CN103467392B - A kind of polyhalo pyrazinecarboxamide derivatives and its esters, preparation method and purposes - Google Patents

A kind of polyhalo pyrazinecarboxamide derivatives and its esters, preparation method and purposes Download PDF

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CN103467392B
CN103467392B CN201310465769.6A CN201310465769A CN103467392B CN 103467392 B CN103467392 B CN 103467392B CN 201310465769 A CN201310465769 A CN 201310465769A CN 103467392 B CN103467392 B CN 103467392B
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polyhalo
pyrazinecarboxamide
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derivatives
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CN103467392A (en
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蒋彦可
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Chongqing Technology and Business University
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Abstract

The invention belongs to technical field of medicine synthesis, relate to a kind of polyhalo pyrazinecarboxamide derivatives I, in order to solve the against mycobacterium tuberculosis limited activity of existing pyrazinecarboxamide, along with mycobacterium tuberculosis drug-resistant strains occurs, the problem that its against mycobacterium tuberculosis effect will be further compromised, the invention provides a kind of polyhalo pyrazinecarboxamide derivatives I, experiment proves that halo pyrazinecarboxamide derivatives I has good Killing Mycobacterium Tuberculosis performance, the present invention is implemented for the ease of those skilled in the art, present invention also offers polyhalo pyrazinecarboxamide derivatives I and the preparation method of its esters and the medicinal usage in terms of Killing Mycobacterium Tuberculosis and multi-drug resistance tubercule bacillus thereof.

Description

A kind of polyhalo pyrazinecarboxamide derivatives and its esters, preparation method and purposes
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of polyhalo pyrazinecarboxamide derivatives I, its chemical structural formula is as follows.The present invention sends out Existing polyhalo pyrazinecarboxamide derivatives I has good Killing Mycobacterium Tuberculosis and the effect of multi-drug resistance tubercule bacillus, to this end, the present invention also relates to And the preparation method of a kind of polyhalo pyrazinecarboxamide derivatives I and polyhalo pyrazinecarboxamide derivatives I application pharmaceutically, in order to ability Field technique personnel implement the present invention smoothly.
Technical background
Find treatment tuberculosis new, effective is current pharmacy and clinical medicine circle is paid special attention to difficult point and focus.Pyrazinecarboxamide Have notable at anti-tubercular, be a kind of important antituberculotics, be applied to clinic as far back as nineteen fifty, be mainly used in because of other resistive connection Core medicine Endodontic failure answer example of curing the disease.
Pyrazinecarboxamide is the prodrug of pyrazine carboxylic acid, and its antibacterial mechanisms is mostly derived from pyrazine acid (HPOA) dynamic equilibrium inside and outside antibacterial. Pyrazinamide is diffused in mycobacterium tuberculosis body, pyrazinamidase change into pyrazine acid, and a part of pyrazine acid is discharged and made environmental acidification outside bacterial body, In the pyrazine acid of protonation is diffused into bacterial body by outer row's mechanism of passive transport and defect again and constantly accumulate, thus suppress the transportation function of film, Make cell death.Pyrazinecarboxamide can also upset mycobacterium smegmatis cell Metabolism of nitrogen source, carboxylic acid and metabolism of organic acids, and then specifically upsets Glutamate, Glu metabolism and the degraded of amine.Pyrazinecarboxamide and pyrazine carboxylic acid mainly act on mycobacteria fatty acid synthase I in mycobacteria body (FASI) FASI, FASI, can be suppressed to have become the potential target of Effect of Anti tulase novel drugs.Pyrazinecarboxamide is in medical applications and research In importance in the prior art document (Int J Tuberc Lung Dis, 2003,26,6；Chem Prop Polym Mater, 2002,88,4) existing Describe.
Sickness rate lungy and case fatality rate are in rising trend in many countries, and substance of medicines-resistant branched tubercle bacillus (tulase) strain occur, endanger the tightest Weight.But, the against mycobacterium tuberculosis effect of pyrazinecarboxamide is limited, and especially for having, drug-fast tuberculosis branch strain drug effect is limited.
Summary of the invention
The technical problem to be solved is the against mycobacterium tuberculosis limited activity of existing pyrazinecarboxamide, and long-term prescription causes tuberculosis Mycobacteria drug-resistant strains generates and causes drug resistance to occur, and its against mycobacterium tuberculosis effect will be further compromised, and provides for this problem A kind of polyhalo pyrazinecarboxamide derivatives I, this derivant has a following chemical constitution:
Wherein R1For the one in F, Cl, Br, I；
R2For the one in H, group a, group b；
R in group a3For H, F or CF3In one；
R in group b4For H or F, R5For H, F or OCH3In one, R6For CH2CH3Or
Present invention discover that polyhalo pyrazinecarboxamide derivatives I has a good Killing Mycobacterium Tuberculosis activity, additionally it has also been found that to pyrazine It is the major reason of Killing Mycobacterium Tuberculosis increased activity that the structure of Methanamide carries out modifying, modification group at least include group a, group b and Multiple halogen substituent groups on pyrazine ring, the such as present invention has randomly choosed the representative derivant of three kinds of polyhalo pyrazinecarboxamide derivatives I, they It is respectively derivant 1, derivant 4 and derivant 6.
The antibacterial activity in vitro that derivant 1,4 and 6 and pyrazinecarboxamide carry out anti-mycobacterium tuberculosis and multi-drug resistance tubercule bacillus is tested and right The cytotoxicity experiment of VERO cell, result such as table 1.
Table 1
In table 1, MIC MTBaRepresent minimum inhibitory concentration when mycobacterium tuberculosis is had 90% suppression ratio, mycobacterium tuberculosis H in table37Rv (ATCC 27294) is purchased from DSMZ of country；MIC MDRTBbRepresent when multi-drug resistance mycobacterium tuberculosis is had 90% suppression ratio Minimum inhibitory concentration；In table, the source of multi-drug resistance tubercule bacillus is described as follows: 84 strain mycobacterium tuberculosis clinical separation strains are Shanghai City lung section doctor Institute's mycobacterium strain storehouse preserves bacterial strain, all is from the specimen culture of tuberculosis patient, and through strain identification be mycobacterium tuberculosis, with PhaB Method detection Drug Resistance of Mycobacterium Tuberculosis, obtains 56 strain persisters, and in table, data are meansigma methods.
The present invention still further provides inorganic acid salt and the acylate of some polyhalos pyrazinecarboxamide derivatives III, IV and II, described inorganic Hydrochlorate includes hydrochlorate, sulfate, phosphate, hydrobromate, metaphosphate, nitrate and sulfonate；Described acylate include acetate, Benzene sulfonate, benzoate, citrate, esilate, fumarate, gluconate, glycollate, isethionate, lactate, Lactobionate, maleate, malate, mesylate, succinate, tosilate and tartrate.
The basic salt of described polyhalo pyrazinecarboxamide derivatives IV includes the ammonium salt of polyhalo pyrazinecarboxamide derivatives IV, alkali metal salt and alkali Earth metal salt.
Above-mentioned salt has potential medical value, but its preparation method is simple, by polyhalo pyrazinecarboxamide derivatives III, IV and II is separately added into the bronsted lowry acids and bases bronsted lowry of correspondence, and regulation pH value also carries out crystallization treatment, i.e. available corresponding salt.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of polyhalo pyrazinecarboxamide derivatives I.
Detailed description of the invention
Being carried out for ease of technology of the present invention, the present invention lists the preparation method of a kind of polyhalo pyrazinecarboxamide derivatives I, including:
1., the preparation process of polyhalo pyrazinecarboxamide II；
2., polyhalo pyrazinecarboxamide II, formaldehyde prepare polyhalo pyrazinecarboxamide derivatives with secondary amine c or secondary amine d through Mannich reaction The step of I.
One, to step explanation 1.
1. described step includes:
I, under aprotic solvent atmosphere and at a temperature of-78 DEG C～-45 DEG C, will be relative to 2, the radical initiator of 6-dichloropyrazine excess is with anti- Answering thing hybrid reaction to form the step of the first mixed reaction solution, described radical initiator is the one in n-BuLi, isobutyl group lithium or tert-butyl lithium, Described reactant is 2,2,6,6-tetramethyl piperidines or 2, the one in 2,5,5-tetramethyl pyrroles；
Ii, in anhydrous conditions, adds 2 to the first mixed reaction solution, and 6-dichloropyrazine, reaction forms the step of the second mixed reaction solution；
Iii, in anhydrous conditions, adds halogen to the second mixed reaction solution, and reaction forms the step of the 3rd mixed reaction solution；
Iv, in anhydrous conditions, adds the one in methyl formate, Ethyl formate, propyl formate and butyl formate to the 3rd mixed reaction solution, Reaction forms the step of the 4th mixed reaction solution；
V, add reaction terminating agent to the 4th mixed reaction solution and be passed through the step of ammonia the most continuously；And subsequent purification steps, described reaction is eventually Only agent is lewis acid.
The initial temperature of described i step is normally controlled in-78 DEG C～-45 DEG C, after being mixed with reactant by radical initiator, gradually rises to 5 DEG C, in order to radical initiator can obtain electronics from reactant, enables the first mixed reaction solution stable existence, and controls radical reaction, Prevent radical initiator and reactant reaction, reactant nitrogen position is formed free radical.
Additionally, also should make to comprise in the first mixed reaction solution sufficient concentrations of reactant free radical, namely reactant free radical and 2,6-dichloro pyrrole The reasonable concentration ratio of piperazine, at least can make both be combined into new free radical smoothly.In order to achieve the above object, first those skilled in the art should The reactant free radical of q.s can be produced with radical initiator after making reactant react, generally can adding radical initiator and reactant Dosage is relative to 2, and 6-dichloropyrazine excess processes, but excess in general sense (such as radical initiator and 2, mole feeding intake of 6-dichloropyrazine Than being 2: 1 etc.), generally cannot produce or cannot obtain enough reactant free radicals, to this end, it is considered herein that should be by radical initiator With 2, the mol ratio of 6-dichloropyrazine is at least set to 8: 1, and reactant and 2, the mol ratio of 6-dichloropyrazine is at least 2.8: 1, secondly, also should make First mixed reaction solution has enough reactant number of free radical, if the volume ratio of the aprotic solvent of interpolation Yu reactant is set in 15～1: 1 can ensure that reactant number of free radical can be with 2, the high efficiency reaction of 6-dichloropyrazine.
Aprotic solvent of the present invention is one or more in hexamethylene, dichloromethane, dimethyl sulfoxide and oxolane, free radical Initiator is the one in n-BuLi, isobutyl group lithium or tert-butyl lithium, and reactant is 2,2,6,6-tetramethyl piperidines or 2,2,5,5-tetramethyl pyrroles In one, present invention discover that radical initiator and reactant are made above-mentioned restriction the most at least can implement the present invention smoothly, but as a kind of Preferably, described radical initiator is n-BuLi, and described reactant is 2,2,6,6-tetramethyl piperidines.
Radical reaction is not usually required to higher temperature, and temperature rising often means that the aggravation of reaction and the substantial increase of side reaction, therefore The reaction temperature general control of ii, iii, iv step is at-78 DEG C～-45 DEG C, and ii step should also be included and puts into 2 to the first mixed reaction solution, 6-bis- Before chloropyrazine, the first mixed reaction solution is cooled to rapidly the step of-78 DEG C～-45 DEG C.
In some embodiments of the invention, the one in methyl formate, Ethyl formate, propyl formate and butyl formate and halogen relative to The molar ratio of 2,6-dichloropyrazines all controls, 0.5～5, to present invention discover that outside this range and there is corresponding reaction yield downward trend.
In some embodiments of the invention, the reaction terminating agent of v step is the one in various lewis acid, such as hydrochloric acid, sulphuric acid, nitric acid, Phosphoric acid, thoroughly eliminates various free radicals present in the 4th mixed reaction solution, reaches to cut off the purpose of radical reaction, of course for follow-up logical ammonia Reaction, also should add pH adjusting agent, such as NaHCO subsequently3Deng.
In some embodiments of the invention, v step is passed through continuously ammonia be the temperature of the 4th mixed reaction solution rise to 0 DEG C～10 DEG C laggard OK, too high temperature can reduce ammonia dissolubility in the 4th mixed reaction solution, and too low temperature can lower reaction efficiency.1. step reacts Overall yield is all more than 55%.
Two, to step explanation 2.
Described 2. step includes that material addition step and heating steps, described material addition step are included under proton solvent, according to polyhalo pyrazinecarboxamide, Formaldehyde, secondary amine c or secondary amine d feed intake with the molar ratio of 1: 1～5: 1～10.
Described heating steps includes that the reactant liquor to being formed after material addition step heats under inert gas atmosphere, makes reaction temperature be maintained at 0 DEG C～50 DEG C.The yield that step is 2. obtained on this basis is more than 63%.
Preferred as one, polyhalo pyrazinecarboxamide, formaldehyde, secondary amine c or secondary amine d feed intake with the molar ratio of 1: 1～2: 1～3. Preferred as one, reaction temperature can also control between 10 DEG C～40 DEG C, and most preferred reaction temperature is between 20 DEG C～30 DEG C.
Embodiment 1 (preparation of derivant 1)
A kind of polyhalo pyrazinecarboxamide, chemical name is 3, and the chloro-6-of 5-bis-iodo-pyrazine-2-Methanamide (derivant 1), its structural formula is as follows.
Preparation method is as follows:
Under the conditions of-78 DEG C, at 200mL oxolane and 2, mixed solvent (oxolane and 2,2,6, the 6-tetramethyls of 2,6,6-tetramethyl piperidines The volume ratio of phenylpiperidines is 15: 1) the middle n-BuLi hexane solution adding 25mL2.5mol/L, the temperature of reaction solution is gradually risen To 5 DEG C, stirring reaction 15 minutes, form the first mixed reaction solution.
Then, reduce rapidly temperature to-78 DEG C, be initially charged the 2 of 30mL 1.2mol/L, 6-dichloropyrazine tetrahydrofuran solution, stir 30 minutes, Form the second mixed reaction solution；Secondly the I of 30mL 1.2mol/L is added2Tetrahydrofuran solution, stirs 30 minutes, forms the 3rd mixed reaction solution； It is eventually adding 4g Ethyl formate, stirs 30 minutes, form the 4th mixed reaction solution；Described second and third, the temperature of four mixed reaction solutions the most not Must be higher than-45 DEG C.
Subsequently, add termination reactant (the HCl tetrahydrofuran solution of 100mL 1mol/L) to the 4th mixed reaction solution and terminate reaction；And use Saturated NaHCO3Till neutralization is reacted to not have bubble to produce, the temperature of control mixed reaction solution, to 5 DEG C, is continually fed into ammonia, after 1 hour, Stop ventilation.Add the extraction of 500mL water, and rinse organic layer 3 times with 150mL water, collect aqueous phase, under vacuum (temperature ＜ 30 DEG C) anhydrous sodium sulfate is dried, and filters, concentrate, silica gel column layer analysis, obtain 6.6g yellow solid and be target product, productivity 58%.
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:318.9 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 6.22 (s, 2H)
Embodiment 2 (preparation of derivant 2)
A kind of polyhalo pyrazinecarboxamide, chemical name is 3, and the chloro-6-of 5-bis-bromo-pyrazine-2-Methanamide (derivant 2), its structural formula is as follows.
Preparation method is as follows:
Under the conditions of-60 DEG C, at 400mL oxolane and 2, mixed solvent (oxolane and 2,2,6, the 6-tetramethyls of 2,6,6-tetramethyl piperidines The volume ratio of phenylpiperidines is 15: 1) the middle n-BuLi hexane solution adding 60mL2.5mol/L, the temperature of reaction solution is gradually risen To 5 DEG C, stirring reaction 15 minutes, form the first mixed reaction solution.
Then, reduce rapidly temperature to-60 DEG C, be initially charged the 2 of 30mL 1.2mol/L, 6-dichloropyrazine tetrahydrofuran solution, stir 1 hour, Form the second mixed reaction solution；Secondly the Br of 30mL 1.2mol/L is added2Tetrahydrofuran solution, stirs 5 minutes, forms the 3rd mixed reaction solution； It is eventually adding 4g Ethyl formate, stirs 1 hour, form the 4th mixed reaction solution；Described second and third, the temperature of four mixed reaction solutions all must not Higher than-45 DEG C.
Subsequently, add termination reactant (the HCl tetrahydrofuran solution of 100mL 1mol/L) to the 4th mixed reaction solution and terminate reaction；And use Saturated NaHCO3Till neutralization is reacted to not have bubble to produce, the temperature of control mixed reaction solution, to 0 DEG C, is continually fed into ammonia, after 1 hour, Stop ventilation.Add the extraction of 800mL water, and rinse organic layer 3 times with 300mL water, collect aqueous phase, under vacuum (temperature ＜ 30 DEG C) anhydrous sodium sulfate is dried, and filters, concentrate, silica gel column layer analysis, obtain 6.2g light yellow solid and be target product, productivity 64%.
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:271.8 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 6.20 (s, 2H)
Embodiment 3 (preparation of derivant 3)
A kind of polyhalo pyrazinecarboxamide, chemical name is 3,5,6-tri-chloro-pyrazine-2-Methanamides (derivant 3), and its structural formula is as follows.
Preparation method is as follows:
Under the conditions of-50 DEG C, at 400mL oxolane and 2, mixed solvent (oxolane and 2,2,6, the 6-tetramethyls of 2,6,6-tetramethyl piperidines The volume ratio of phenylpiperidines is 15: 1) the middle n-BuLi hexane solution adding 60mL 2.5mol/L, the temperature of reaction solution is gradually risen To 5 DEG C, stirring reaction 30 minutes, form the first mixed reaction solution.
Then, reduce rapidly temperature to-50 DEG C, be initially charged the 2 of 30mL 1.2mol/L, 6-dichloropyrazine tetrahydrofuran solution, stir 1 hour, Form the second mixed reaction solution；Secondly the Cl of 30mL 1.2mol/L is added2Tetrahydrofuran solution, stirs 15 minutes, forms the 3rd hybrid reaction Liquid；It is eventually adding 4g Ethyl formate, stirs 1 hour, form the 4th mixed reaction solution；Described second and third, the temperature of four mixed reaction solutions equal Must not be higher than-45 DEG C.
Subsequently, add termination reactant (the HCl tetrahydrofuran solution of 200mL 1mol/L) to the 4th mixed reaction solution and terminate reaction；And use Saturated NaHCO3Till neutralization is reacted to not have bubble to produce, the temperature of control mixed reaction solution, to 5 DEG C, is continually fed into ammonia, after 1 hour, Stop ventilation.Add the extraction of 800mL water, and rinse organic layer 3 times with 300mL water, collect aqueous phase, under vacuum (temperature ＜ 30 DEG C) anhydrous sodium sulfate is dried, and filters, concentrate, silica gel column layer analysis, obtain 6.8g light yellow solid and be target product, productivity 83%.
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:227.5 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 6.17 (s, 2H)
Embodiment 4 (preparation of derivant 4)
A kind of polyhalo pyrazinecarboxamide derivatives, chemical name is 3, the chloro-N-of 5-bis-((4-(4-fluorobenzene) piperazine-1-base) methyl)-6-iodine pyrazine-2-amide (derivant 4), its structural formula is as follows.
By 3, the chloro-6-of 5-bis-iodo-pyrazine-2-Methanamide (derivant 1) synthesis of derivatives 4:
By the chloro-6-of 3.2g 3,5-bis-iodo-pyrazine-2-Methanamide (derivant 1), 20mL 0.8mol/L formaldehyde ethanol solution, 1.8g 1-(4-fluorobenzene) Piperazine dissolves in 30mL ethanol solution, is sufficiently stirred for, and after mix homogeneously, is added by reactant in the flask of microwave reactor, at 500w microwave Under power illumination, controlling in nitrogen gas atmosphere microwave radiation heating temperature at 20 DEG C, after static holding 10 minutes, decompression is distilled off solvent.Anhydrous Sodium sulfate is dried, and filters, and silica gel column chromatography separates, and obtains target product (4.3g, yield 84%).
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:511.1 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 2.3～3.4 (m, 8H), 4.4 (s, 2H), 7.01～7.5 (m, 4H), 9.85 (s, 1H)
Embodiment 5 (preparation of derivant 6)
A kind of polyhalo pyrazinecarboxamide derivatives, chemical name is 1-cyclopropyl-6-fluoro-8-methoxyl group-7-(3-methyl-4-((2-iodo-3,5-dichloropyrazine -2-carboxamide groups) methyl) piperazine-1-base)-4-oxygen quinoline-3-carboxylic acid (derivant 6), its structural formula is as follows.
By 3, the chloro-6-of 5-bis-iodo-pyrazine-2-Methanamide (derivant 1) synthesis of derivatives 6:
By the chloro-6-of 3.2g 3,5-bis-iodo-pyrazine-2-Methanamide (derivant 1), 20mL0.8mol/L formaldehyde ethanol solution, 3.6g 1-cyclopropyl-6- Fluoro-8-methoxyl group-7-(piperazine-1-base)-4-oxygen quinoline-3-carboxylic acid dissolves in 30mL ethanol solution, is sufficiently stirred for, after mix homogeneously, added by reactant Entering in the flask of microwave reactor, under 500w microwave power irradiates, in control nitrogen gas atmosphere, microwave radiation heating-up temperature is at 30 DEG C, static guarantor After holding 10 minutes, decompression is distilled off solvent.Anhydrous sodium sulfate is dried, and filters, and silica gel column chromatography separates, and (5.0g receives to obtain target product Rate 73%).
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:691.0 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 0.30～0.54 (m, 4H), 1.5 (m, 1H), 2.5～3.5 (m, 8H), 3.77 (s, 3H), 4.1 (s, 2H), 7.3～8.0 (m, 2H), 9.75 (s, 1H), 14.86 (br s, 1H)
Embodiment 6 (preparation of derivant 7)
A kind of polyhalo pyrazinecarboxamide derivatives, chemical name is 1-ethyl-6-fluoro-8-methoxyl group-7-(3-methyl-4-((2-bromo-3,5-dichloropyrazine-2- Carboxamide groups) methyl) piperazine-1-base)-4-oxygen quinoline-3-carboxylic acid (derivant 7), its structural formula is as follows.
By 3, the chloro-6-of 5-bis-iodo-pyrazine-2-Methanamide (derivant 2) synthesis of derivatives 7:
By the chloro-6-of 2.7g 3,5-bis-iodo-pyrazine-2-Methanamide (derivant 2), 20mL0.8mol/L formaldehyde ethanol solution, 3.5g 1-ethyl-6- Fluoro-8-methoxyl group-7-(piperazine-1-base)-4-oxygen quinoline-3-carboxylic acid dissolves in 30mL ethanol solution, is sufficiently stirred for, after mix homogeneously, added by reactant Entering in the flask of microwave reactor, under 500w microwave power irradiates, in control nitrogen gas atmosphere, microwave radiation heating-up temperature is at 10 DEG C, static guarantor After holding 10 minutes, decompression is distilled off solvent.Anhydrous sodium sulfate is dried, and filters, and silica gel column chromatography separates, and (4.3g receives to obtain target product Rate 68%).
Composing nuclear magnetic resonance spectroscopy through mass spectrum and hydrogen, result is as follows:
MS:631.0 (M+H)+
1H-NMR (400MHz, DMSO-d6): δ 0.15～0.35 (m, 3H), 1.0 (m, 2H), 2.4～3.3 (m, 8H), 3.75 (s, 3H), 4.0 (s, 2H), 7.15～7.9 (m, 2H), 9.77 (s, 1H), 14.70 (br s, 1H)
Embodiment 7 (preparation of derivant 1 hydrochloride)
The hydrochloride of a kind of polyhalo pyrazinecarboxamide derivatives, chemical name is 3, the chloro-6-'s of 5-bis-iodo-pyrazine-2-Methanamide (derivant 1) Hydrochloride.
Its preparation method is: at room temperature, by the chloro-6-of 1g 3,5-bis-iodo-pyrazine-2-Methanamide (derivant 1) in 100mL 50% concentrated hydrochloric acid Stirring 10 hours, leach product by suction filtration, simply wash with cold water, obtain the hydrochloride of derivant 1, fusing point is 230 DEG C.
Embodiment 8 (preparation of derivant 6 sodium salt compound)
The sodium salt compound of a kind of polyhalo pyrazinecarboxamide derivatives, chemical name is 1-cyclopropyl-6-fluoro-8-methoxyl group-7-(3-methyl-4-((2-iodine -3,5-dichloropyrazine-2-carboxamide groups) methyl) piperazine-1-base) the sodium salt compound of-4-oxygen quinoline-3-carboxylic acid (derivant 6).
Its preparation method is: 10mL water and 32mg sodium bicarbonate is added and neutralizes in pot, is heated to 70 DEG C, and stirring is lower adds 1-cyclopropyl-6- Fluoro-8-methoxyl group-7-(3-methyl-4-((2-iodo-3,5-dichloropyrazine-2-carboxamide groups) methyl) piperazine-1-base)-4-oxygen quinoline-3-carboxylic acid (derivant 6) It is 7～7.5 to pH value in reaction.Heating makes carbon dioxide take off, sucking filtration, and concentrated filtrate obtains the sodium salt compound of derivant 6, fusing point ＞ 350 DEG C.
Embodiment 10 (tubercle bacillus resistant activity experiment on rat model)
Derivant 6 and pyrazinecarboxamide carry out the tubercle bacillus resistant activity Experimental comparison in rat body.
Selected 54 six week old female CD-1 Mus, infect tubercule bacillus ATCC 27294 by tail vein injection.44 infection animals are divided equally It is two groups, respectively experimental group and blank group.To experimental group, proceeding by Drug therapy in lumbar injection mode, dosage is 100mg/kg, Continue 10 days.Infecting latter 35 days, extract spleen and right lung tissue, in homogenate, aseptic taking-up is ground in cell homogeniser, after diluting 10 times 7H10 agar plate is inoculated.Hatch 4 weeks at 37 DEG C before counting.Antibacterial is carried out counting measure, and with lung (7.88 ± 0.22) and spleen (8.84 ± 0.21) In negative (untreated) control number (cultivate and form unit deviation, CFU) and contrast, result is as shown in table 2.
Table 2
As can be seen here, derivant 6 can reduce tubercule bacillus inoculum concentration in lung and spleen tissue and be respectively 2.50-log10 and 1.95-log10, is better than pyrazine Methanamide reduces the value of tubercule bacillus inoculum concentration in lung and spleen tissue.

Claims (9)

1. a polyhalo pyrazinecarboxamide derivatives I, the basic salt of polyhalo pyrazinecarboxamide derivatives IV and polyhalo pyrazinecarboxamide are derivative The inorganic acid salt of thing III, IV and II or acylate；
R1For the one in F, Cl, Br, I；
R2For the one in H, group a, group b；
R in group a3For H, F or CF3In one；
R in group b4For H or F, R5For H, F or OCH3In one, R6For CH2CH3Or
The inorganic acid salt of described polyhalo pyrazinecarboxamide derivatives III, IV and II includes hydrochlorate, sulfate, phosphate, hydrobromate, partially Phosphate, nitrate and sulfonate；The acylate of polyhalo pyrazinecarboxamide derivatives III, IV and II includes acetate, benzene sulfonate, benzene first Hydrochlorate, citrate, esilate, fumarate, gluconate, glycollate, isethionate, lactate, Lactobionate, Malaysia Hydrochlorate, malate, mesylate, succinate, tosilate and tartrate；The alkali of described polyhalo pyrazinecarboxamide derivatives IV Formula salt includes the ammonium salt of polyhalo pyrazinecarboxamide derivatives IV, alkali metal salt and alkali salt
2. prepare a method of polyhalo pyrazinecarboxamide derivatives I described in claim 1, including:
1., the preparation process of polyhalo pyrazinecarboxamide II；
2., polyhalo pyrazinecarboxamide II, formaldehyde prepare polyhalo pyrazinecarboxamide derivatives with secondary amine c or secondary amine d through Mannich reaction The step of I；
Described 1. step includes:
I, under aprotic solvent atmosphere and at a temperature of-78 DEG C～-45 DEG C, will relative to 2,6-dichloropyrazine excess radical initiator and reaction Thing hybrid reaction forms the step of the first mixed reaction solution, and described radical initiator is the one in n-BuLi, tert-butyl lithium or isobutyl group lithium, Described reactant is 2,2,6,6-tetramethyl piperidines or 2, the one in 2,5,5-tetramethyl pyrroles；
Ii, in anhydrous conditions, adds 2 to the first mixed reaction solution, and 6-dichloropyrazine, reaction forms the step of the second mixed reaction solution；
Iii, in anhydrous conditions, adds halogen to the second mixed reaction solution, and reaction forms the step of the 3rd mixed reaction solution；
Iv, in anhydrous conditions, adds the one in methyl formate, Ethyl formate, propyl formate and butyl formate to the 3rd mixed reaction solution, Reaction forms the step of the 4th mixed reaction solution；
V, add reaction terminating agent to the 4th mixed reaction solution and be passed through the step of ammonia the most continuously；And subsequent purification steps, described reaction is eventually Only agent is lewis acid.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 2, it is characterised in that n-BuLi, tertiary fourth A kind of radical initiator and 2 in base lithium or isobutyl group lithium, the mol ratio of 6-dichloropyrazine is at least 8: 1,2,2,6,6-tetramethyl piperidines or 2, and 2, A kind of reactant and 2 in 5,5-tetramethyl pyrroles, the mol ratio of 6-dichloropyrazine is at least 2.8: 1.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 2, it is characterised in that described i step is also wrapped Include the step that the first mixed reaction solution is stirred and is progressively warming up to 5 DEG C.Described ii step is additionally included in adds 2,6-to the first mixed reaction solution -45 DEG C of below step it are cooled to before dichloropyrazine.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 2, it is characterised in that ii, iii and iv walk Rapid reaction temperature controls at-78 DEG C～-45 DEG C, and one and halogen in methyl formate, Ethyl formate, propyl formate and butyl formate are relative In 2, the molar ratio of 6-dichloropyrazine all controls 0.5～5.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 2, it is characterised in that v step is additionally included in Before being passed through ammonia continuously, the temperature of the 4th mixed reaction solution is risen to 0 DEG C～the step of 10 DEG C.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 2, it is characterised in that described 2. step includes Material addition step and heating steps, described material addition step is included under proton solvent, according to polyhalo pyrazinecarboxamide, formaldehyde, secondary amine c or two Level amine d feeds intake with the mol ratio of 1: 1: 1～1: 5: 10.
A kind of method preparing polyhalo pyrazinecarboxamide derivatives I the most according to claim 7, it is characterised in that described heating steps bag Include the reactant liquor to being formed after material addition step to heat under inert gas atmosphere, make reaction temperature be maintained at 0 DEG C～50 DEG C.
The most according to claim 1, polyhalo pyrazinecarboxamide derivatives I is at preparation Killing Mycobacterium Tuberculosis and multi-drug resistance tubercule bacillus medicine The purposes of aspect.
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