active ingredient contained in dosage unit forms may vary, it will generally be adjusted within the range of 1-500 mg, depending on the potency of the active ingredient chosen.

When the active compound of formula (I) of the present invention is used as a drug for the treatment of bacterial infections, an amount of 6-14 mg/kg body weight administered in the first phase is preferred. However, the dosage administered will vary with the needs of the patient, the severity of the infection to be treated, the compound selected, and the like.

Those skilled in the art can routinely determine the preferred dosage for a particular situation. Generally, the initial treatment dose is lower than the optimum dose of the active ingredient, and then the dose is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dosage may be divided and administered in divided doses.

As mentioned above, the antibacterial activity of the compounds of the present invention against Gram-positive strains, especially drug-resistant bacteria, is much higher than that of known antibacterial agents.

In order to highlight the practical application value and significance of the patented compound, the latest listing of Gatifloxacin (provided by Zhejiang Xinchang Jingxin Pharmaceutical Factory, batch number 020716) among the eighteenth and twentyth embodiments of the same compound, and the Ciprofloxacin (provided by Tianjin Central Pharmaceutical Factory, batch number 020307) is widely used and occupies a large market share. The minimum inhibitory concentration is determined by the following method: Dilute the test compound according to the two-fold dilution method, then disperse it in the DIFCO medium whose pH is adjusted to 8.0, and have been sterilized by autoclaving, inoculate the bacterial solution, and incubate at 37°C for 18 hours , observe and record the minimum concentration (MIC) that inhibits bacterial growth. The measurement results are listed in Table 1.

Table 1 experimental bacteria MIC (mg/L) Example compound Control drug eighteen twenty Ciprofloxacin Gatifloxacin Staphylococcus aureus MRSA 03-1 0.125 0.03 0.125 0.125 Staphylococcus aureus MRSA03-19 0.125 0.015 0.125 0.06 Enterococcus 30428 2 0.5 16 16 Staphylococcus 03-10 0.25 0.06 2 1 Staphylococcus MRSE 03-2 2 0.125 16 4 Staphylococcus MRSE03-32 0.5 0.5 2 1

The activity assay uses the plate double dilution method, and the medium is MH (DIFCO) medium. The bacterial strains used in the experiment are all clinically isolated pathogenic bacteria collected from Sichuan and Beijing in 2002-2003. The Laboratory Department of West China Medical University, the Department of Infectious Diseases of Chongqing Medical University, and the Bacteria Laboratory of Beijing Hospital) were all identified by the automatic bacteria detector, and then re-identified by the API system used by the Sichuan Antibiotic Industry Research Institute before use.

In terms of pharmacokinetic performance, compared with known quinolone compounds, the compound of the present invention has suitable water solubility, so it can be well absorbed in the body, exhibits very high bioavailability, and is suitable for use as an antibacterial agent.

In addition, because the compound of the present invention has low toxicity and high curative effect, it can be effectively used for the prevention and treatment of diseases caused by bacterial infection in warm-blooded animals including humans.

Detailed ways:

In the following examples, the present invention will be explained more specifically. However, it should be understood that the following examples are intended to illustrate the present invention and not to limit the scope of the present invention.

Example 1 1-benzyl-3,3-dimethyl-2,4-dioxopyrrolidine

In a 1000ml three-neck flask equipped with a drying tube and a mechanical stirrer, add dry DMF (300ml), ethyl acetoacetate (130g, 1mol), add anhydrous potassium carbonate (286g, 2.2mol) under stirring, and drop Add iodomethane (390 g, 2.8 mol). After completion, the reaction was stirred at room temperature for 7 days. Filter off the solid, and wash the solid with dichloromethane (about 100ml), add water (500ml) to the filtrate, extract with dichloromethane (about 100ml×3), combine the organic layers, wash three times with water, dry over anhydrous magnesium sulfate, filter, and evaporate The solvent was dried to obtain light yellow oil (125 g, yield 79.0%).

In a 500ml three-necked flask, add the above compound oil (77g, 0.487mol), absolute ethanol (180ml), add bromine (77g, 0.481mol) dropwise under ice bath, complete, stir at room temperature for 2hr, evaporate under reduced pressure Add about half of the solvent, add water (200ml), extract with dichloromethane (about 100ml×3), combine the organic layers, wash with water three times, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to dryness.

Anhydrous ethanol (160ml) was added to the above residue, and benzylamine (98g, 0.92mol) was added dropwise under ice-cooling. After completion, the reaction was carried out at room temperature for 20 hours, and the reaction was tracked by TLC. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane (300ml), washed twice with 1N hydrochloric acid, washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain a crude product (90g).

Dissolve the crude product in dichloromethane (200ml), thicken silica gel (90g), evaporate to dryness under reduced pressure, use ethyl acetate and petroleum ether as gradient elution solvents, and separate by VLC column chromatography to obtain the product, pale yellow Solid (50.0 g, 47.6%).

¹ HNMR (CDCl ₃ ) δppm: 1.257 (6H, s, 3-2×CH ₃ ), 3.694 (2H, s, 5-CH ₂ ), 4.626 (2H, s, benzyl-CH ₂ ), 7.225～7.348 (5H, m, ArH)

¹³ CNMR (CDCl ₃ ) and DEPTδppm: 20.523 (primary C, 2×CH3), 45.805 (secondary C, 5-CH2), 47.124 (quaternary C, 3-C), 53.588 (secondary C, benzyl-CH2), 128.019 ～128.947 (tertiary C, aromatic ring CH), 135.213 (quaternary C, aromatic ring C), 175.550 (quaternary C, 4-C=O), 210.399 (quaternary C, 2-C=O)

EIMS: 217 (M ⁺ )

Example 2 1-benzyl-3,3-dimethyl-2-oxo-4-ethoxycarbonylmethylenepyrrolidine

Add 60% sodium hydride (6.5g) to dry tetrahydrofuran (150ml), stir and cool down to 0°C ~ -5°C, add triethyl phosphonate dropwise, complete, stir at room temperature for 1.5hr, the reaction liquid is jelly-like , compound Example 1 (28.0 g, 0.129 mol) was added dropwise at room temperature. After completion, react at room temperature for 2 hr, dilute with ethyl acetate (300 ml), wash with saturated brine until neutral, dry over anhydrous magnesium sulfate, and evaporate the solvent to The oily product C-7 was obtained by drying (30.95 g, 83.6%).

¹ HNMR (CDCl ₃ ) δppm: 1.163～1.276 (3H, t, ethyl ester CH ₃ ), 1.316 (6H, s, 3-2×CH ₃ ), 4.066～4.135 (2H, q, ethyl ester CH ₂ ), 4.342, 4.351 (2H, d, benzyl-CH ₂ ), 4.524 (2H, s, 5-CH ₂ ), 5.813~5.829 (1H, t, alkene=CH), 7.219~7.346 (5H, m, ArH)

_EIMS : 287(M ⁺ ₎ , 258(M ⁺ -CO-H), 91( _C6H5CH2 ⁺ )

Example three 1-benzyl-3,3-dimethyl-2-oxo-4-ethoxycarbonylmethylpyrrolidine

Add absolute ethanol (700ml), active nickel and the compound of Compound Example 2 (30.95g, 0.108mol), and react at room temperature under 40-50psi hydrogen pressure for 12hr. TLC shows that the reaction is complete, and the nickel powder is filtered off, and the solvent is evaporated to After drying, a pale yellow oil (29.3 g, 94.0%) was obtained.

¹ HNMR (CDCl ₃ ) δppm: 0.970 (3H, s, 3-CH ₃ ), 1.187 (3H, s, 3-CH ₃ ), 1.187～1.244 (3H, t, ethyl ester CH ₃ , J=7.8Hz) , 2.197～2.253 (1H, m, 4-CH), 2.403～2.478 (2H, m, side chain CH ₂ ), 2.789～2.850, 3.330～3.387 (2H, t t, 5-CH ₂ , coupling with hydrocarbon, J=9Hz), 4.060~4.131 (2H, q, ethyl ester CH ₂ , J=7.2Hz), 4.297~4.575 (2H, dd, benzyl-CH ₂ ), 7.180~7.314 (5H, m, ArH)

EIMS: 289 (M ⁺ ), 244 (M ⁺ -OEt), 114 (C ₆ H ₅ N=CH ₂ ), 91 (C ₆ H ₅ CH ₂ ⁺ )

Example four 1-benzyl-3,3-dimethyl-2-oxo-4-carboxymethylpyrrolidine

In a 500ml single-necked flask, add compound example three compound (29.3g, 0.101mol), 95% ethanol (150ml), 5% aqueous sodium hydroxide solution (150ml), stir at room temperature for 3hr, TLC shows that the reaction is complete, evaporate under reduced pressure Remove part of ethanol, add active carbon for decolorization, filter, adjust the pH of the filtrate to less than 2 with 10% hydrochloric acid, cool, filter out the solid, extract the aqueous layer with dichloromethane, wash the organic layer with water, dry, and evaporate the solvent to obtain a light yellow solid (21.6 g, 81.6%).

¹ HNMR (CDCl ₃ ) δppm: 0.853 (3H, s, 3-CH ₃ ), 1.055 (3H, s, 3-CH ₃ ), 2.150～2.434 (2H, m, side chain -CH ₂ ), 2.795～2.856 (1H, m, 5-CH), 3.255~3.337 (2H, m, 5-CH ₂ and 4-CH), 4.282~4.419 (2H, dd, benzyl-CH ₂ , J=14.7Hz), 7.161~ 7.366 (5H, m, ArH)

EIMS: 261 (M ⁺ ), 91 (C ₆ H ₅ CH ₂ ⁺ )

Example five 1-benzyl-3,3-dimethyl-2-oxo-4-aminomethylpyrrolidine

Take Compound Example 4 (8.0g, 31mmol), add acetone (40ml) and triethylamine (3.9ml), add isobutyl chloroformate (5.2ml) dropwise between 0°C and -5°C, complete, Reacted for 40min, added dropwise a solution of sodium azide (4.2g, 0.7mol) dissolved in water (15ml) at this temperature, stirred for another 30min, added ice water (100ml), extracted with xylene (50ml×4), Combined, washed three times with water, dried over anhydrous magnesium sulfate, and filtered.

The xylene solution was distilled under atmospheric pressure until the internal temperature rose to about 140°C, and changed to a reflux device, refluxed for 3 hours, evaporated the solvent under reduced pressure, added 8N hydrochloric acid (60ml), refluxed for 0.5hr, cooled, and washed with benzene (20ml× 2) Extract and discard, adjust the pH of the aqueous layer to greater than 10 with 30% sodium hydroxide solution, extract with dichloromethane (30ml×4), combine the organic layers, wash twice with saturated brine, dry over anhydrous magnesium sulfate, filter, evaporate Removal of the solvent gave a pale yellow oil (3.59 g, 49.9%).

¹ HNMR (CDCl ₃ ) δppm: 0.990 (3H, s, 3-CH ₃ ), 1.227 (3H, s, 3-CH ₃ ), 1.740 (bro, NH ₂ plus D ₂ O exchange disappears), 1.986～2.061 ( 1H, m, 4-CH), 2.538～2.613 (1H, m, 5-CH), 2.841～2.925 (2H, m, 5-CH and side chain -CH), 3.276～3.333 (1H, m, side chain -CH), 4.356~4.605 (2H, dd, benzyl-CH ₂ ), 7.192~7.342 (5H, m, ArH)

FABMS: 233 (M ⁺ +1), 91 (C ₆ H ₅ CH ₂ ⁺ )

Example 6 1-benzyl-4,4-dimethyl-3-aminomethylpyrrolidine

LiAlH ₄ (2.54g, 54mmol) was added to dry tetrahydrofuran (25ml), and a solution of compound Example 5 (2.59g, 11.6mmol) dissolved in tetrahydrofuran (10ml) was added dropwise under ice-cooling, and heated to reflux for 5hr. After cooling, water (2ml), 15% aqueous sodium hydroxide solution (2ml), and water (6ml) were added dropwise successively, stirred at room temperature for 20min, filtered, and the solvent was evaporated to give a light yellow oil (2.22g, 87.7%). Take a small amount of lamellar separation analysis.

¹ HNMR (CDCl ₃ ) δppm: 0.975 (3H, s, 3-CH ₃ ), 0.998 (3H, s, 3-CH ₃ ), 0.852～2.082 (5H, m), 3.059～3.107 (2H, m, side chain-CH ₂ ), 4.075, 4.097 (2H, d, benzyl-CH ₂ ), 7.355～7.723 (5H, m, ArH)

ESIMS: 219 (M ⁺ +1)

Example 7 1-benzyl-4,4-dimethyl-3-N-tert-butoxycarbonylaminomethylpyrrolidine

Dissolve Compound Example VI (3.0g, 13.7mmol) in dichloromethane (30ml), add tert-butoxycarbonyl dicarbonate (5.56g, 32mmol), stir at room temperature for 2hr, then wash with water (50ml×3) . Dry over anhydrous magnesium sulfate, and evaporate the solvent to dryness. VLC column chromatography separation (petroleum ether, ethyl acetate as eluent). A pale yellow oil (3.9 g, 89.0%) was obtained.

¹ HNMR (CDCl ₃ ) δppm: 0.993 (3H, s, 3-CH ₃ ), 1.089 (3H, s, 3-CH ₃ ), 1.433 (9H, s, -COC(CH ₃ ) ₃ ), 1.896～1.940 , 2.370～3.226 (7H, m, 3×CH ₂ and 4-CH), 3.598 (2H, s, benzyl-CH ₂ ), 7.222～7.331 (5H, m, ArH)

ESIMS: 319 (M ⁺ +1)

Example 8 4,4-Dimethyl-3-N-tert-butoxycarbonylaminomethylpyrrolidine

Take Compound Example 7 (6.0g, 18.6mmol), dissolve it in absolute ethanol (about 100ml), add freshly prepared 10% Pd/C (8.0g), and react under hydrogen pressure of 40-50Psi at room temperature for 24hr. TLC showed that the starting material disappeared, and the Pd/C was filtered off, and concentrated to dryness to obtain a pale yellow oil (3.4 g, 79.8%).

¹ HNMR (CDCl ₃ ) δppm: 0.991 (3H, s, 3-CH ₃ ), 1.086 (3H, s, 3-CH ₃ ), 1.431 (9H, s, -COC(CH ₃ ) ₃ ), 1.890～1.941 , 2.366～3.220 (7H, m, 3×CH ₂ and 4-CH)

ESIMS: 229 (M ⁺ +1)

Example 9 4,4-Dimethyl-3-aminomethylpyrrolidine hydrochloride

The compound of Example 8 (2.28g, 10mmol) was added to anhydrous HCl methanol/methyl acetate solution (10ml), stirred for 0.5hr to remove BOC, and the solvent was distilled off to obtain an oil (1.09g, 85.3%).

¹ HNMR (CDCl ₃ ) δppm: 0.995 (3H, s, 3-CH ₃ ), 1.080 (3H, s, 3-CH ₃ ), 1.890～1.941, 2.366～3.220 (7H, m, 3×CH ₂ and 4 -CH)

ESIMS: 129 (M ⁺ +1)

Example 10 1-benzyl-3,3-dimethyl-4-(N-methyl-N-tert-butoxycarbonyl)aminomethylpyrrolidine

In dry tetrahydrofuran (40ml), add the compound of Example VIII (4.0g, 12.5mmol), add dropwise methyl iodide (3.55g, 25mmol) in an ice bath, react at room temperature for 2hr, slowly add water, extract with dichloromethane (100ml× 3), the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain a light yellow oil (3.42 g, 82.3%).

¹ HNMR (CDCl ₃ ) δppm: 0.976 (3H, s, 3-CH ₃ ), 0.980 (3H, s, 3-CH ₃ ), 0.840～2.009 (5H, m), 1.430 (9H, s, -COC( CH ₃ ) ₃ , 2.130 (3H, s, -N(CH ₃ ), 3.048～3.100 (2H, m, side chain -CH ₂ ), 4.080, 4.077 (2H, d, benzyl-CH ₂ ), 7.345～ 7.633 (5H, m, ArH)

ESIMS: 333 (M ⁺ +1)

Example 11 3,3-Dimethyl-4-(N-methyl-N-tert-butoxycarbonyl)aminomethylpyrrolidine

Take the compound of Example 10 (3.4g, 10.2mmol), dissolve it in absolute ethanol (80ml), add freshly prepared 10% Pd/C (4.0g), and react under hydrogen pressure of 40-50Psi at room temperature for 24hr, TLC shows The starting material disappeared, Pd/C was filtered off, and concentrated to dryness to obtain a pale yellow oil (0.87g, 90.1%).

¹ HNMR (CDCl ₃ ) δppm: 0.980 (3H, s, 3-CH ₃ ), 0.996 (3H, s, 3-CH ₃ ), 0.839～2.105 (5H, m), 1.430 (9H, s, -COC( CH ₃ ) ₃ , 2.134(3H, s, -N(CH ₃ ), 3.048～3.003(2H, m, side chain -CH ₂ )

ESIMS: 243 (M ⁺ +1)

Example 12 3,3-Dimethyl-4-methylaminomethylpyrrolidine hydrochloride

The compound of Example 11 (2.43 g, 10 mmol) was added with anhydrous HCl in methanol/methyl acetate solution (10 ml), stirred for 0.5 hr to remove BOC, and the solvent was evaporated to obtain an oil (1.31 g, 92%).

¹ HNMR (CDCl ₃ ) δppm: 0.990 (3H, s, 3-CH ₃ ), 1.000 (3H, s, 3-CH ₃ ), 0.839～2.105 (5H, m), 2.160 (3H, s, -N( CH ₃ ), 3.048～3.003 (2H, m, side chain -CH ₂ )

ESIMS: 143 (M ⁺ +1)

Example 13 1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4 -Dihydro-4-oxo-1,8-naphthyridine-3-carboxylate hydrochloride

Method one: compound 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g, 1.40mmol), DBU (0.43ml, 5mmol) and the compound of Example 11 (0.47g, 2.1mmol) were dissolved in acetonitrile (10ml), reacted at room temperature for 8h, and filtered off the solid.

Methanol (10ml) was ice-cooled, and acetyl chloride (5ml) was slowly added thereto. The mixture was stirred at room temperature for 30 minutes to prepare anhydrous HCl in methanol/methyl acetate solution, to which was added the above solid (0.30 g, 0.56 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to a small amount of solvent remaining. After cooling down, diethyl ether (50ml) was added and stirred rapidly to solidify the product. 90.1%).

¹ HNMR (CF ₃ COOD) δppm: 0.938-1.304 (6H, m, 2 CH ₃ at the 4' position), 2.517 (1H, m, 3'-H), 2.940 (3H, s, NCH ₃ ), 2.700- 4.547 (6H, m, 2', 5'-H and5'-CH ₂ N), 7.122-7.147 (2H, m, Ar-H), 7.354-7.501 (3H, m, bro, Ar-H, NH ₂ ), 8.050, 8.082 (1H, d, 5-H), 9.034 (1H, s, 2-H).

MS (ESI m/z): 461 (M ⁺ +1).

Similarly, salts such as

1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid hydrobromide;

1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro- 4-Oxo-1,8-naphthyridine-3-carboxylic acid sulfate.

Method two: compound 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g, 1.40mmol), DBU (0.43ml, 5mmol) and the compound of Example 12 (0.30g, 2.1mmol) were dissolved in acetonitrile (10ml), reacted at room temperature for 8h, filtered off the solid, and then recrystallized with 80% ethanol Obtained as off-white solid (0.54 g, 80.3%), C ₂₃ H ₂₃ F ₃ N ₄ O ₃ .H ₂ O C h N Calculated 57.68 5.36 11.61 measured value 57.74 5.27 11.71

Example 14 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo Subo-quinoline-3-carboxylic acid trifluoroacetate

Method 1: boric acid (1.50g, 24.2mmol), acetic anhydride (8ml, 80mmol), react at 110° for 1.5hr, cool slightly, add 1-cyclopropyl-6-fluoro7-chloro-1,4-dihydro -4-oxo-quinoline-3-carboxylic acid (5.0g, 15mmol), reacted at the same temperature for 6hr, cooled to room temperature, poured into ice water, filtered, washed with ethanol, and dried in vacuo to give 1-cyclopropyl-6 -Fluoro-7-chloro-1,4-dihydro-4-oxo-3-carboxyborondiethyl ester. After the compound thus obtained and the compound of Example 11 were condensed in acetonitrile/DBU, it was directly hydrolyzed with 5% NaOH, and the pH was adjusted to neutral with HCl, and the solid was filtered out and dried in vacuo. Using trifluoroacetic acid to remove BOC, a light yellow solid was obtained with a yield of 76.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 1.064-1.573 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.553 (1H, m, pyrrole Alkyl 3'-H), 2.948 (3H, s, -NCH ₃ ), 3.298-4.270 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1-position cyclopropyl 1H) , 7.216 (1H, 8-H), 7.969, 8.013 (1H, d, 5-H), 9.368 (1H, s, 2-H).

MS (ESI m/z): 388.7 (M ⁺ +2).

Similarly, salts such as

1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline -3-Carboxylic acid acetate;

1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline -3-Carboxylate lactate;

1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline -3-Carboxylic acid maleate;

1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline -3-Carboxylic acid oxalate.

Method 2: After preparing 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxyborondiethyl ester according to method 1, the compound and After the compound of Example 12 was condensed in acetonitrile/DBU, it was directly hydrolyzed with 5% NaOH, and the pH was adjusted to neutral with HCl. The solid was filtered out, dried in vacuo to obtain a solid, and salified with trifluoroacetic acid to obtain the title compound. The characteristic data of the compound are the same as the product of Method 1.

Example 15 5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-8-methoxy- 1,4-Dihydro-4-oxoquinoline-3-carboxylate hydrochloride

5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50g, 1.6mmol) and implementation The compound of Example 11 (0.72g, 3.2mmol) was dissolved in pyridine (10.0ml) and reacted at 100°C for 6h. After the reaction was complete, the solvent was distilled off, and the residue was de-BOCed with anhydrous HCl in methanol/methyl acetate solution, and then recrystallized from ethanol to obtain a yellow solid product (45.6%).

¹ HNMR (300MHz, CF ₃ COOD) δppm: 0.828-1.414 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.407 (1H, m, pyrrole Alkyl 3'-H), 2.907 (3H, s, -NCH ₃ ), 3.562 (3H, s, -OCH ₃ ), 3.005-4.535 (7H, m, pyrrolidinyl 2', 5', 4'- CH ₂ -, 1-position cyclopropyl 1H), 7.069, 7.452 (bro, -NH), 8.908, 9.071 (1H, d, 2-H).

MS (ESI m/z): 433.5 (M ⁺ +1).

Example 16 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo Di-1,8-naphthyridine-3-carboxylate hydrochloride

Condensation in pyridine with 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-dinaphthyridine-3-carboxylic acid and embodiment eleven Afterwards, it was concentrated to dryness, and de-BOC was directly used with anhydrous HCl in methanol/methyl acetate solution to obtain an off-white solid with a yield of 80.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 1.056-1.467 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.505-2.663 (1H, m , pyrrolidinyl 3'-H), 2.932 (3H, s, -NCH ₃ ), 2.663-4.575 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1-position cyclopropyl 1H), 7.362-7.879 (bro, -NH ₃ ⁺ ), 7.956, 7.993 (1H, d, 5-H), 9.026 (1H, s, 2-H).

MS (ESI m/z): 389.5 (M ⁺ +1).

Example 17 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-8-methoxy-1,4- Dihydro-4-oxoquinoline-3-carboxylate hydrochloride

Boric acid, acetic anhydride, react at 110° for 1.5hr, cool slightly, when the temperature drops to 80°C, add 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4 -Ethyl oxo-3-quinolinecarboxylate, stirred at 80-100°C for 5h. After cooling down to room temperature, the above reaction solution was slowly poured into ice-water, and stirring was continued for 0.5 h. Filter, wash with a large amount of water and a small amount of ethanol successively, and dry the filter cake in vacuum at room temperature overnight to obtain 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4 -Oxo-3-quinolinecarboxyborondiethyl ester. This compound and Example 11 were dissolved in pyridine and reacted at 100°C for 6h. After the reaction was complete, the solvent was distilled off, and the residue was de-BOCed with anhydrous HCl in methanol/methyl acetate solution, concentrated to dryness, and recrystallized from ethanol to obtain a khaki solid product, 53.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 1.093-1.508 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.480 (1H, m, pyrrole Alkyl 3'-H), 2.940 (3H, s, -NCH ₃ ), 3.648 (3H, s, -OCH ₃ ), 3.432-4.409 (7H, m, pyrrolidinyl 2', 5', 4'- CH ₂ -, 1-position cyclopropyl 1H), 7.143-7.358 (bro, -NH), 7.920 (1H, s, 5-H), 9.189 (1H, s, 2-H).

MS (ESI m/z): 418.7 (M ⁺ +1).

Example 18 1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-di Hydrogen-4-oxo-1,8-naphthyridine-3-carboxylate hydrochloride

Method 1: The preparation method is the same as in Example 13, 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine -3-Carboxylic acid was reacted with the compound of Example 8 to obtain an off-white solid with a yield of 84.3%.

¹ HNMR (CF ₃ COOD) δppm: 0.975-1.340 (6H, m, 4' position 2×CH ₃ ), 2.540 (1H, m, 3'-H), 3.164-4.606 (6H, m, 2', 5 '-H and 5'-CH ₂ N), 7.354-7.501 (3H, m, bro, Ar-H, NH ₂ ), 7.539-7.554 (1H, m, Ar-H), 8.080, 8.117 (1H, d , 5-H), 9.071 (1H, s, 2-H).

MS (ESI m/z): 447.6 (M ⁺ +1).

Method 2: The preparation method is the same as in Example 13. Method 2, 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8- Naphthyridine-3-carboxylic acid was reacted with Example 9, and the obtained product was treated with 80% ethanol to obtain an off-white solid with a yield of 86.3%. C ₂₂ H ₂₁ F ₃ N ₄ O ₃ .H ₂ O C h N Calculated 56.78 5.08 11.98 measured value 56.89 4.99 12.06

Example 19 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo- Quinoline-3-carboxylate hydrochloride

The preparation method is the same as in Example 14, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-carboxyborondiethyl ester is reacted with the compound of Example 8, and processed to obtain Off-white solid, yield: 84.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 1.015-1.504 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.484 (1H, m, pyrrole Alkyl 3'-H), 3.245-4.291 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1-position cyclopropyl 1H), 7.216-7.716 (4H, m, bro, 8-Ar-H, NH ₃ ⁺ ), 7.956, 7.997 (1H, d, 5-H), 9.022 (1H, s, 2-H).

MS (ESI m/z): 374 (M ⁺ ).

Example 20 5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-8-methoxy-1, 4-Dihydro-4-oxoquinoline-3-carboxylate hydrochloride

The preparation method is the same as in Example 15, 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and The compound of Example 8 was reacted to obtain a green solid with a yield of 34.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 0.849-1.443 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.394-431 (1H, m , pyrrolidinyl 3'-H), 3.591 (3H, s, -OCH ₃ ), 3.135-4.441 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1-position cyclopropyl 1H), 7.269-7.387 (bro, -NH), 8.993, 9.091 (1H, d, 2-H).

MS (ESI m/z): 419.5 (M ⁺ +1).

Example 21 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo -1,8-Naphthyridine-3-carboxylate hydrochloride

The preparation method is the same as in Example 16, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-dinaphthyridine-3-carboxylic acid and Example 8 The compound was reacted to obtain an off-white solid, yield: 67.3%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 0.954-1.455 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.606 (1H, m, pyrrole Alkyl 3'-H), 3.334-4.584 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1 cyclopropyl 1H), 7.102-7.757 (bro, -NH ₃ ⁺ ), 7.985, 8.021 (1H, d, 5-H), 9.047 (1H, s, 2-H).

MS (ESI m/z): 375 (M ⁺ +1)

Example 22 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-8-methoxy-1,4-di Hydrogen-4-oxoquinoline-3-carboxylate hydrochloride

The preparation method is the same as in Example 17, 11-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxyborondiethyl ester and implementation The compound of Example 8 was reacted to obtain a khaki solid with a yield of 72.5%.

¹ HNMR (300MHz, CF ₃ COOD) δppm: 0.958-1.528 (10H, m, two -CH ₂ spirocyclopropyl, two -CH ₃ at the 4' position of pyrrolidinyl), 2.382-2.582 (1H, m , pyrrolidinyl 3'-H), 3.591 (3H, s, -OCH ₃ ), 3.261-4.356 (7H, m, pyrrolidinyl 2', 5', 4'-CH ₂ -, 1-position cyclopropyl 1H), 7.000-7.728 (bro, -NH ₃ ⁺ ), 7.867, 7.912 (1H, s, 5-H), 9.140 (1H, s, 2-H).

MS (ESI m/z): 404 (M ⁺ +1).

Example 23 1-benzyl-4,4-dimethyl-3-N-acetylaminomethylpyrrolidine

Compound Example 6 (3.0 g, 13.7 mmol) was dissolved in dichloromethane (30 ml), acetyl chloride (2.51 g, 32 mmol) was added dropwise, stirred at room temperature for 2 hr, and then washed with water (50 ml×3). Dry over anhydrous magnesium sulfate, and evaporate the solvent to dryness. VLC column chromatography separation (petroleum ether, ethyl acetate as eluent). A pale yellow oil (2.96 g, 83.1%) was obtained.

¹ HNMR (CDCl ₃ ) δppm: 0.991 (3H, s, 3-CH ₃ ), 1.092 (3H, s, 3-CH ₃ ), 2.425 (3H, s, -COCH ₃ ), 1.906～1.957, 2.400～3.226 (7H, m, 3×CH ₂ and 4-CH), 3.600 (2H, s, benzyl-CH ₂ ), 7.219～7.321 (5H, m, ArH)

ESIMS: 261 (M ⁺ +1)

Example 24 4,4-Dimethyl-3-N-acetylaminomethylpyrrolidine

Take the compound of Example 22 (2.5g, 9.6mmol), dissolve it in absolute ethanol (about 50ml), add freshly prepared 10% Pd/C (4.0g), and react under hydrogen pressure of 40-50Psi at room temperature for 24hr , TLC showed that the starting material disappeared, the Pd/C was filtered off, and concentrated to dryness to obtain a pale yellow oil (1.32 g, 80.0%).

¹ HNMR (CDCl ₃ ) δppm: 0.989 (3H, s, 3-CH ₃ ), 1.100 (3H, s, 3-CH ₃ ), 2.359 (H, s, -COCH ₃ ), 1.900～1.941, 2.370～3.230 (7H, m, 3×CH ₂ and 4-CH)

ESIMS: 173 (M ⁺ +1)

Example 25 1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4- Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

Compound 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5g, 1.40 mmol), DBU (0.43ml, 5mmol) and the compound of Example 24 (0.36g, 2.1mmol) were dissolved in acetonitrile (10ml), reacted at room temperature for 8h, filtered off the solid, and then hydrolyzed with 30% sodium hydroxide for 4h , dilute hydrochloric acid to adjust the pH to 7, filter out the solid, 80%, and recrystallize from ethanol to obtain an off-white solid.

The analytical data of the obtained product is the same as that of Example 18 Method 2 compound.

Embodiment 26 coated tablet:

Tablet prescription:

Example compound eighteen 10.0g

Lactose 50.0g

Starch 40.0g

Hydroxypropyl Cellulose 4.0g

10% progesterone appropriate amount

Magnesium stearate 0.5g

Take the above ingredients and mix evenly, granulate, sieve and adjust the granules, dry and tablet to make 100 tablet cores.

Coating Solution Prescription:

Opadry (Opadry) 5g, 80% ethanol appropriate amount of coating.

Example 27 Capsules

prescription:

Example compound 20 100g

Starch 10g

Sodium carboxymethyl starch 20g

Low-substituted hydroxypropyl cellulose 10g

Tween 80 Appropriate amount

Proper amount of polyvinylpyrrolidone 5% ethanol solution

Sodium Lauryl Sulfate 8g

No. 0 Gastric Dissolved Capsules 1000 Capsules

Made into 1000 capsules

Preparation:

Take the raw and auxiliary materials of the prescription amount, sieve them separately, add 5% polyvinylpyrrolidone alcohol solution and Tween 80 soft material, granulate with a 20-mesh sieve, dry at room temperature at 15°C, add sodium lauryl sulfate, mix Evenly, according to 0.27g/S, put into No. 0 stomach-soluble capsules, take a sample for testing, the dissolution limit is Q=80%, and the content should be 90-110% of the labeled amount.

Claims (7)

1. A compound of formula (I) or its pharmaceutically acceptable salt, hydrate, or optical isomer with the following structure,

In the formula Y represents: H, C ₁ -C ₆ alkyl with or without hydroxyl, halogen or amino substitution, or 5-methyl-2-oxo-1,3-dioxol-4-enylmethyl, Or alkylacyloxymethyl; A represents: CH, CF, C-Cl, C-OCH ₃ , C-CH ₃ or N; R ₁ represents C ₁ -C ₃ -alkyl, F-CH ₂ CH ₂ - , cyclopropyl, fluorocyclopropyl or phenyl which may be monosubstituted to trisubstituted by halogen, Or A and R ₁ together represent: a bridge with a CO-CH ₂ -CH(CH ₃ )-structure; Z represents: H, halogen, NH ₂ , CH ₃ ; R ₂ and R ₃ may be the same or different, each representing H, C ₁ -C ₆ -alkyl, amino protecting group; wherein the amino protecting group represented by R ₂ and R ₃ is selected from: formyl, Acetyl, trifluoroacetyl, benzoyl, p-toluenesulfonyl, methoxy or ethoxy or tert-butoxy or isobutoxy or trichloroethoxycarbonyl, p-methoxybenzyloxycarbonyl or benzyloxycarbonyl, alkane Acyloxymethyl, p-methoxybenzyl and benzyl, trityl, tetrahydrofuryl, 5-methyl-2-oxo-1,3-oxol-4-enyl, α -Aminoalkylacyl. 2. by the formula (I) compound described in claim 1 or its pharmaceutically acceptable salt, hydrate, optical isomer, be following compound: 1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline -3-carboxylic acid, 5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-8-methoxy-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methylaminomethylpyrrolidin-1-yl)-8-methoxy-1,4-dihydro-4 -Oxoquinoline-3-carboxylic acid, 1-(2,4-difluorophenyl)-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3 -carboxylic acid, 5-Amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-8-methoxy-1,4-dihydro -4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-1,4-dihydro-4-oxo-1,8- Naphthyridine-3-carboxylic acid, Or 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethylpyrrolidin-1-yl)-8-methoxy-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid. 3. The preparation method of the formula (I) compound of claim 1, comprising: Method A: reacting a compound of formula (II) with a compound of formula (III) or a derivative thereof, In the formula, X is a halogen atom, and the definitions of A, R ₁ , Z, and Y are the same as in claim 1; In the formula, R ₂ and R ₃ are as defined in claim 1; it is characterized in that: in the presence of an acid acceptor in the solvent, the compound of formula (II) is reacted with the compound of formula (III); if necessary, the compound of formula (I) can be removed the protecting group of the compound; Method B: reacting a compound of formula (IV) with a compound of formula (III) or a derivative thereof,

In the formula, X is a halogen atom, R represents an aliphatic carboxyl group of 2 to 6 carbon atoms with or without heteroatom substitution, or an aromatic carboxyl group of 7 to 11 carbon atoms, and the definitions of A, R ₁ and Z are the same as in the claims 1; it is characterized in that: react in the presence of an acid acceptor in a solvent to obtain the (V) compound; remove the boron-containing group in the compound of the formula (V) to obtain the compound of the formula (I), if necessary, remove the compound of the formula (I) Protecting group of compound

In the formula, R ₁ , R ₂ , R ₃ , A, Z are the same as claim 1; If necessary, the compound (I) prepared by the above method is converted into a pharmaceutically acceptable salt, hydrate, or optical isomer. 4. The antibacterial pharmaceutical composition using the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, hydrate or optical isomer thereof as an active ingredient. 5. The antibacterial pharmaceutical composition according to claim 4, which can be used for gastrointestinal or parenteral administration. 6. The antibacterial pharmaceutical composition of claim 5, these compositions are tablet, capsule, dry suspension, ointment, suppository, injection. 7. Compounds of the following formula

Wherein R ₂ and R ₃ are as defined in claim 1.