CN1273452C - 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation - Google Patents
7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation Download PDFInfo
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- CN1273452C CN1273452C CN 200410046130 CN200410046130A CN1273452C CN 1273452 C CN1273452 C CN 1273452C CN 200410046130 CN200410046130 CN 200410046130 CN 200410046130 A CN200410046130 A CN 200410046130A CN 1273452 C CN1273452 C CN 1273452C
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Abstract
The present invention relates to a 7-(4, 4-dimethyl-3-aminomethyl pyrrolidine-1-yl) substituted neoquinoline carbonic acid derivative with the structure disclosed in a formula (I) and a preparation method thereof. The compound can be used as an antibacterial agent or feed additive, wherein A represents CH, or CF, or CCl, or COCH3, or CCH3 or N; Z represents H, or halogen, or NH2 or CH3; R1 represents C1-C3-alkyl, or FCH2CH2-, or cyclopropyl, or fluorine cyclopropyl or trisubstituted phenyl singly substituted by halogen, or A and R1 represent a bridge with the structure of C-O-CH2-CH (CH3)-; Y represents H, or hydroxy or no hydroxy, or C1-C6-alkyl substituted by halogen or amido, or 5-methyl-2-oxo-1, 3-dioxolan-4-alkenyl methyl, or alkyl acyl-oxygen methyl; R2 and R3 can be identical or different and respectively represent H.
Description
Technical field:
The present invention relates to have the active new fluoroquinolone of excellent antibacterial and naphthalene piperidine ketone acid derivant and preparation method thereof; Relate to the antiseptic-germicide and the fodder additives that contain them.
Background technology:
Quinolones develops into the synthetic drugs that has become a class wide spectrum, efficient, low toxicity now from Nalidixic Acid (nalidixic acid, J.Med.Chem.1962,5,1063) in 1962.Early stage quinolones has stronger anti-microbial activity to Gram-negative bacteria, but it is lower to gram-positive bacteria activity, though Shang Shi quinolones such as Gatifloxacin (Drug recently, 1999,58 (4): 683) etc. anti-microbial activity makes moderate progress, the activity of resisting gram-positive bacteria remains further to be strengthened, and needs to strengthen the anti-microbial activity to some specific bacteria such as streptococcus pneumoniae, faecalis etc. simultaneously but in general.
Report (JP05,345,777 are arranged; Chem.Pharm.Bull.44 (7) 1376-1386 (1996)), 7 certain anti-microbial activities of quinlone compounds that have (4,4-dimethyl-3-amino-pyrryl) to replace.
Aminomethyl-(CN.1400209 2003-03-05), has broad spectrum antibiotic activity to 5-azaspiro [2,4] heptane substituting group to introduce 7-in the 7-position of the female ring of quinlone.The active of resisting gram-positive bacteria obviously strengthens.
We introduce aminomethyl in the 3-position of tetramethyleneimine, and dimethyl is introduced in the 4-position, has obtained new quinoline carboxylic acid compound, these compounds document compound known different from the past.Through measuring the pharmacologically active of these compounds, discovery has beyond thought effect, they are to gram-positive microorganism, particularly to resistant organism (two strain MRSA-methicillin-resistants gold Portugal bacterium, two strain MRSE-methicillin-resistant staphylococcus epidermidiss) show strong anti-microbial activity, thereby finished the present invention.
Summary of the invention:
The invention provides formula (I) compound or the acceptable salt of its medicine, ester, acid amides, hydrate, optical isomer, xln.
Compound of the present invention is that a kind of examining on the 7-position at quinolone has (4,4-dimethyl-3-aminomethyl-tetramethyleneimine) substituent quinolone compounds.Compound of the present invention is compared the more weak quinolone antimicrobial thing of the activity of gram-positive microorganism with known, has particularly anti-MRSA of superior resisting gram-positive bacteria and MRSE bacterium activity.Formula of the present invention (I) compound structure is as follows:
Wherein:
A represents CH, CF, CCl, COCH
3, CCH
3Or N
Z represents H, halogen, NH
2, CH
3
R
1Represent C
1-C
3-alkyl, FCH
2CH
2-, cyclopropyl, fluorine cyclopropyl or can be replaced to trisubstd phenyl, perhaps A and R by the halogen list
1Representative has C-O-CH together
2-CH (CH
3The bridge of)-structure;
Y represents H, has or do not have hydroxyl, halogen or the amino C that replaces
1-C
6-alkyl, or 5-methyl-2-oxo-1,3-dioxane penta-4-thiazolinyl methyl or alkyl acyl-oxygen methyl;
R
2, R
3Can be identical, also can be different, represents H separately, C
1-C
6-alkyl; amino protecting group etc.; these amino protecting groups have: formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formyl radical, p-toluenesulfonyl, methoxy or ethoxy or uncle's fourth oxygen or isobutyl oxygen or trichloro-ethoxycarbonyl, replacement or substituted benzyl oxygen carbonyl not; alkyl acyl-oxygen methyl, replacement or not substituted benzyl, trityl, tetrahydrofuran base, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alpha-aminoalkyl acyl group.
The invention still further relates to the preparation method of formula (I) compound as defined above and contain the antibacterial combination of formula (I) compound as activeconstituents.
The formula that the present invention relates to (I) compound, in the tetramethyleneimine of formula (I) compound part, wherein replace aminomethyl carbon atom be unsymmetrical carbon, therefore can R or S or R and S blended form exist, the present invention includes all these isomer and mixture.
Formula of the present invention (I) compound can form pharmaceutically acceptable non-toxic salt.These salt comprise the salt with mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc., with organic acid such as acetate, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or malate, and resemble amino acid saltss such as L-Ala, aspartic acid, Methionin or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc.Also their an alkali metal salt of conversion processes, alkaline earth salt, silver salt, barium salt etc. routinely.
The ester class of formula of the present invention (I) compound not only comprises and replacing or unsubstituted fatty ester, especially 1-6 carbon atom, as lower alkyl esters such as methyl esters, and comprise by intravital chemical hydrolysis or enzymic hydrolysis, at least can partly be converted into the ester class of formula (I) compound, as acetyl oxygen methyl esters, pivalyl oxygen methyl esters, the ethoxycarbonyl 2-ethoxyethyl acetate, cholinesterase, amino ethyl ester (as: diformazan ammonia ethyl ester or 1-piperazinyl ethyl ester), 5-2,3-indanyl ester, phthalidyl ester and hydroxy alkyl ester (as: 2-hydroxyl ethyl ester or 2,3-two hydroxypropyl acrylates), 5-methyl-2-oxo-1,3-dioxane penta-4-alkene methyl ester.
Formula of the present invention (I) compound also can solvate (as hydrate) form exist, therefore, these solvates are also included within the compound of the present invention.
The invention still further relates to the preparation method of formula (I) compound, compound of the present invention can adopt the method preparation shown in the following reaction scheme 1.
Reaction scheme 1:
In above route, Y, R
1, R
2, R
3, Z and A define as the aforementioned; Reach X and represent halogen atom, be preferably fluorine and chlorine.
According to reaction scheme, can be by in the presence of solvent and add suitable alkali, or without solvent, satisfy the demand with excessive formula (III) compound, ℃ have or do not have under the pressure condition stirring reaction formula (II) compound and formula (III) compound 0.5-10 hour in room temperature to 200, come preparation formula (I) compound.Formula (III) compound of available free form of mixtures or itself and the formed salt of example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid in this reaction.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine or the hexamethyl-phosphoramide of using.
This reaction is generally carried out in the presence of acid acceptor.In this case, in order to improve the reaction efficiency of more expensive initiator formula (II) compound, using excessive reactant formula (III) compound, is to wait mole to 10 times of molar weights to relative initiator for example, superior equimolar amount to 5 times molar weight.When using excess reactant formula (III) compound, the unreacted mixture that stays after the reaction is recyclable and be reused for reaction.The superior acid acceptor that is used for this reaction comprises mineral alkali such as sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride etc., organic bases such as triethylamine, diisopropylethylamine, pyridine, N, N-dimethylamino pyridine, N, N-dimethylamino-aniline, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU), 1,4-diazabicyclo [2,2,2] octanes (DABCO) etc.
Routine is used for organic chemistry filed and that be easy to remove after reaction and does not decompose any protecting group of the structure of target compound, can be used as amino protecting group suitable in formula (III) compound.The object lesson that can be used for this object protecting group comprises formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formyl radical, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, replacement or not substituted benzyl oxygen carbonyl, replacement or not substituted benzyl, trityl, THP trtrahydropyranyl, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alkyloyloxyethyl methyl, alpha-aminoalkyl acyl group etc.
After reaction was finished, the amino protecting group that exists in the formula of formation (I) compound can be removed by hydrolysis, solvolysis or reduction according to the relevant nature of protecting group.For example, formula (I) compound in solvent have or mineral acid or alkali in the presence of under 0-150 ℃ of temperature, handle and slough protecting group.The acid that can be used for this purpose can relate to mineral acid as hydrochloric acid, Hydrogen bromide, phosphoric acid etc., and organic acid is as acetate, trifluoroacetic acid, formic acid, toluenesulphonic acids etc.Or lewis acid as: boron tribromide, aluminum oxide etc.The alkali that is used for this purpose can use the oxyhydroxide of basic metal or alkaline-earth metal, as: sodium hydroxide, hydrated barta etc., alkaline carbonate be as yellow soda ash, lime carbonate etc., and alkali metal alcoholates is as sodium methylate, sodium ethylate etc., or sodium acetate etc.Reaction can carry out in solvent, and for example water or organic solvent be as ethanol, tetrahydrofuran (THF), dioxan, ethylene glycol, acetate etc., or the mixture of this organic solvent and water, as needs, this reaction also can be carried out in no any solvent.
In addition, when protecting group be p-toluenesulfonyl, benzyl, trityl, during to methoxy-benzyl, carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, trichloro-ethoxycarbonyl, β-iodo ethoxycarbonyl etc., these groups can be removed effectively by reduction.Though removing the reduction reaction conditions of protecting group changes along with the character of relevant protecting group; but hydrogen stream is generally used in this reduction; in inert solvent; catalyzer as: under 10-150 ℃ of temperature, carry out in the presence of platinum, palladium, the Raney nickel etc., or in ammoniacal liquor, under-50 ℃ to-10 ℃ temperature, carry out with sodium Metal 99.5 or metallic lithium.
Formula of the present invention (I) compound also can prepare by the method shown in the following reaction scheme 2.
Reaction scheme 2:
The R representative has or does not have the aliphatics carboxyl of 2-6 carbon atom of heteroatoms replacement in the above-claimed cpd, or is the aromatic carboxyl of 7-11 carbon atom, Y, R
1, R
2, R
3, Z and A define as the aforementioned; Reach X and represent halogen atom, superior is fluorine and chlorine.
It is currently known methods that Chinese style of the present invention (II) compound is converted into formula (IV) compound earlier, and can easily realize transforming (seeing CN 1059527A) by existing disclosed method.
The compound of logical formula V can prepare like this:
Make the compound of represented compound of general formula (IV) and general formula (III) expression carry out condensation.
According to reaction scheme, can be by in the presence of solvent and add suitable alkali, or without solvent, satisfy the demand with excessive formula (III) compound, ℃ have or do not have under the pressure condition stirring reaction formula (IV) compound and formula (III) compound 0.5-10 hour in room temperature to 200, prepare the formula V compound.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine or the hexamethyl-phosphoramide of using.
This reaction is generally carried out in the presence of acid acceptor.In this case, in order to improve the reaction efficiency of more expensive initiator formula (IV) compound, using excessive reactant formula (III) compound, is to wait mole to 10 times of molar weights to relative initiator for example, superior equimolar amount to 5 times molar weight.When using excess reactant formula (III) compound, the unreacted mixture that stays after the reaction is recyclable and be reused for reaction.The superior acid acceptor that is used for this reaction comprises mineral alkali such as sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride etc., organic bases such as triethylamine, diisopropylethylamine, pyridine, N, N-dimethylamino pyridine, N, N-dimethylamino-aniline, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU), 1,4-diazabicyclo [2,2,2] octanes (DABCO) etc.
The hydrolysis of logical formula V compound in basic solvent (for example: the solution in methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane or water such as triethylamine, ammoniacal liquor, sodium bicarbonate, salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, or in acidic solution (for example: the solution in water, alcohol, tetrahydrofuran (THF), dioxane, chloroform, methylene dichloride such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid, Hydrogen bromide) in 0-150 ℃ of reaction 0.5-10 hour down.
Routine is used for organic chemistry filed and that be easy to remove after reaction and does not decompose any protecting group of the structure of target compound, can be used as amino protecting group suitable in formula (III) compound.The object lesson that can be used for this object protecting group comprises formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formyl radical, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, replacement or not substituted benzyl oxygen carbonyl, replacement or not substituted benzyl, trityl, THP trtrahydropyranyl, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alkyloyloxyethyl methyl, alpha-aminoalkyl acyl group etc.
After reaction is finished, if having amino protecting group, can remove by hydrolysis, solvolysis or reduction in the formula of formation (I) compound according to the relevant nature of protecting group.For example, the formula V compound is sloughed protecting group handling in the presence of organic acid or mineral acid or the alkali under 0-150 ℃ of temperature in solvent.The acid that can be used for this purpose can relate to mineral acid as hydrochloric acid, Hydrogen bromide, phosphoric acid etc., and organic acid is as acetate, trifluoroacetic acid, formic acid, toluenesulphonic acids etc.Or lewis acid as: boron tribromide, aluminum oxide etc.The alkali that is used for this purpose can use the oxyhydroxide of basic metal or alkaline-earth metal, as: sodium hydroxide, hydrated barta etc., alkaline carbonate be as yellow soda ash, lime carbonate etc., and alkali metal alcoholates is as sodium methylate, sodium ethylate etc., or sodium acetate etc.Reaction can carry out in solvent, and for example water or organic solvent be as ethanol, tetrahydrofuran (THF), dioxan, ethylene glycol, acetate etc., or the mixture of this organic solvent and water, as needs, this reaction also can be carried out in no any solvent.
In addition, when protecting group be p-toluenesulfonyl, benzyl, trityl, during to methoxy-benzyl, benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, trichlorine ethoxy carbonyl, β-iodo ethoxy carbonyl etc., these groups can be removed effectively by reduction.Though removing the reduction reaction conditions of protecting group changes along with the character of relevant protecting group; but hydrogen stream is generally used in this reduction; in inert solvent; in the presence of catalyzer such as platinum palladium Raney nickel etc., under 10-150 ℃ of temperature, carry out, or in ammoniacal liquor, under-50 ℃ to-10 ℃ temperature, carry out with sodium Metal 99.5 or metallic lithium.
Formula (II) compound as initiator is a known compound in the present invention, and (for example: L.A.Mitscher etc., J.Med.Chem.30,2283 (1987) can easily make by known method in the existing publication; J.M.Domagala etc., J.Med.Chem.31,503 (1988); D.T.W.Chu etc., J.Med.Chem.29,2633 (1986); J.M.Domagala etc., J.Med.Chem.34,1142 (1991); D.Bouzard etc., J.Med.Chem.35,518 (1992); J.M.Domagala etc., J.Med.Chem.31,991 (1988)).
According to the method shown in the following reaction scheme 3, can prepare formula (III) compound of another initiator of the present invention.
Reaction scheme 3:
P represents amino protecting group.The definition of its protecting group as mentioned above.
The present invention also provides and contains formula (I) compound, or the acceptable salt of its medicine, ester, acid amides, hydrate, optical isomer, xln are as the antimicrobial compound of activeconstituents.When this antimicrobial compound is used for clinical purpose, can combines with pharmaceutically acceptable inert support by it it is mixed with solid, semisolid or the liquid pharmaceutical formulation that oral, non-stomach and intestine use or use the part.The pharmaceutically acceptable inert support that can be used for this purpose can be solid-state or liquid.But can prepare the solid or the semisolid pharmaceutical formulation of pulvis, tablet dispersion powder, capsule, suppository and glue cream form, use solid-state carrier in the case usually.Spendable solid carrier is preferably one or more materials in thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain the micronize activeconstituents of 5%-70%.The specific examples of suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, Huang are had a liking for glue, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc., because they are easy to the oral solid formulation that favorable for absorption is represented in administration, tablet, pulvis, capsule.
Liquid preparation comprises solution, suspension and emulsion.For example the injectable formulation of parenteral canal drug administration can be water or water and propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. are suitable for the physiological condition of live body.Liquid preparation also can be made into form in the polyoxyethylene glycol aqueous solution.Can add appropriate colouring agent, seasonings, stablizer and thickening material again by being dissolved in the water activeconstituents is molten, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to prepare in viscous substance such as natural or synthetical glue, methylcellulose gum, acid methyl cellulose sodium and other the known suspension agent and be used in oral aqeous suspension.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in the 1-500mg scope according to the effectiveness of selected activeconstituents.
When formula of the present invention (I) active compound during as the medicine of treatment infectation of bacteria, the preferred amount of the 6-14mg/kg body weight of giving in the fs.But dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can determine to be suitable for the preferred dose of certain situation according to a conventional method.Generally, the amount of begin treatment is lower than the optimal dose of activeconstituents, increases dosage then gradually, up to reaching optimum therapeuticing effect.For simplicity, total per daily dose can be divided into several parts, divides administration for several times.
As mentioned above, The compounds of this invention to gram positive bacterial strain particularly the anti-microbial activity of resistant organism far above the activity of known antimicrobial agents.
Actual application value and meaning for outstanding this patent compound, (Jing Xin pharmaceutical factory provides by the Xinchang, Zhejiang with the Gatifloxacin of up-to-date listing in wherein embodiment 18,20 and the similar compound, lot number 020716), and the Ciprofloxacin (pharmaceutical factory of central authorities provides lot number 020307 by Tianjin) that is extensive use of and occupies all the time the very big market share.Minimum inhibitory concentration such as laxative remedy are measured: the compound of pressing the double dilution method dilution test, then it is dispersed in pH and transfers to 8.0, and in autoclaved DIFCO substratum, behind the inoculation bacterium liquid, cultivated the minimum concentration of observed and recorded bacteria growing inhibiting (MIC) 18 hours in 37 ℃.Measurement result is listed in the table 1.
Table 1
| The experiment bacterium | MIC(mg/L) | |||
| The embodiment compound | The contrast medicine | |||
| 18 | 20 | Ciprofloxacin | Gatifloxacin | |
| The gold bacterium MRSA 03-1 of Portugal | 0.125 | 0.03 | 0.125 | 0.125 |
| The gold bacterium MRSA 03-19 of Portugal | 0.125 | 0.015 | 0.125 | 0.06 |
| Faecalis 30428 | 2 | 0.5 | 16 | 16 |
| Form staph 03-10 | 0.25 | 0.06 | 2 | 1 |
| Form staph MRSE 03-2 | 2 | 0.125 | 16 | 4 |
| Form staph MRSE 03-32 | 0.5 | 0.5 | 2 | 1 |
The plate doubling dilution is used in determination of activity, substratum is MH (DIFCO) substratum, the experiment bacterial strain uses therefor be 2002-2003 from Sichuan, the Beijing area clinical separation pathogenic bacterium of collecting, used bacterial classification is being collected isolating unit (clinical laboratory of Huaxi Medical Univ, Medical University Of Chongqing's contagious department and Beijing Hospital's Bacteriology Room) all after the automatic bacteria detector is identified, use after Sichuan Industrial Institute of Antibiotics identifies again with the API system again.
The pharmacokinetics aspect of performance is compared with known quinolone compounds, and The compounds of this invention has suitable water-soluble, therefore can be absorbed well in vivo, show very high bioavailability, the suitable antiseptic-germicide that is used as.
In addition, because the low curative effect height of the toxicity of The compounds of this invention, it can be used for prevention effectively and the treatment warm blooded animal comprises that the mankind are by the caused disease of infectation of bacteria.
Embodiment:
In the following example, will more specifically explain the present invention.But should be understood that the following example to be intended to the present invention is described and scope of the present invention is not constituted any restriction.
Embodiment one 1-benzyl-3,3-dimethyl-2,4-dioxo tetramethyleneimine
In being furnished with drying tube and churned mechanically 1000ml there-necked flask, adding exsiccant DMF (300ml), methyl aceto acetate (130g, 1mol), adding Anhydrous potassium carbonate under stirring (286g, 2.2mol), dropping methyl iodide under the ice bath (390g, 2.8mol).Finish stirring at room reaction 7 days.The elimination solid, and with methylene dichloride (about 100ml) washing solid, filtrate adds water (500ml), extracts with methylene dichloride (about 100ml * 3), merge organic layer, wash three times, anhydrous magnesium sulfate drying filters, steaming desolventizes to doing, and gets light yellow oil (125g, yield 79.0%).
In the 500ml there-necked flask, and the above-mentioned oily matter of adding compound (77g, 0.487mol), dropping bromine under the dehydrated alcohol (180ml), ice bath (77g, 0.481mol), finish, stirring at room reaction 2hr removes the solvent of half approximately under reduced pressure, add water (200ml),, merge organic layer with methylene dichloride (about 100ml * 3) extraction, wash three times, anhydrous magnesium sulfate drying filters, and steams to desolventize to doing.
In above-mentioned residue, add dehydrated alcohol (160ml), and dropping benzylamine under ice bath (98g, 0.92mol).Finish, in room temperature reaction 20hr, thin layer is followed the tracks of reaction.Remove solvent under reduced pressure, residue is dissolved in the methylene dichloride (300ml), with 1N hydrochloric acid washed twice, is washed to neutrality, and anhydrous magnesium sulfate drying filters, steam desolventize crude product (90g).
This crude product is dissolved in the methylene dichloride (200ml), overstriking silica gel (90g), evaporated under reduced pressure is the gradient elution solvent with ethyl acetate and sherwood oil, uses the VLC column chromatography for separation, gets product, faint yellow solid (50.0g, 47.6%).
1HNMR (CDCl
3) δ ppm: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)
13CNMR (CDCl
3) and DEPT δ ppm:20.523 (uncle C, 2 * CH3), 45.805 (secondary C, 5-CH2), 47.124 (season C, 3-C), 53.588 (secondary C, benzyl-CH2), 128.019～128.947 (uncle C, aromatic ring CH), 135.213 (season C, aromatic ring C), 175.550 (season C, 4-C=O), 210.399 (season C, 2-C=O)
EIMS：217(M
+)
Embodiment two 1-benzyls-3,3-dimethyl-2-oxo-4-ethoxycarbonyl methylene pyrrolidine
The sodium hydride (6.5g) of adding 60% in exsiccant tetrahydrofuran (THF) (150ml) stirs and is cooled to 0 ℃～-5 ℃, drips the phosphonic acids triethyl, finish, stirring at room reaction 1.5hr, reaction solution is the jelly shape, room temperature drips compound embodiment one compound, and (28.0g 0.129mol), finishes, room temperature reaction 2hr, with ethyl acetate (300ml) dilution, the saturated common salt water washing is to neutral, anhydrous magnesium sulfate drying, steaming desolventize to do oily product C-7, (30.95g, 83.6%).
1HNMR (CDCl
3) δ ppm: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(C
6H
5CH
2 +)
Embodiment three 1-benzyls-3,3-dimethyl-2-oxo-4-ethoxycarbonylmethyl group tetramethyleneimine
Add dehydrated alcohol (700ml), and active nickel and compound embodiment two compounds (30.95g, 0.108mol), in room temperature, 40～50psi hydrogen pressure is reaction 12hr down, and TLC shows that reaction finishes the elimination nickel powder, steaming desolventizes to doing, and gets light yellow oil (29.3g, 94.0%).
1HNMR (CDCl
3) δ ppm: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, with hydrocarbon coupling, 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
6H
5N＝CH
2)，91(C
6H
5CH
2 +)
Embodiment four 1-benzyls-3,3-dimethyl-2-oxo-4-carboxyl crassitude
In 500ml single port flask, add compound execute example three compounds (29.3g, 0.101mol), 95% ethanol (150ml), 5% aqueous sodium hydroxide solution (150ml), stirring at room reaction 3hr, TLC shows that reaction finishes, remove part ethanol under reduced pressure, add decolorizing with activated carbon, filter, filtrate transfers pH less than 2 with 10% hydrochloric acid, and cooling leaches solid, the water layer dichloromethane extraction, organic layer washing, drying, steaming desolventizes, altogether faint yellow solid (21.6g, 81.6%).
1HNMR (CDCl
3) δ ppm: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
2And 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
6H
5CH
2 +)
Embodiment five 1-benzyls-3,3-dimethyl-2-oxo-4-aminomethyl pyrrolidine
Getting compound executes routine Four Modernizations compound (8.0g 31mmol), adds acetone (40ml) and triethylamine (3.9ml), between 0 ℃～-5 ℃, drip isobutyl chlorocarbonate (5.2ml), finish, reaction 40min, under this temperature, drip sodiumazide (4.2g, the 0.7mol) solution of water-soluble (15ml), restir 30min, with frozen water (100ml), with dimethylbenzene (50ml * 4) extraction, merge, wash three times, anhydrous magnesium sulfate drying filters.
With this xylene solution air distillation, to interior temperature rise to 140 ℃, change reflux into, backflow 3hr removes solvent under reduced pressure, adds 8N hydrochloric acid (60ml), backflow 0.5hr, cooling is abandoned it with benzene (20ml * 2) extraction, water layer transfers pH greater than 10 with 30% sodium hydroxide solution, with methylene dichloride (30ml * 4) extraction, merges organic layer, saturated common salt washing twice, anhydrous magnesium sulfate drying filters, steaming desolventizes, and gets faint yellow oily thing (3.59g, 49.9%).
1HNMR (CDCl
3) δ ppm:0.990 (3H, s, 3-CH
3), 1.227 (3H, s, 3-CH
3), 1.740 (bro, NH
2Add D
2O exchanges disappearance), 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
6H
5CH
2 +)
Embodiment six 1-benzyls-4,4-dimethyl-3-aminomethyl pyrrolidine
In exsiccant tetrahydrofuran (THF) (25ml), add LiAlH
4(2.54g, 54mmol), ice bath drips down compound and executes example five compounds (2.59g 11.6mmol) is dissolved in the solution of tetrahydrofuran (THF) (10ml), the reflux that finishes 5hr.Cooling drips water (2ml) successively, 15% aqueous sodium hydroxide solution (2ml), water (6ml), stirring at room 20min filters, steam desolventize as for, faint yellow oily thing (2.22g, 87.7%).The flaggy compartment analysis takes a morsel.
1HNMR (CDCl
3) δ ppm: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)
Embodiment seven 1-benzyls-4,4-dimethyl-3-N-tertbutyloxycarbonyl aminomethyl pyrrolidine
Get compound execute example six compounds (3.0g 13.7mmol) is dissolved in methylene dichloride (30ml), add tertbutyloxycarbonyl two carbonic ethers (5.56g, 32mmol), stirring at room reaction 2hr, water (50ml * 3) is washed then.Anhydrous magnesium sulfate drying, steaming desolventize to doing.VLC column chromatography for separation (sherwood oil, ethyl acetate are eluent).Get faint yellow oily thing (3.9g, 89.0%).
1HNMR (CDCl
3) δ ppm: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
2And 4-CH), 3.598 (2H, s, benzyl-CH
2), 7.222～7.331 (5H, m, ArH)
ESIMS：319(M
++1)
Embodiment 84,4-dimethyl-3-N-tertbutyloxycarbonyl aminomethyl pyrrolidine
Get compound and execute example seven compound (6.0g, 18.6mmol), be dissolved in the dehydrated alcohol (about 100ml), add freshly prepd 10% Pd/C (8.0g), room temperature 40～50Psi hydrogen pressure is reaction 24hr down, and TLC shows that raw material disappears, elimination Pd/C, be concentrated into dried, faint yellow oily thing (3.4g, 79.8%).
1HNMR (CDCl
3) δ ppm: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
2And 4-CH)
ESIMS：229(M
++1)
Embodiment 94,4-dimethyl-3-aminomethyl pyrrolidine hydrochloride
With the compound of embodiment eight (2.28g 10mmol), adds the methanol/methyl acetate solution (10ml) of anhydrous HCl, stirs 0.5hr and takes off BOC, steam desolventize oily matter (1.09g, 85.3%).
1HNMR (CDCl
3) δ ppm: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
2And 4-CH)
ESIMS：129(M
++1)
Embodiment ten 1-benzyls-3,3-dimethyl-4-(N-methyl-N-tertbutyloxycarbonyl) aminomethyl pyrrolidine
In exsiccant tetrahydrofuran (THF) (40ml), add embodiment eight compounds (4.0g, 12.5mmol), ice bath dropping methyl iodide (3.55g, 25mmol), room temperature reaction 2hr, slowly add water, dichloromethane extraction (100ml * 3), washing organic layer, anhydrous sodium sulfate drying, filter, steaming desolventizes to doing, and gets faint yellow oily thing (3.42g, 82.3%).
1HNMR (CDCl
3) δ ppm: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)
Embodiment 11,3-dimethyl-4-(N-methyl-N-tertbutyloxycarbonyl) aminomethyl pyrrolidine
(3.4g 10.2mmol), is dissolved in the dehydrated alcohol (80ml), adds freshly prepd 10% Pd/C (4.0g) to get embodiment ten compounds, room temperature 40～50Psi hydrogen pressure is reaction 24hr down, and TLC shows that raw material disappears elimination Pd/C, be concentrated into dried, faint yellow oily thing (0.87g, 90.1%).
1HNMR (CDCl
3) δ ppm: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)
Embodiment 12,3-dimethyl-4-methyl aminomethyl pyrrolidine hydrochloride
With the compound of embodiment 11 (2.43g 10mmol), adds the methanol/methyl acetate solution (10ml) of anhydrous HCl, stirs 0.5hr and takes off BOC, steam desolventize oily matter (1.31g, 92%).
1HNMR (CDCl
3) δ ppm: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)
Embodiment 13 1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
Method one: compound 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (0.5g, 1.40mmol), DBU (0.43ml, 5mmol) (0.47g 2.1mmol) is dissolved in the acetonitrile (10ml) with the compound of embodiment 11, room temperature reaction 8h leaches solid.
With the cooling of methyl alcohol (10ml) ice bath, toward wherein slowly adding Acetyl Chloride 98Min. (5ml).This mixture stirring at room 30 minutes to be preparing the methanol/methyl acetate solution of anhydrous HCl, toward wherein add above-mentioned solid (0.30g, 0.56mmol).Reaction mixture is evaporated to the residue a small amount of solvent then in stirring at room 30 minutes, and the cooling back adds ether (50ml) and stirs fast solidifies product, abundant sedimentation after-filtration, and filter cake gets off-white color solid (0.58g, 90.1%) with ethyl alcohol recrystallization.
1HNMR (CF
3COOD) δ ppm:0.938-1.304 (6H, m, 4 ' 2 CH
3), 2.517 (1H, m, 3 '-H), 2.940 (3H, s, NCH
3), 2.700-4.547 (6H, m, 2 ', 5 '-H and5 '-CH
2N), and 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, also can prepare following salt, for example
1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrobromate;
1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid vitriol.
Method two: compound 7-chloro-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (0.5g, 1.40mmol), DBU (0.43ml, 5mmol) (0.30g 2.1mmol) is dissolved in the acetonitrile (10ml) room temperature reaction 8h with the compound of embodiment 12, leach solid, get off-white color solid (0.54g, 80.3%), C with 80% ethyl alcohol recrystallization then
23H
23F
3N
4O
3.H
2O
| C | H | N | |
| Calculated value | 57.68 | 5.36 | 11.61 |
| Measured value | 57.74 | 5.27 | 11.71 |
Embodiment 14 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid trifluoroacetate
Method one: boric acid (1.50g, 24.2mmol), diacetyl oxide (8ml, 80mmol), in 110 ° of reaction 1.5hr, cold slightly, add 1-cyclopropyl-6-fluorine 7-chloro-1, and 4-dihydro-4-oxo-quinoline-3-carboxylic acid (5.0g, 15mmol), equality of temperature reaction 6hr reduces to room temperature, in the impouring frozen water, filter, ethanol is washed, vacuum-drying, get 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-carboxylic boron diethyl ester.The compound of compound and embodiment 11 after the condensation, is directly used the 5%NaOH hydrolysis in acetonitrile/DBU thus, transfers pH to neutral with HCl, leaches solid, vacuum-drying.Take off BOC with trifluoroacetic acid, get faint yellow solid, productive rate 76.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:1.064-1.573 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.553 (1H, m, pyrrolidyl 3 '-H), 2.948 (3H, s ,-NCH
3), 3.298-4.270 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 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, also can prepare following salt, for example
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid acetate;
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid lactic acid salt;
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid maleate;
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid oxalate.
Method two: the method by method one prepares 1-cyclopropyl-6-fluoro-7-chloro-1, behind 4-dihydro-4-Oxoquinoline-3-carboxylic boron diethyl ester, the compound of compound and embodiment 12 is in acetonitrile/DBU after the condensation thus, directly use the 5%NaOH hydrolysis, transfer pH to neutral with HCl, leach solid, vacuum-drying gets solid, use the trifluoroacetic acid salify, get title compound.The characteristic of compound is with the product of method one.
Embodiment 15 5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride
5-amino-1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (0.50g, 1.6mmol) and the compound of embodiment 11 (0.72g 3.2mmol) is dissolved in the pyridine (10.0ml), in 100 ℃ of following reaction 6h.Reaction finishes, and steaming desolventizes, and resistates takes off BOC with the methanol/methyl acetate solution of anhydrous HCl, again to get yellow solid product (45.6%) behind the ethyl alcohol recrystallization.
1HNMR (300MHz, CF
3COOD) δ ppm:0.828-1.414 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.407 (1H, m, pyrrolidyl 3 '-H), 2.907 (3H, s ,-NCH
3), 3.562 (3H, s ,-OCH
3), 3.005-4.535 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 cyclopropyl 1H), 7.069,7.452 (bro ,-NH), 8.908,9.071 (1H, d, 2-H).
MS(ESI m/z)：433.5(M
++1)。
Embodiment 16 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
With 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1, the compound of 8-two naphthyridines-3-carboxylic acid and embodiment 11 are in pyridine after the condensation, be concentrated into dried, directly the methanol/methyl acetate solution with anhydrous HCl takes off BOC, gets the off-white color solid, productive rate 80.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:1.056-1.467 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.505-2.663 (1H, m, pyrrolidyl 3 '-H), 2.932 (3H, s ,-NCH
3), 2.663-4.575 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 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)。
Embodiment 17 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride
Boric acid, diacetyl oxide, cold slightly in 110 ° of reaction 1.5hr, treat that temperature reduces to 80 ℃, add 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, 80-100 ℃ is stirred 5h.Reduce to room temperature, in the slow impouring ice-water of above-mentioned reaction solution, continue to stir 0.5h.Filter, wash with big water gaging, small amount of ethanol successively, filter cake spends the night in room temperature vacuum-drying, gets the 1-cyclopropyl-6 of white solid, 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic boron diethyl ester.This compound and embodiment 11 are dissolved in the pyridine, react 6h down in 100 ℃.Reaction finishes, and steaming desolventizes, and resistates takes off BOC with the methanol/methyl acetate solution of anhydrous HCl, be concentrated into dried, with behind the ethyl alcohol recrystallization the khaki color solid product, 53.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:1.093-1.508 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.480 (1H, m, pyrrolidyl 3 '-H), 2.940 (3H, s ,-NCH
3), 3.648 (3H, s ,-OCH
3), 3.432-4.409 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 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)。
Embodiment 18 1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
Method one: the preparation method is with embodiment 13,7-chloro-1-(2,4 difluorobenzene base)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid and the reaction of embodiment eight compounds, the off-white color solid, yield: 84.3%.
1HNMR (CF
3COOD) δ ppm:0.975-1.340 (6H, m, 4 ' 2 * CH
3), 2.540 (1H, m, 3 '-H), 3.164-4.606 (6H, m, 2 ', 5 '-H and, 5 '-CH
2N), 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 two: the preparation method is with embodiment 13 method twos, 7-chloro-1-(2,4 difluorobenzene base)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid and embodiment nine reactions, the product of gained gets the off-white color solid, yield with 80% Ethanol Treatment: 86.3%.C
22H
21F
3N
4O
3.H
2O
| C | H | N | |
| Calculated value | 56.78 | 5.08 | 11.98 |
| Measured value | 56.89 | 4.99 | 12.06 |
Embodiment 19 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride
The preparation method is with embodiment 14,1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-carboxylic boron diethyl ester and the reaction of embodiment eight compounds, handle the off-white color solid, yield: 84.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:1.015-1.504 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.484 (1H, m, pyrrolidyl 3 '-H), 3.245-4.291 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 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
+)。
Embodiment 20 5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride
The preparation method is with embodiment 15,5-amino-1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and the reaction of embodiment eight compounds, green solid, yield: 34.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:0.849-1.443 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.394-431 (1H, m, pyrrolidyl 3 '-H), 3.591 (3H, s ,-OCH
3), 3.135-4.441 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 cyclopropyl 1H), 7.269-7.387 (bro ,-NH), 8.993,9.091 (1H, d, 2-H).
MS(ESI m/z)：419.5(M
++1)。
Embodiment 21 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
The preparation method is with embodiment 16,1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-two naphthyridines-3-carboxylic acid and the reaction of embodiment eight compounds, the off-white color solid, yield: 67.3%.
1HNMR (300MHz, CF
3COOD) δ ppm:0.954-1.455 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.606 (1H, m, pyrrolidyl 3 '-H), 3.334-4.584 (7H, m, pyrrolidyl 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)
Embodiment 22 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride
The preparation method is with embodiment 17,11-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic boron diethyl ester and the reaction of embodiment eight compounds, the khaki color solid, yield: 72.5%.
1HNMR (300MHz, CF
3COOD) δ ppm:0.958-1.528 (10H, m, two-CH of volution cyclopropyl
2, 4 ' two-CH of pyrrolidyl
3), 2.382-2.582 (1H, m, pyrrolidyl 3 '-H), 3.591 (3H, s ,-OCH
3), 3.261-4.356 (7H, m, pyrrolidyl 2 ', 5 ', 4 '-CH
2-, 1 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)。
Embodiment 23 1-benzyls-4,4-dimethyl-3-N-ethanoyl aminomethyl pyrrolidine
Get compound execute example six compounds (3.0g 13.7mmol) is dissolved in methylene dichloride (30ml), dripping acetyl chloride (2.51g, 32mmol), stirring at room reaction 2hr, water (50ml * 3) is washed then.Anhydrous magnesium sulfate drying, steaming desolventize to doing.VLC column chromatography for separation (sherwood oil, ethyl acetate are eluent).Get faint yellow oily thing (2.96g, 83.1%).
1HNMR (CDCl
3) δ ppm: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
2And 4-CH), 3.600 (2H, s, benzyl-CH
2), 7.219～7.321 (5H, m, ArH)
ESIMS：261(M
++1)
Embodiment 24,4-dimethyl-3-N-ethanoyl aminomethyl pyrrolidine
Get and execute example 22 compounds (2.5g 9.6mmol), is dissolved in the dehydrated alcohol (about 50ml), adds freshly prepd 10% Pd/C (4.0g), room temperature 40～50Psi hydrogen pressure is reaction 24hr down, and TLC shows that raw material disappears elimination Pd/C, be concentrated into dried, faint yellow oily thing (1.32g, 80.0%).
1HNMR (CDCl
3) δ ppm: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
2And 4-CH)
ESIMS：173(M
++1)
Embodiment 25 1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Compound 7-chloro-1-(2,4 difluorobenzene base)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (0.5g, 1.40mmol), (0.43ml is 5mmol) with the compound (0.36g of embodiment 24 for DBU, 2.1mmol) be dissolved in the acetonitrile (10ml), room temperature reaction 8h leaches solid, uses 30% sodium hydroxide hydrolysis 4h then, dilute hydrochloric acid is transferred pH to 7, leach solid, 80%, ethyl alcohol recrystallization gets the off-white color solid.
The analytical data of products therefrom is with embodiment 18 method two compounds.
Embodiment 26 coating tablets:
The label prescription:
Embodiment compound 18 10.0g
Lactose 50.0g
Starch 40.0g
Hydroxypropylcellulose 4.0g
10% pregnant dimension ketone is an amount of
Magnesium Stearate 0.5g
Get mentioned component and mix, the whole grain that sieves after the granulation, dry, compressing tablet is made 100 labels.
Coating fluid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
Embodiment 27 capsules
Prescription:
Embodiment compound 20 100g
Starch 10g
Sodium starch glycolate 20g
Low-substituted hydroxypropyl cellulose 10g
Tween 80 is an amount of
Polyvinylpyrrolidone 5% ethanol liquid is an amount of
Sodium lauryl sulphate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules
The preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and tween 80 system softwood,, under 15 ℃ of room temperatures, dry with the granulation of 20 mesh sieves, add sodium lauryl sulphate, mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
Claims (7)
1. the formula that structure is following (I) compound or the acceptable salt of its medicine, hydrate, optical isomer,
In the formula
Y representative: H, there are or do not have hydroxyl, halogen or the amino C that replaces
1-C
6Alkyl, or 5-methyl-2-oxo-1,3-dioxane penta-4-alkene methyl, or alkyl acyl-oxygen methyl; A representative: C-H, C-F, C-Cl, C-OCH
3, C-CH
3Or N; R
1Represent C
1-C
3-alkyl, F-CH
2CH
2-, cyclopropyl, fluorine cyclopropyl or can be replaced to trisubstd phenyl by the halogen list,
Perhaps A and R
1Representative together: have C-O-CH
2-CH (CH
3The bridge of)-structure;
Z representative: H, halogen, NH
2, CH
3
R
2, R
3Can be identical, also can be different, represents H, C separately
1-C
6-alkyl, amino protecting group; R wherein
2, R
3The amino protecting group of representative is selected from: formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxy or ethoxy or uncle's fourth oxygen or isobutyl oxygen or trichloro-ethoxycarbonyl, to methoxyl group benzyloxy carbonyl or carbobenzoxy-(Cbz); alkyl acyl-oxygen methyl, to methoxy-benzyl and benzyl, trityl, tetrahydrofuran base, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alpha-aminoalkyl acyl group.
2. pressing the described formula of claim 1 (I) compound or the acceptable salt of its medicine, hydrate, optical isomer, is following compound:
1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid,
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid,
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid,
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-methyl aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid,
1-(2,4 difluorobenzene base)-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid,
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
5-amino-1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid,
1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid,
Or 1-cyclopropyl-6-fluoro-7-(4,4-dimethyl-3-aminomethyl pyrrolidine-1-yl)-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid.
3. the preparation method of the formula of claim 1 (I) compound comprises:
Method A:
With formula (II) compound and the reaction of formula (III) compound or derivatives thereof,
X is a halogen atom in the formula, A, R
1, Z, Y define with claim 1;
R in the formula
2, R
3Definition is with claim 1; It is characterized in that: in solvent, have in the presence of the acid acceptor, make the reaction of formula (II) compound and formula (III) compound; As needs, can remove the blocking group of formula (I) compound;
Method B:
With formula (IV) compound and the reaction of formula (III) compound or derivatives thereof,
X is a halogen atom in the formula, and R represents to have or do not have the aliphatics carboxyl of 2～6 carbon atoms of heteroatoms replacement, or the aromatic carboxyl of 7～11 carbon atoms, A, R
1, Z, definition be with claim 1; It is characterized in that: reaction in the presence of the acid acceptor is arranged in solvent, obtain (V) compound; Remove the formula V compound in the group of boracic get formula (I) compound, as needs, can remove the blocking group of formula (I) compound
R in the formula
1, R
2, R
3, A, Z be with claim 1;
As needs, the compound (I) of method for preparing is converted at pharmaceutically acceptable salt, hydrate, optical isomer.
4. formula (I) compound or the acceptable salt of its medicine, hydrate or the optical isomer with claim 1 is the antibacterial combination of activeconstituents.
5. the antibacterial combination of claim 4 can be used for gi tract or parenteral administration.
6. the antibacterial combination of claim 5, these compositions are tablet, capsule, dry suspensoid, paste, suppository, injection.
7. following formula: compound
R wherein
2, R
3Definition is with claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410046130 CN1273452C (en) | 2004-06-01 | 2004-06-01 | 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410046130 CN1273452C (en) | 2004-06-01 | 2004-06-01 | 7-(4,4-dimethyl 3-aminomethylpentazane-1-radicle) substituted, quinoline carboxylic acid derivative and its preparation |
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|---|---|
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| CN1273452C true CN1273452C (en) | 2006-09-06 |
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| SG144936A1 (en) | 2003-09-10 | 2008-08-28 | Kyorin Seiyaku Kk | 7-(4-substituted-3-cyclopropylaminomethyl-1- pyrrolidinyl)quinolonecarboxylic acid derivative |
| GB0505969D0 (en) * | 2005-03-23 | 2005-04-27 | Novartis Ag | Organic compounds |
| US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| CN107400075A (en) * | 2016-05-19 | 2017-11-28 | 湖南华腾制药有限公司 | A kind of preparation method of pregabalin intermediate |
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