CN102731296A - Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines - Google Patents
Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines Download PDFInfo
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Abstract
The invention provides a rosmarinic acid derivative which comprises compounds 1-47 and their R-isomers or S-isomers. The structural general formula of the derivative is represented by a formula in the specification; and in the formula, R1, R2, R3 and R4 are defined in the specification. According to in-vitro anti-Mycobacterium tuberculosis experiments of the rosmarinic acid derivative of the invention, a medicine to be detected and a positive contrast medicine are respectively added to a small bottle containing a liquid medium in a continuous two-time dilution manner, a certain bacterium amount of Mycobacterium tuberculosis standard strains H37Rv is inoculated and is cultured for 14 days at 37DEG C, and the minimum inhibitory concentration (MIC) of each medicine to the Mycobacterium tuberculosis is observed. And experiment results show that the compounds in the invention have good anti-Mycobacterium tuberculosis activities, so the compounds can be used for preparing medicines for treating tuberculosis infection, and have large clinical application values. The invention provides a preparation method of the rosmarinic acid derivative.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to rosmarinic acid verivate and preparation method thereof with in the application of preparation in the antitubercular agent.
Background technology
White plaque (Tuberculosis) is a kind of common lethal infection disease that is caused by mycobacterium tuberculosis, and mycobacterium tuberculosis infects lung's (like pulmonary tuberculosis), lymphsystem, the recycle system, urinary system, joint and the skin of attacking the people usually.Guo Huoshi found mycobacterium tuberculosis (Mycobacterium Tuberculosis) first in 1882, for human treatment's white plaque has been brought hope.Since the 1950's, because the continuous discovery of antitubercular agent makes popular certain control that obtains lungy.But over nearly 30 years; Because to ignorance lungy, add flowing and the factor such as popular of growth, AIDS of population, cause the white plaque epidemic situation revivable; Part countries and regions even the rise phenomenon also occurred have become the serious problems of global effect life and health.Estimating that according to global white plaque control report in 2009 Chinese white plaque number of the infected was 1,300,000 in 2007, account for 14.0% of the whole world, occupy second in the whole world, is one of white plaque ground occurred frequently.Another important reasons that the white plaque epidemic situation can not effectively be controlled is the sick medicine of tuberculosis such as vazadrine, Rifampin, pyrazinoic acid amide, Tibutol, Streptomycin sulphate and the sodium para-aminosalicylate etc. that use clinically, because clinical application for many years makes mycobacterium tuberculosis produce resistance in various degree to them.Infect in order to control multi-drug resistant bacteria; Slow down resistant organism and spread, improve curative ratio, shorten treatment time; The curative effect of the existing medicine of performance; The World Health Organization once proposed multiple standard therapy, and the short course of therapy schemes such as (DOTS) under advocating complete monitoring treatment (DOT) and directly monitoring, the ideal but existing antituberculosis therapy scheme also is nowhere near; Can't fundamentally solve mycobacterium tuberculosis at intravital property stayed and resistance two hang-ups held of tuberculosis patient, bring exceptional hardship for clinical treatment lungy.The World Health Organization develops into DOTS " containment white plaque strategy (Stop TB Strategy) " on the basis of successful implementation DOTS strategy, be intended to by 2015 global tuberculosis rate significantly reduced.For realizing this goal, the sick new drug of tuberculosis of finding, research and develop brand new becomes important research direction at present.The novel antitubercular agent of report like nitro glyoxaline compound PA-824 and OPC-67683, biaryl quinolin analog derivative TMC207 etc., is carrying out the clinical study that Killing Mycobacterium Tuberculosis infects at present.But being it, the mutagenicity of PA-824 is used for a sick major obstacle of treating pulmonery tuberculosis; And between OPC-67683 and an existing line medicament benemicin or pyrazinoic acid amide drug interaction being arranged, the latter can make its Plasma Concentration reduce, and its exploitation is received restriction to a certain degree; Though the action target spot of TMC207 and mycobacterium tuberculosis is unique and have a brand-new mechanism of action, it can be through the metabolism of Cytochrome P450 isozyme, so and when drug interaction and Rifampin coupling are arranged between Rifampin Plasma Concentration can reduce by 50%.
Since the restriction of said medicine exploitation, people's expectation from natural product, find brand new tuberculosis, can overcome anti-multiple medicines/extensive drug-fast compound, and it is developed into the sick new drug of tuberculosis, this is the important goal of current research.The inventor finds that the rosmarinic acid verivate has good matrix metalloproteinase inhibitory activity under study for action; Especially matrix metalloproteinase-1 had selective inhibitory activity preferably; And the content of the interior matrix metalloproteinase-1 of tuberculosis patient body is apparently higher than normal people's level; Pharmacological research shows; The raising of matrix metalloproteinase-1 contents level can cause the lung of white plaque model mice or cavy to produce with human tuberculosis patient lung and similarly damage, and research thinks that the activity that suppresses matrix metalloproteinase-1 targetedly can be used as treatment novel targets approach lungy.Therefore, the rosmarinic acid verivate can the development of new antitubercular agent as one type of matrix metalloproteinase-1 suppressor factor optionally.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design rosmarinic acid verivate prepares sick new drug of tuberculosis and preparation method thereof.
The invention provides a kind of rosmarinic acid verivate, said rosmarinic acid verivate comprises its R-type and S-type isomer, and their general structure is following:
Rosmarinic acid verivate (R)-rosmarinic acid verivate (S) rosmarinic acid verivate
Wherein: R
1Be hydrogen, benzyl, allyl group, alkyl or substituted silane base; Said alkyl is the straight or branched alkyl with 1～4 carbon atom, like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl, preferably has the alkyl of 1～2 carbon atom, special preferable methyl; Said substituted silane base is for having 3 substituted siloyl group of alkyl or phenyl; As trimethyl silicon based, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based, triisopropylsilyl; Preferred trimethyl silicon based or tertiary butyl dimethyl-is silica-based, special preferred tertiary butyl dimethyl-is silica-based;
R
2Be hydrogen, benzyl, allyl group, alkyl or substituted silane base; Said alkyl is the straight or branched alkyl of 1～4 carbon atom, like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl, preferably has the alkyl of 1～2 carbon atom, special preferable methyl; Said substituted silane base is for having 3 substituted siloyl group of alkyl or phenyl; As trimethyl silicon based, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based or triisopropylsilyl; Preferred trimethyl silicon based or tertiary butyl dimethyl-is silica-based, special preferred tertiary butyl dimethyl-is silica-based;
R
1And R
2For identical or different, perhaps R
1And R
2Link to each other and represent methylene radical;
W is Sauerstoffatom, sulphur atom or NH;
R
3Be hydroxyl, hydroxyl amino or alkoxyl group;
Said alkoxyl group is the straight or branched alkoxyl group of 1～4 carbon atom; Like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy; Be preferably the alkoxyl group of 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the allyloxy or the alkyl replacement allyloxy of 3～6 carbon atoms;
R
4Be phenyl, substituted-phenyl, heterocycle or substituted heterocycle;
Substituting group in the said substituted-phenyl be positioned at the neighbour, or contraposition, be substituted by single replace or polysubstituted; Said substituting group is a halogen, like fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1～6 carbon atom; Like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl or new hexyl; The alkyl of preferred 3～4 carbon atoms, the preferred especially sec.-propyl or the tertiary butyl; Or be the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom; Like methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, tetrafluoro propyl group; The substituted alkyl of preferred 2～3 fluorine atoms with 1～2 carbon atom, preferred especially trifluoromethyl; Or be the straight or branched alkoxyl group of 1～4 carbon atom, like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, the alkoxyl group of preferred 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the straight or branched alkoxyl group of 1～4 substituted 1～4 carbon atom of fluorine atom, like trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of preferred 1～4 substituted 1～2 carbon atom of fluorine atom, preferred especially trifluoromethoxy; Or be methylene-dioxy; Or be the allyloxy or the alkyl replacement allyloxy of 3～6 carbon atoms; Or be cyanic acid; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be the 1-naphthyl; Or be the 2-naphthyl; Or be benzyloxy or substituted benzyloxy, or said substituting group is that allyloxy or the alkyl of the straight or branched alkoxyl group of the straight or branched alkyl of halogen, 1～6 carbon atom, the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom, 1～4 carbon atom, the straight or branched alkoxyl group of 1～4 substituted 1～4 carbon atom of fluorine atom, 3～6 carbon atoms replaces allyloxy, cyanic acid, nitro; The acyloxy of 1-4 carbon atom, amino, hydroxyl; Or be heterocycle methoxyl group or substituted heterocycle methoxyl group; Said heterocycle is five yuan or hexa-atomic single heterocycle and five yuan or hexa-atomic fused heterocycle; Like furans, thiophene, pyrroles, pyrazoles, imidazoles 、 oxazole, thiazole 、 isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, the pyridine of talking endlessly, purine or 2,3-Dihydrobenzofuranes-6-base; Or be phenyl or substituted-phenyl; Said substituting group is benzyloxy or substituted benzyloxy; Or said substituting group is heterocycle methoxyl group or substituted heterocycle methoxyl group; Said heterocycle is five yuan or hexa-atomic single heterocycle and five yuan or hexa-atomic fused heterocycle, like furans, thiophene, pyrroles, pyrazoles, imidazoles 、 oxazole, thiazole 、 isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, the pyridine of talking endlessly, purine or 2, and 3-Dihydrobenzofuranes-6-base; Substituting group in the said substituted heterocycle be positioned at the neighbour, or contraposition, be substituted by single replace or polysubstituted; Substituting group in the said substituted heterocycle is a halogen, like fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1～4 carbon atom, like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl, the alkyl of preferred 3～4 carbon atoms, the preferred especially sec.-propyl or the tertiary butyl; Or be the straight or branched alkoxyl group of 1～4 carbon atom; Like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy; The alkoxyl group that preferably has 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom, like methyl fluoride, difluoromethyl, trifluoromethyl or trifluoroethyl tetrafluoro propyl group, the alkyl of preferred 2～3 substituted 1～2 carbon atoms of fluorine atom, preferred especially trifluoromethyl; Or be 1～4 substituted straight or branched alkoxyl group with 1～4 carbon atom of fluorine atom, like trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of preferred 2～4 substituted 3～4 carbon atoms of fluorine atom, preferred especially tetrafluoro propoxy-; Or be methylene-dioxy; Or allyloxy or alkyl replacement allyloxy for having 3～6 carbon atoms; Or be cyanic acid; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be phenyl; Or be the 2-naphthyl; Or be the 1-naphthyl.
Rosmarinic acid verivate according to the invention is following compounds 1-47 and R-type or S-type isomer.The general structure of this analog derivative is following:
R wherein
1, R
2, R
3And R
4Like above-mentioned definition.
Table 1 rosmarinic acid verivate
Another object of the present invention has provided the preparation method of above-mentioned rosmarinic acid verivate.This method comprises the following steps that reaction formula is following:
(1) compound IV 3-(3,4-dialkoxy phenyl)-2-hydroxyl (or amino, or sulfydryl) propionic acid is under acid catalysis, and esterification obtains compound V 3-(3,4-dialkoxy phenyl)-2-hydroxyl (or amino, or sulfydryl) propionic ester;
(2) compound V and various different substituted cinnamic acid VI generation condensation reactions obtain the esterified derivative VII of (±)-rosmarinic acid;
The esterified derivative VII of (3) (±)-rosmarinic acid is sloughed the protection of allyl group or methyl through catalysis and is obtained corresponding (±)-rosmarinic acid verivate VIII;
(4) (±)-rosmarinic acid verivate VIII and oxammonium hydrochloride; Condensation in the presence of condensing agent; Make (±)-rosmarinic acid hydroxamic acid derivatives IX (±)-2-substitutional crylic acid (sulphur) ester or acrylamido-3-(3,4-dimethoxy or dihydroxyl) phenyl propyl hydroximic acid;
(5) (±)-rosmarinic acid verivate VIII gets rosmarinic acid derivative compound X (±)-2-substitutional crylic acid (sulphur) ester or acrylamido-3-(3, the 4-dihydroxyl) phenylpropionic acid through the catalysis demethylating;
(6) chirality of rosmarinic acid verivate R-type and S-type isomer preparation
Get compound VIII, IX or X, select suitable moving phase dissolving, split the post fractionation through chirality and be prepared into R-type and S-type isomer.
Said step (1) esterification be the compound IV under acid catalysis, back flow reaction in appropriate solvent; Said acid is tosic acid, methanesulfonic, phospho-molybdic acid, molecular sieve or acid zeyssatite, preferred molecular sieve, acid zeyssatite, tosic acid or methanesulfonic, preferred especially tosic acid; Said solvent is benzene,toluene,xylene, normal hexane, hexanaphthene or octane-iso equal solvent, preferred toluene, normal hexane or hexanaphthene, preferred especially toluene; Said compound IV is 1:10 with the consumption mol ratio of acid, preferred 1:6, preferred especially 1:3; The reaction times of said step (1) esterification is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (2) condensation reaction is compound V and condensing agent, in appropriate solvent, reacts; Said condensing agent is N; N-dicyclohexyl carbon imide (DCC), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), 3-(diethoxy phosphoryl oxy)-1; 2; 3-phentriazine-4-ketone (DEPBT), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP) or 1-hydroxyl-benzo-triazole (HOBt) etc.; Preferred DCC, HOBt or EDCI, preferred especially EDCI; Said solvent is ETHYLE ACETATE, methylene dichloride, chloroform, THF, dioxane, N, dinethylformamide or methyl-sulphoxide etc., ethyl acetate, methylene dichloride or THF, preferred especially methylene dichloride; The temperature of reaction of condensation reaction is-20-50 ℃, and preferred 0-50 ℃, preferred 20-35 ℃ especially; The consumption mol ratio of said compound V and condensing agent is 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (2) condensation reaction is 8-72 hour, preferred 12-36 hour, and preferred 12-24 hour especially;
Said step (3) deprotection reaction be the esterified derivative VII of (±)-rosmarinic acid under catalyst action, in appropriate solvent, carry out; Said catalyzer is palladium carbon, tetrakis triphenylphosphine palladium, Palladous chloride, three (triphenylphosphine) or rhodium chloride etc., preferred three (triphenylphosphine) rhodium chloride or tetrakis triphenylphosphine palladiums, preferred especially tetrakis triphenylphosphine palladium; Said solvent is methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, THF or N, dinethylformamide etc., ethyl acetate, methylene dichloride or THF, preferred especially THF; The temperature of reaction of deprotection reaction is 0-90 ℃, preferred 20-50 ℃, and preferred 25-30 ℃ especially.The esterified derivative VII of said (±)-rosmarinic acid and catalyst consumption mol ratio are 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (3) deprotection reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (4) condensation reaction is compound VIII and condensing agent, in appropriate solvent, reacts; Said condensing agent is N; N-dicyclohexyl carbon imide (DCC), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), 3-(diethoxy phosphoryl oxy)-1; 2; 3-phentriazine-4-ketone (DEPBT), phosphofluoric acid benzotriazole-1-base oxygen base tripyrrole alkyl phosphorus (PyBOP) or 1-hydroxyl-benzo-triazole (HOBt) etc.; Preferred DCC, HOBt or EDCI, preferred especially EDCI; Said solvent is ETHYLE ACETATE, methylene dichloride, chloroform, THF, dioxane, N, N--N or methyl-sulphoxide etc., ethyl acetate, methylene dichloride or THF, preferred especially methylene dichloride; The temperature of reaction of condensation reaction is-20-50 ℃, and preferred 0-50 ℃, preferred 20-35 ℃ especially; The consumption mol ratio of said compound VIII and condensing agent is 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (4) condensation reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (5) deprotection reaction be the compound VIII under catalyst action, in appropriate solvent, carry out; Said catalyzer is palladium carbon, tetrakis triphenylphosphine palladium, Palladous chloride, three (triphenylphosphine) or rhodium chloride etc., preferred three (triphenylphosphine) rhodium chloride or tetrakis triphenylphosphine palladiums, preferred especially tetrakis triphenylphosphine palladium; Said solvent is methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, THF or N, dinethylformamide etc., ethyl acetate, methylene dichloride or THF, preferred especially THF; The temperature of reaction of deprotection reaction is 0-90 ℃, preferred 20-50 ℃, and preferred 25-30 ℃ especially.Said compound VIII and catalyst consumption mol ratio are 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (5) deprotection reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
The chiral method for preparing of said step (6) rosmarinic acid verivate R-type and S-type isomer is: get compound VIII, IX or X, dissolution with solvents, through chirality split post R-type and S-type isomer; Said solvent is a methylene dichloride, chloroform, THF; Normal hexane, MTBE, ETHYLE ACETATE; Ethanol, Virahol, acetonitrile; One or more mixed solvents in acetone or the acetic acid, one or more mixed solvents in preferred normal hexane, methylene dichloride, Virahol and the acetic acid, it is preferred especially that normal hexane/methylene dichloride/Virahol/acetic acid ratio is 65/20/15/0.1 mixed solvent; Said chiral separation temperature is 0-60 ℃, preferred 20-50 ℃, and preferred 30-35 ℃ especially; Said chiral separation post is a polysaccharide derivates class chiral column; Preferred bonding type polysaccharide derivates chiral column, Daicel CHIRALPAK IA type, CHIRALPAK IB type or CHIRALPAK IC type, preferred especially Daicel CHIRALPAK IC type; Packing material size is 3 μ m or 5 μ m, preferred 5 μ m.
Another purpose of the present invention has provided the preparation method of aforesaid method compound IV, and this method comprises the following steps that reaction formula is following:
(1) be starting raw material with the substituted benzaldehyde I, in the presence of alkali and diacetyl oxide with acetyl-glycine through cyclization De Dao the azolactone compound ii;
(2) compound ii hydrolysis under acidic conditions obtains the compound III;
(3) the compound III obtains the compound IV through reduction.
The alkali of said step (1) cyclization is sodium hydride, sodium methylate, sodium ethylate, sodium isopropylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium-acetate, Potassium ethanoate, triethylamine or Trimethylamine 99 etc.; Preferred sodium-acetate, Potassium ethanoate, sodium ethylate, sodium hydroxide, Pottasium Hydroxide or triethylamine, preferred especially sodium-acetate or Potassium ethanoate; Temperature of reaction is 80-150 ℃, and preferred temperature is 100-130 ℃, and preferred especially temperature is 110-115 ℃;
The acid of said step (2) acidic hydrolysis is sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, hydroiodic acid HI, acetate or formic acid etc., preferably sulfuric acid, hydrochloric acid, Hydrogen bromide or hydroiodic acid HI, special preferably sulfuric acid or hydrochloric acid; The concentration of said acid is 2M-10M, preferred 3M-6M, preferred especially 3-4M; Temperature of reaction is 70-110 ℃, and preferred temperature is 80-100 ℃, and preferred especially temperature is 90-95 ℃;
Said step (3) is used reductive agent or catalytic hydrogenation reduction; Said reductive agent is metal (like iron, zinc, tin)/hydrochloric acid, sulfide (like sodium sulphite, vat powder), Raney Ni/Hydrazine Hydrate 80, tetrahydrochysene lithium aluminium or Peng Qinghuana; Preferred tetrahydrochysene lithium aluminium, Peng Qinghuana or catalytic hydrogenation reduction, preferred especially sodium borohydride reduction.
Another purpose of the present invention has provided the application of above-mentioned rosmarinic acid verivate in preparation anti-mycobacterium tuberculosis medicine.
Rosmarinic acid verivate of the present invention has carried out the experiment of Tuberculosis in vitro nuclear bacillus; Medicine to be detected and positive control medicine are added respectively in the bottle that contains liquid nutrient medium with continuous 2 times of extent of dilution; Plant the mycobacterium tuberculosis type strain H37Rv of certain bacterium amount then; Cultivated 14 days, and observed the minimum inhibitory concentration (MIC) of each medicine for 37 ℃ mycobacterium tuberculosis.Experimental result shows that the compound that relates among the present invention has tubercle bacillus resistant activity preferably, explains that The compounds of this invention can be used for preparing the medicine of treating tuberculosis infection.
Said medicine is the pharmaceutical composition of being made up of as activeconstituents and pharmaceutical carrier the rosmarinic acid verivate.
Described activeconstituents rosmarinic acid verivate comprises its R-type isomer or S-type isomer.
Said activeconstituents is a compound that is selected among the rosmarinic acid derivative compound 1-47; Preferred compound is 5,15,19,26,33 or 41; More preferably 26 or 33.
Rosmarinic acid verivate provided by the invention has tubercle bacillus resistant activity preferably, and this compounds can be used for preparing the medicine of treating mycobacterium tuberculosis infection has bigger clinical value, the invention provides the preparation method of rosmarinic acid verivate.
Description of drawings
The chiral separation liquid phase figure of Fig. 1 compound 26
The circular dichroism spectrogram of Fig. 2 compound 26
Embodiment
Specify content of the present invention through embodiment below.In the present invention, the embodiment of the following stated is in order to set forth the present invention better, is not to be used for limiting scope of the present invention.
Synthesizing of embodiment 1, (Z)-4-(3,4-dimethoxy methylene-benzene)-2-Jia oxazolones
In the 50mL round-bottomed flask, add veratryl aldehyde (10mmol, 1.66g), acetyl glycine (10mmol, 1.17g), anhydrous sodium acetate (20mmol, 1.64g) with the anhydrous aceticanhydride of 20mL; Stirring makes it dissolving, be warming up to 110 ° of C reaction 8h after, be cooled to room temperature; Smash solid in the bottle to pieces after adding the 20mL frozen water, filter, with distilled water wash filter cake (5 * 10mL); Use again 50% washing with alcohol (5 * 10mL), after the drying, use acetone recrystallization; Get yellow crystalline product (Z)-4-(3,4-dimethoxy methylene-benzene)-2-Jia oxazolones 2.11g, yield 85%; M.p.166 ~ 168 ℃;
1H NMR (DMSO-d
6, 300MHz): δ 2.37 (s, 3H, CH
3), 3.83 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 7.01 (d, J=7.7Hz, 1H, ArH), 7.10 (s, 1H, ArH), 7.66 (d, J=7.7Hz, 1H, ArH), 7.93 (s, 1H, CH); ESI-MS m/z 270.1 [M+Na]
+, 246.1 [M-H]
-HRMS (ESI): m/z calcd for C
13H
13NO
4Na [M+Na]
+: 270.0742, found 270.0736.
Synthesizing of embodiment 2,3,4 – dimethoxy phenyl-pyruvic acids
(90 ° of C react 10h down for 9mmol, 2.01g) (2), 3M HCl 50mL in the 100mL round-bottomed flask, to add (Z)-4-(3,4-dimethoxy methylene-benzene)-2-Jia oxazolones.Behind the stopped reaction, be cooled to room temperature, filter, and washing (3 * 10mL), drying, bullion is through MeOH/H
2The O recrystallization must get light yellow solid 3,4 – dimethoxy phenyl-pyruvic acid 1.80g, yield 89%; M.p.200 ~ 203 ℃;
1H NMR (DMSO-d
6, 300MHz): δ 3.74 (s, 3H, OCH
3), 3.75 (s, 3H, OCH
3), 6.37 (s, 1H, CH), 6.94 (d, J=8.7Hz, 1H, ArH), 7.30 (dd, J=2.1,1.8Hz, 1H, ArH), 7.42 (d, J=1.8Hz, 1H, ArH), 8.99 (brs, 1H, OH), 13.02 (brs, 1H, COOH); ESI-MS m/z 247.0 [M+Na]
+, 471.0 [2M+Na]
+, 222.9 [M-H]
-HRMS (ESI): m/z calcd for C
11H
12O
5Na [M+Na]
+: 247.0582, found 247.0598.
Synthesizing of embodiment 3,3,4 – dimethoxy phenylpropyl alcohol lactic acid
(6.7mmol 1.5g), 25% methyl alcohol 30mL, is stirred to the solid dissolving under the ice-water bath, behind 10%NaOH solution accent pH=10, add NaBH in batches in the 50mL round-bottomed flask, to add 3,4 – dimethoxy phenyl-pyruvic acids
4(10mmol 0.54g), finishes, and room temperature reaction spends the night.0.1 M HCl transfers to acidity, and ethyl acetate extraction (4 * 25mL), merge organic phase, anhydrous MgSO
4Drying is filtered, evaporate to dryness, and (V (methylene dichloride): V (methyl alcohol): V (acetic acid)=90:9:1) gets light yellow solid 3,4 – dimethoxy phenylpropyl alcohol lactic acid 1.18g, yield 78% to column chromatography; M.p.124 ~ 126 ℃;
1H NMR (DMSO-d
6, 300MHz) δ 2.94 (dd, J=14.1,6.9Hz, 1H, CH
2), 3.14 (dd, J=14.1,14.1Hz, 1H, CH
2), 3.85 (s, 6H, OCH
3), 4.48 (dd, J=6.9,4.2Hz, 1H, CH), 6.82 (s, 3H, ArH); ESI-MS m/z 249.1 [M+Na]
+, 225.1 [M-H]
-HRMS (ESI): m/z calcd forC
11H
14O
5Na [M+Na]
+: 249.0739, found 249.0721.
Synthesizing of embodiment 4,3,4 – dimethoxy phenylpropyl alcohol lactic acid allyl esters
In the 25mL round-bottomed flask, add 5mmol phenylpropyl alcohol lactic acid, 0.09mmol p-TsOH, 5mmol allyl alcohol and 20mL toluene, be heated to back flow reaction 10h, be cooled to room temperature after; (2 * 15mL), the organic phase rotary evaporation boils off solvent, and thick product is through column chromatography (sherwood oil: ETHYLE ACETATE=80:20) for reaction solution washing; Get 3; 4 – dimethoxy phenylpropyl alcohol lactic acid allyl esters, yellow crystal solid 1.01g, yield 84%; M.p.40 ~ 41 ℃;
1H NMR (CDCl
3, 400MHz): δ 2.94 (dd, J=14.1,6.6Hz, 1H, CH
2), 3.11 (dd, J=14.1,4.1Hz, 1H, CH
2), 3.88 (s, 6H, OCH
3), 4.48 (m, 1H, CH), 4.68 (d, J=4.5Hz, 2H, CH
2), 5.35 (m, 2H, CH
2), 5.92 (m, 1H, CH), 6.79 (m, 3H, ArH); ESI-MS m/z 289.1 [M+Na]
+, 555.0 [2M+Na]
+HRMS (ESI): m/z calcd for C
14H
18O
5Na [M+Na]
+: 289.1052, found 289.1066.
Synthesizing of embodiment 5, (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-laurate (compound 1 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 266 milligrams) 3,4-dimethoxy phenylpropyl alcohol lactic acid allyl ester, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 222 milligrams) phenylacrylic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=85:15) purifying gets (E)-1-(allyloxy)-3-(3 to thick product through column chromatography; The 4-dimethoxy benzene)-and 368 milligrams of 1-oxygen propyl group-2-laurate, white solid (93%yield);
1H NMR (CDCl
3, 300MHz): δ 3.20 (m, 2H, CH
2), 3.85 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 4.65 (d, J=5.7Hz, 2H, CH
2), 5.22-5.39 (m, 3H, CH), 5.86 (m, 1H, CH), 6.47 (d, J=16.2Hz, 1H, CH), 6.84 (m, 3H, ArH), 7.37-7.52 (m, 5H, ArH), 7.71 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.1,55.8, and 65.8,73.1,111.2,112.5,116.7,118.7,121.5,128.1,128.3,128.9,130.5,131.4,134.1,146.0,148.1,148.8,166.0,169.4; ESI-MS m/z 419.2 [M+Na]
+, 815.2 [2M+Na]
+, 395.1 [M-H]
-HRMS (ESI): m/z calcd for C
23H
24O
6Na [M+Na]
+: 419.1471, found 419.1486.
Synthesizing of embodiment 6, (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(4-(methyl) phenyl) propenoate (compound 2 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 266 milligrams) 3,4-dimethoxy phenylpropyl alcohol lactic acid allyl ester, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 243 milligrams) 4-aminomethyl phenyl vinylformic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=85:15) purifying gets (E)-1-(allyloxy)-3-(3 to thick product through column chromatography; The 4-dimethoxy benzene)-and 394 milligrams of 1-oxygen propyl group-2-3-(4-(methyl) phenyl) propenoate, white solid (96%yield);
1H NMR (CDCl
3, 300MHz): δ 2.35 (s, 3H, CH
3), 3.19 (m, 2H, CH
2), 3.84 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 4.64 (d, J=5.4Hz, 2H, CH
2), 5.21-5.39 (m, 3H, CH), 5.86 (m, 1H, CH), 6.42 (d, J=15.9Hz, 1H, CH), 6.84 (m, 3H, ArH), 7.17 (d, J=8.1Hz, 2H, ArH), 7.45 (d, J=8.1Hz, 2H, ArH), 7.69 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 21.4,37.0, and 55.7,65.8,73.0,111.1,112.5,115.8,118.6,121.4,128.1,128.3,129.6,131.4,140.9,145.9,148.0,148.7,166.2,169.4; ESI-MS m/z 411.0 [M+H]
+, 433.2 [M+Na]
+, 843.2 [2M+Na]
+HRMS (ESI): m/zcalcd for C
24H
26O
6Na [M+Na]
+: 433.1627, found 433.1619.
Synthesizing of embodiment 7, (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(4-(trifluoromethyl) phenyl) propenoate (compound 3 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 266 milligrams) 3,4-dimethoxy phenylpropyl alcohol lactic acid allyl ester, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 324 milligrams) 4-trifluoromethyl vinylformic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=80:20) purifying gets (E)-1-(allyloxy)-3-(3 to thick product through column chromatography; The 4-dimethoxy benzene)-and 418 milligrams of 1-oxygen propyl group-2-3-(4-(trifluoromethyl) phenyl) propenoate, white solid (90%yield);
1H NMR (CDCl
3, 300MHz): δ 3.15 (dd, J=8.1,8.4Hz, 1H, CH
2), 3.23 (dd, J=5.1,5.1Hz, 1H, CH
2), 3.86 (s, 3H, OCH
3) 3.87 (s, 3H, OCH
3), 4.68 (d, J=5.7Hz, 2H, CH
2), 5.24-5.40 (m, 3H, CH), 5.86 (m, 1H, CH), 6.54 (d, J=15.9Hz, 1H, CH), 6.86 (d, J=9.9Hz, 3H, ArH), 7.67 (m, 4H, ArH), 7.72 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.1,55.9, and 66.0,73.4,111.3,112.5,118.9,119.6,121.5,125.9,128.2,128.3,131.4,137.5,144.1,148.2,148.9,165.5,169.3; ESI-MS m/z 487.2 [M+Na]
+, 951.2 [2M+Na]
+HRMS (ESI): m/z calcd for C
24H
23F
3O
6Na [M+Na]
+: 487.1344, found 487.1359.
Synthesizing of embodiment 8, (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(4-(benzyloxy) phenyl) propenoate (compound 5 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 266 milligrams) 3,4-dimethoxy phenylpropyl alcohol lactic acid allyl ester, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 381 milligrams) 4-benzyloxy base phenylacrylic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=80:20) purifying gets (E)-1-(allyloxy)-3-(3 to thick product through column chromatography; The 4-dimethoxy benzene)-and 467 milligrams of 1-oxygen propyl group-2-3-(4-(benzyloxy) phenyl) propenoate, white solid (93%yield);
1H NMR (CDCl
3, 300MHz): δ 3.19 (m, 2H, CH
2), 3.83 (s, 3H, OCH
3), 3.85 (s, 3H, OCH
3), 4.65 (tt, J=2.7,2.7Hz, 2H, CH
2), 5.22-5.41 (m, 6H, CH), 5.83 (m, 1H, CH), 6.41 (d, J=15.9Hz, 1H, CH), 6.65 (m, 3H, ArH), 6.92 (m, 2H, ArH), 7.27-7.46 (m, 7H, ArH), 7.64 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 36.9,55.9, and 71.0,71.2,73.1,112.2,113.3,114.4,115.0,115.6,116.1,117.2,121.5,122.7,127.5,127.9,129.9,144.6,145.5,146.1,146.3,148.6,165.6,167.6; ESI-MS m/z 503.2 [M+H]
+, 525.3 [M+Na]
+HRMS (ESI): m/zcalcd for C
30H
30O
7Na [M+Na]
+: 525.1889, found 525.1869.
Synthesizing of embodiment 9, (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(3, the 4-benzyloxy phenenyl) propenoate (compound 7 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 266 milligrams) 3,4-dimethoxy phenylpropyl alcohol lactic acid allyl ester, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 540 milligrams) 3,4-benzyloxy base phenylacrylic acid, 10mL methylene dichloride; After stirring, add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature; The TLC monitoring after reacting completely, is washed 3 times; Anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=80:20) purifying gets (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(3 to thick product through column chromatography; The 4-benzyloxy phenenyl) propenoate is 541 milligrams, Off-white solid (89%yield);
1H NMR (CDCl
3, 300MHz): δ 3.18 (m, 2H, CH
2), 3.81 (s, 3H, OCH
3), 3.83 (s, 3H, OCH
3), 4.64 (m, 2H, CH
2), 5.15-5.38 (m, 7H, CH and CH
2), 5.87 (m, 1H, CH), 6.27 (d, J=15.9Hz, 1H, CH), 6.75-7.46 (m, 16H, ArH), 7.59 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 36.9,55.9, and 71.0,71.3,73.0,112.7,113.8,114.8,115.0,115.8,116.1,117.0,121.4,122.4,127.3,127.8,129.0,144.6,145.5,146.1,146.3,148.6,165.6,167.6; ESI-MS m/z 631.3 [M+Na]
+HRMS (ESI): m/z calcd for C
37H
36O
8Na [M+Na]
+: 631.2308, found 631.2301.
Synthesizing of embodiment 10, (E)-2-(cinnamoyloxy group)-3-(3, the 4-dimethoxy benzene) propionic acid (compound 9 in the table 1)
Drop in the 25mL round-bottomed flask (0.3mmol, 119 milligrams) (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-laurate, 15mg Pd (PPh
3)
4, 10mL anhydrous tetrahydro furan THF, be stirred to dissolving, slowly drip the 10mmol morpholine, after stirring at room, TLC detection reaction are accomplished; Low temperature evaporate to dryness, bullion are dissolved in the ether, 1M HCl washing, back extraction; Merge organic phase, anhydrous sodium sulfate drying filters evaporate to dryness; Preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1), get 295 milligrams of (E)-2-(cinnamoyloxy group)-3-(3, the 4-dimethoxy benzene) propionic acid, Off-white solid (83%yield);
1H NMR (CDCl
3, 300MHz): δ 3.16 (dd, J=8.7,8.4Hz, 1H, CH
2), 3.25 (dd, J=4.2,4.2Hz, 1H, CH
2), 3.85 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 5.37 (m, 1H, CH), 6.46 (d, J=15.9Hz, 1H, CH), 6.85 (m, 3H, ArH), 7.38 (m, 3H, ArH), 7.51 (m, 2H, ArH) 7.68-7.74 (d, J=15.9Hz, 1H, CH);
13CNMR (CDCl
3, 75MHz): δ 37.1,55.9, and 73.3,111.2,112.7,119.5,121.5,125.9,128.8,130.9,132.2,137.7,143.7,148.1,148.7,165.9,167.7; ESIMS m/z379.1 [M+Na]
+, 355.0 [M-H]
-HRMS (ESI): m/z calcd for C
20H
20O
6Na [M+Na]
+: 379.1158, found 379.1139.
Synthesizing of embodiment 11, (E)-2-(3-(to fluorophenyl) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid (compound 15 in the table 1)
Drop in the 25mL round-bottomed flask (0.3mmol, 124 milligrams) (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(4-fluorophenyl) propenoate, 15mg Pd (PPh
3)
4, 10mL anhydrous tetrahydro furan THF, be stirred to dissolving, slowly drip the 10mmol morpholine, after stirring at room, TLC detection reaction are accomplished; Low temperature evaporate to dryness, bullion are dissolved in the ether, 1M HCl washing, back extraction; Merge organic phase, anhydrous sodium sulfate drying filters evaporate to dryness; The preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1), 284 milligrams of (E)-2-(3-(to fluorophenyl) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid, white solid (76%yield);
1H NMR (CDCl
3, 300MHz): δ 3.18 (m, 2H, CH
2), 3.84 (s, 3H, OCH
3), 3.85 (s, 3H, OCH
3), 5.34 (m, 1H, CH), 6.36 (d, J=15.9Hz, 1H, CH), 6.80 (m, 3H, ArH), 7.07 (m, 2H, ArH), 7.47 (m, 2H, ArH), 7.65 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.1,55.9, and 73.5,111.1,112.5,119.8,121.9,125.3,128.2,131.3,132.8,137.9,144.3,148.6,148.9,166.2,167.9; ESI-MS m/z 397.2 [M+Na]
+, 372.9 [M-H]
-HRMS (ESI): m/z calcd for C
20H
19FO
6Na [M+Na]
+: 397.1063, found 397.1054.
Synthesizing of embodiment 12, (E)-2-(3-(4-benzyloxy benzene) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid (compound 19 in the table 1)
Drop in the 25mL round-bottomed flask (0.3mmol, 151 milligrams) (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(4-(benzyloxy) phenyl) propenoate, 15mg Pd (PPh
3)
4, 10mL anhydrous tetrahydro furan THF, be stirred to dissolving, slowly drip the 10mmol morpholine, after stirring at room, TLC detection reaction are accomplished; Low temperature evaporate to dryness, bullion are dissolved in the ether, 1M HCl washing, back extraction; Merge organic phase, anhydrous sodium sulfate drying filters evaporate to dryness; The preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1), 370 milligrams of (E)-2-(3-(4 benzyloxy benzene) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid, Off-white solid (80%yield);
1HNMR (CDCl
3, 300MHz): δ 3.19 (m, 2H, CH
2), 3.84 (s, 3H, OCH
3), 3.85 (s, 3H, OCH
3), 4.66 (s, 2H, CH
2), 5.23 (m, 11H, CH), 6.26 (d, J=16.2Hz, 1H, CH), 6.65 (m, 3H, ArH), 6.93 (m, 2H, ArH), 7.26-7.49 (m, 7H, ArH), 7.56 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.0,55.9, and 71.0,71.2,73.0,112.2,113.3,114.4,115.6,117.2,121.5,122.7,127.9,129.9,144.3,145.3,146.0,146.4,148.7,165.7,168.1; ESI-MS m/z 463.2 [M+H]
+, 485.3 [M+Na]
+, 461.0 [M-H]
-HRMS (ESI): m/z calcd for C
27H
26O
7Na [M+Na]
+: 485.1576, found 485.1568.
Synthesizing of embodiment 13, (E)-2-(3-(3, the 4-dibenzyloxy benzene) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid (compound 26 in the table 1)
Drop in the 25mL round-bottomed flask (0.3mmol, 182 milligrams) (E)-1-(allyloxy)-3-(3, the 4-dimethoxy benzene)-1-oxygen propyl group-2-3-(3, the 4-benzyloxy phenenyl) propenoate, 15mg Pd (PPh
3)
4, 10mL anhydrous tetrahydro furan THF, be stirred to dissolving, slowly drip the 10mmol morpholine, after stirring at room, TLC detection reaction are accomplished; Low temperature evaporate to dryness, bullion are dissolved in the ether, 1M HCl washing, and back extraction merges organic phase; Anhydrous sodium sulfate drying filters, evaporate to dryness, the preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1); (E)-2-(3, the 4-dibenzyloxy benzene) acryloxy)-460 milligrams of 3-(3, the 4-dimethoxy benzene) propionic acid, white solid (81%yield);
1H NMR (CDCl
3, 300MHz): δ 3.19 (m, 2H, CH
2), 3.82 (s, 3H, OCH
3) 3.84 (s, 3H, OCH
3), 5.17 (m, 4H, CH
2), 5.34 (m, 1H, CH), 6.26 (d, J=15.9Hz, 1H, CH), 6.75-7.61 (m, 17H, ArH and CH);
13C NMR (CDCl
3, 75MHz): δ 36.9,55.9, and 71.1,71.3,72.9,111.2,112.7,113.6,114.4,114.9,121.6,122.0,123.3,123.8,127.2,127.5,128.1,128.8,136.9,148.3,149.2,165.7,168.1; ESI-MS m/z 569.2 [M+H]
+, 591.3 [M+Na]
+HRMS (ESI): m/z calcd for C
34H
32O
8Na [M+Na]
+: 591.1995, found591.1979.
Synthesizing of embodiment 14, (E)-1-(hydroximic acid)-1-oxygen propyl group-2-3-(4-bromophenyl)-3-(3, the 4-dimethoxy benzene) propenoate (compound 29 in the table 1)
In the 25mL round-bottomed flask, drop into (0.3mmol, 131 milligrams) (E)-2-(3-(to bromophenyl) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid, (0.03mmol; 37 milligrams) 4-Dimethylamino pyridine (DMAP), (0.03mmol, 2 milligrams) oxammonium hydrochloride, 10mL anhydrous methylene chloride, after ice bath stirs 15min down; Add (0.36mmol, 74 milligrams) dicyclohexyl carbon imide (DCC), after the TLC detection reaction is accomplished; Filter washing, anhydrous sodium sulfate drying; Filter, evaporate to dryness, the preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1); 270 milligrams of (E)-1-(hydroximic acid)-1-oxygen propyl group-2-3-(4-bromophenyl)-3-(3, the 4-dimethoxy benzene) propenoate, white solid (60%yield);
1H NMR (CDCl
3, 300MHz): δ 3.19 (m, 2H, CH
2), 3.84 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 5.52 (brs, 1H, CH), 6.38 (d, J=16.2Hz, 1H, CH), 6.74 (m, 3H, ArH), 7.34 (d, J=9.0Hz, 2H, ArH), 7.52 (d, J=8.1Hz, 2H, ArH), 7.60 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.0,55.9, and 72.9,111.2,112.6,117.0,117.7,121.7,125.4,127.4,129.6,132.2,132.7,144.7,145.6,148.2,148.9,165.2,166.7; ESI-MS m/z 474.1 [M+Na]
+, 449.9 [M-H]
-, 898.9 [2M-H]
-HRMS (ESI): m/z calcd for C
20H
20BrNO
6Na [M+Na]
+: 472.0372, found 472.0394.
Synthesizing of embodiment 15, (E)-1-(hydroximic acid)-1-oxygen propyl group-2-3-(3, the 4-dibenzyloxy benzene)-3-(3, the 4-dimethoxy benzene) propenoate (compound 33 in the table 1)
In the 25mL round-bottomed flask, drop into (0.3mmol, 170 milligrams) (E)-2-(3-(3, the 4-dibenzyloxy benzene) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid, (0.03mmol; 37 milligrams) 4-Dimethylamino pyridine (DMAP), (0.03mmol, 2 milligrams) oxammonium hydrochloride, 10mL anhydrous methylene chloride, ice bath adds (0.36mmol after stirring 15min down; 74 milligrams) dicyclohexyl carbon imide (DCC), after the TLC detection reaction is accomplished, filter; Washing, anhydrous sodium sulfate drying filters; Evaporate to dryness, preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1), get (E)-1-(hydroximic acid)-1-oxygen propyl group-2-3-(3; The 4-dibenzyloxy benzene)-and 309 milligrams of 3-(3, the 4-dimethoxy benzene) propenoate, Off-white solid (53%yield);
1H NMR (CDCl
3, 300MHz): δ 3.20 (m, 2H, CH
2), 3.81 (s, 3H, OCH
3), 3.84 (s, 3H, OCH
3), 5.20 (m, 4H, CH), 5.40 (m, 1H, CH), 6.20 (d, J=15.9Hz, 1H, CH), 6.71 (m, 3H, ArH), 6.92 (d, J=8.1Hz, 1H, ArH), 7.07 (m, 2H, ArH), 7.42 (m, 10H, ArH), 7.56 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 36.8,55.9, and 71.0,71.4,72.8,107.6,108.7,111.2,112.7,113.9,114.2,114.7,121.6,121.8,123.3,123.5,127.2,127.3,128.0,128.6,136.8,148.2,149.0,165.6,167.9; ESI-MS m/z 606.3 [M+Na]
+, 582.1 [M-H]
-HRMS (ESI): m/z calcd for C
34H
33NO
8Na [M+Na]
+: 606.2104, found 606.2095.
Synthesizing of embodiment 16,2-(3-(4-chloro-phenyl-) acrylamido)-3-(3, the 4-Dimethoxyphenyl) allyl acrylates (compound 38 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 265 milligrams) 2-amino-3,4-dimethoxy benzene allyl propionate, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 273 milligrams) 4-chloro-phenyl-vinylformic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=80:20) purifying gets 2-(3-(4-chloro-phenyl-) acrylamido)-3-(3 to thick product through column chromatography; 343 milligrams of 4-Dimethoxyphenyl allyl acrylates, white solid (80%yield);
1H NMR (CDCl
3, 300MHz): δ 3.17 (dd, J=8.1,8.4Hz, 1H, CH
2), 3.25 (dd, J=5.1,5.1Hz, 1H, CH
2), 3.84 (s, 3H, OCH
3) 3.87 (s, 3H, OCH
3), 4.68 (d, J=5.7Hz, 2H, CH
2), 5.22-5.38 (m, 3H, CH), 5.85 (m, 1H, CH), 6.53 (d, J=15.9Hz, 1H, CH), 6.86 (d, J=9.9Hz, 3H, ArH), 7.66 (m, 4H, ArH), 7.74 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.2,55.9, and 66.0,73.5,111.3,112.5,118.9,119.6,121.5,125.9,128.2,128.3,131.4,137.6,144.2,148.2,148.9,165.5,169.3; ESI-MS m/z452.2 [M+Na]
+HRMS (ESI): m/z calcd for C
23H
24ClNO
5Na [M+Na]
+: 452.1346, found452.1352.
Synthesizing of embodiment 17,2-(3-(4-benzyloxy phenyl) acrylamido)-3-(3, the 4-Dimethoxyphenyl) allyl acrylates (compound 40 in the table 1)
In the 25mL round-bottomed flask, drop into (1mmol, 265 milligrams) 2-amino-3,4-dimethoxy benzene allyl propionate, (0.02mmol; 24 milligrams) 4-Dimethylamino pyridine (DMAP), (1.5mmol, 381 milligrams) 4-benzyloxy phenylacrylic acid, 10mL methylene dichloride, after stirring; Add (1.2mmol, 186 milligrams) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) under the room temperature, the TLC monitoring; After reacting completely; Wash 3 times, anhydrous sodium sulfate drying, (sherwood oil: ETHYLE ACETATE=80:20) purifying gets 2-(3-(4-benzyloxy phenyl) acrylamido)-3-(3 to thick product through column chromatography; The 4-Dimethoxyphenyl) allyl acrylate is 461 milligrams, white solid (92%yield);
1H NMR (CDCl
3, 300MHz): δ 3.18 (m, 2H, CH
2), 3.85 (s, 3H, OCH
3), 3.87 (s, 3H, OCH
3), 4.66 (tt, J=2.7,2.7Hz, 2H, CH
2), 5.23-5.42 (m, 6H, CH), 5.83 (m, 1H, CH), 6.43 (d, J=15.9Hz, 1H, CH), 6.66 (m, 3H, ArH), 6.93 (m, 2H, ArH), 7.26-7.45 (m, 7H, ArH), 7.65 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 36.8,56.0, and 71.1,71.2,73.3,112.2,113.5,114.4,115.0,115.6,116.1,117.2,121.5,122.7,127.5,127.8,129.9,144.6,145.5,146.1,146.5,148.6,165.6,167.6; ESI-MS m/z 502.2 [M+H]
+, 524.3 [M+Na]
+HRMS (ESI): m/z calcd for C
30H
31NO
6Na [M+Na]
+: 524.1888, found 524.1868.
Synthesizing of embodiment 18, (E)-2-(3-(to bromophenyl) acrylamido)-3-(3, the 4-dimethoxy benzene) propionic acid (compound 41 in the table 1)
Drop into (0.3mmol, 142 milligrams) 2-(3-(4-bromophenyl) acrylamido)-3-(3, the 4-Dimethoxyphenyl) allyl acrylate, 15mg Pd (PPh in the 25mL round-bottomed flask
3)
4, 10mL anhydrous tetrahydro furan THF, be stirred to dissolving, slowly drip the 10mmol morpholine, after stirring at room, TLC detection reaction are accomplished; Low temperature evaporate to dryness, bullion are dissolved in the ether, 1M HCl washing, back extraction; Merge organic phase, anhydrous sodium sulfate drying filters evaporate to dryness; The preparation thin layer (sherwood oil: ETHYLE ACETATE: acetic acid=80:20:0.1), 355 milligrams of (E)-2-(3-(to bromophenyl) acrylamido)-3-(3, the 4-dimethoxy benzene) propionic acid, white solid (82%yield);
1H NMR (CDCl
3, 300MHz): δ 3.17 (m, 2H, CH
2), 3.85 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 5.35 (m, 1H, CH), 6.36 (d, J=15.9Hz, 1H, CH), 6.80 (m, 3H, ArH), 7.07 (m, 2H, ArH), 7.47 (m, 2H, ArH), 7.66 (d, J=15.9Hz, 1H, CH);
13C NMR (CDCl
3, 75MHz): δ 37.2,55.9, and 73.6,111.3,112.6,119.8,121.9,125.4,128.2,131.3,132.9,137.9,144.3,148.6,148.9,166.2,167.9; ESI-MS m/z 456.1 [M+Na]
+HRMS (ESI): m/z calcd for C
20H
20BrNO
5Na [M+Na]
+: 456.1066, found 456.1058.
The chirality preparation of embodiment 19, (E)-2-(3-(3, the 4-dibenzyloxy benzene) acryloxy)-3-(3, the 4-dimethoxy benzene) propionic acid
(3-(3, the 4-dibenzyloxy benzene) acryloxy)-(compound 26 in the table 1, R for propionic acid for 3-(3, the 4-dimethoxy benzene) accurately to take by weighing racemic modification (E)-2-
4=3, the 4-benzyloxy phenenyl) 0.5 gram, select normal hexane/methylene dichloride/Virahol/acetic acid (65/20/15/0.1) mixed solvent as moving phase, the chiral separation post is a Daicel CHIRALPAK IC type, splits post specification 0.46cm I.D. * 25cm; Detecting wavelength is UV 254nm; Moving phase speed 1ml/min; Under 35 ° of C conditions of column temperature, the 15ul sample introduction gets peak 1 in RT in the time of about 7.9 minutes, be R-type isomer through structural identification; Getting peak 2 in the time of about 10.3 minutes in RT, is S-type isomer through structural identification.
The Tuberculosis in vitro nuclear bacillus experiment of embodiment 20, compound
Experiment material:
Bacterial strain: Mycobacterium tuberculosis type strain H37Rv is from China national DSMZ.
Liquid nutrient medium: for containing the Middlebrook 7H9 liquid nutrient medium of 10% nutritional additive.The Middlebrook7H9 culture medium dry powder is available from U.S. Becton Dickinson (BD) company, and the nutritional additive (OADC) that is mixed with by oleic acid, bovine serum albumin, glucose and katalase (being Japanese import reagent) is self-control.
Nutritional additive preparation: take by weighing bovine serum albumin 5g, oleic acid 0.06ml, glucose 2g, katalase 0.003g, sodium-chlor 0.85g, add zero(ppm) water to 100 milliliter, heating makes dissolving, and 121 ℃ of autoclavings 15 minutes are subsequent use.
The experiment medicine (in the table compound 26 and compound (R) 26 with 26 be to prepare by embodiment 13 and 19 respectively (S); Compound 33 is by embodiment 15 preparation) be dissolved to 5mg/mL with DMSO respectively after, be diluted to required experimental concentration with liquid nutrient medium.Final concentration in the DMSO liquid medium within 0.01%, the growth of tubercule bacillus there is not influence.
Experimental technique: medicine to be detected and positive control medicine add respectively in the bottle that contains liquid nutrient medium with continuous 2 times of extent of dilution; Plant the mycobacterium tuberculosis type strain H37Rv of 3 milligrams of bacterium amounts then; Cultivated 14 days for 37 ℃; Observe the minimum inhibitory concentration (MIC) of each medicine to mycobacterium tuberculosis, it is parallel that same experimental group is established three pipes.
Experimental result: experimental result sees the following form 2.
The Tuberculosis in vitro pyrenomycetes of table 2 part preferred compound is active
Above-mentioned experimental result shows that the compound that relates among the present invention has tubercle bacillus resistant activity preferably, explains that The compounds of this invention can be used for preparing the medicine of treating tuberculosis infection.
Claims (10)
1. the rosmarinic acid verivate is characterized in that, said rosmarinic acid verivate comprises its R-type and S-type isomer, and general structure is following:
The rosmarinic acid verivate
(R)-rosmarinic acid verivate (S)-rosmarinic acid verivate
Wherein: R
1Be hydrogen, benzyl, allyl group, alkyl or substituted silane base; Said alkyl is the straight or branched alkyl with 1～4 carbon atom, like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl, preferably has the alkyl of 1～2 carbon atom, special preferable methyl; Said substituted silane base is for having 3 substituted siloyl group of alkyl or phenyl: trimethyl silicon based, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based or triisopropylsilyl; Preferred trimethyl silicon based or tertiary butyl dimethyl-is silica-based, special preferred tertiary butyl dimethyl-is silica-based;
R
2Be hydrogen, benzyl, allyl group, alkyl or substituted silane base; Said alkyl is the straight or branched alkyl of 1～4 carbon atom: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl preferably have the alkyl of 1～2 carbon atom, special preferable methyl; Said substituted silane base is for having 3 substituted siloyl group of alkyl or phenyl: trimethyl silicon based, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based or triisopropylsilyl; Preferred trimethyl silicon based or tertiary butyl dimethyl-is silica-based, special preferred tertiary butyl dimethyl-is silica-based;
R
1And R
2For identical or inequality, or R
1And R
2Be connected to methylene radical;
W is Sauerstoffatom, sulphur atom or NH;
R
3Be hydroxyl, hydroxyl amino or alkoxyl group; Said alkoxyl group is the straight or branched alkoxyl group of 1～4 carbon atom: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy; Be preferably the alkoxyl group of 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the allyloxy or the alkyl replacement allyloxy of 3～6 carbon atoms;
R
4Be phenyl, substituted-phenyl, heterocycle or substituted heterocycle;
Substituting group in the said substituted-phenyl be positioned at the neighbour, or contraposition, be substituted by single replace or polysubstituted; Said substituting group is a halogen, like fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1～6 carbon atom; Like methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl or new hexyl; The alkyl of preferred 3～4 carbon atoms, the preferred especially sec.-propyl or the tertiary butyl; Or be the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom; Like methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, tetrafluoro propyl group; The substituted alkyl of preferred 2～3 fluorine atoms with 1～2 carbon atom, preferred especially trifluoromethyl; Or be the straight or branched alkoxyl group of 1～4 carbon atom, like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, the alkoxyl group of preferred 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the straight or branched alkoxyl group of 1～4 substituted 1～4 carbon atom of fluorine atom, like trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of preferred 1～4 substituted 1～2 carbon atom of fluorine atom, preferred especially trifluoromethoxy; Or be methylene-dioxy; Or be the allyloxy or the alkyl replacement allyloxy of 3～6 carbon atoms; Or be cyanic acid; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be the 1-naphthyl; Or be the 2-naphthyl; Or be benzyloxy or substituted benzyloxy, or said substituting group is that allyloxy or the alkyl of the straight or branched alkoxyl group of the straight or branched alkyl of halogen, 1～6 carbon atom, the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom, 1～4 carbon atom, the straight or branched alkoxyl group of 1～4 substituted 1～4 carbon atom of fluorine atom, 3～6 carbon atoms replaces allyloxy, cyanic acid, nitro; The acyloxy of 1-4 carbon atom, amino, hydroxyl; Or be heterocycle methoxyl group or substituted heterocycle methoxyl group; Said heterocycle is five yuan or hexa-atomic single heterocycle and five yuan or hexa-atomic fused heterocycle; Furans, thiophene, pyrroles, pyrazoles, imidazoles 、 oxazole, thiazole 、 isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, talk endlessly pyridine or purine or be 2,3-Dihydrobenzofuranes-6 base; Or be phenyl or substituted-phenyl; Said substituting group is benzyloxy or substituted benzyloxy; Or said substituting group is heterocycle methoxyl group or substituted heterocycle methoxyl group; Said heterocycle is five yuan or hexa-atomic single heterocycle and five yuan or hexa-atomic fused heterocycle, is furans, thiophene, pyrroles, pyrazoles, imidazoles 、 oxazole, thiazole 、 isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, talk endlessly pyridine or purine or be 2,3-Dihydrobenzofuranes-6 base; Substituting group in the said substituted heterocycle be positioned at the neighbour, or contraposition, be substituted by single replace or polysubstituted; Substituting group in the said substituted heterocycle is a halogen, fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1～4 carbon atom, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec.-butyl, the alkyl of preferred 3～4 carbon atoms, the preferred especially sec.-propyl or the tertiary butyl; Or be the straight or branched alkoxyl group of 1～4 carbon atom, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy preferably have the alkoxyl group of 1～3 carbon atom, preferred especially methoxy or ethoxy; Or be the straight or branched alkyl of 1～4 substituted 1～4 carbon atom of fluorine atom, methyl fluoride, difluoromethyl, trifluoromethyl or trifluoroethyl tetrafluoro propyl group, the alkyl of preferred 2～3 substituted 1～2 carbon atoms of fluorine atom, preferred especially trifluoromethyl; Or be 1～4 substituted straight or branched alkoxyl group with 1～4 carbon atom of fluorine atom, trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of preferred 2～4 substituted 3～4 carbon atoms of fluorine atom, preferred especially tetrafluoro propoxy-; Or be methylene-dioxy; Or allyloxy or alkyl replacement allyloxy for having 3～6 carbon atoms; Or be cyanic acid; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be phenyl; Or be the 2-naphthyl; Or be the 1-naphthyl.
2. rosmarinic acid verivate according to claim 1 is characterized in that, described rosmarinic acid verivate is following compounds 1-47:
R wherein
1, R
2, R
3And R
4Definition according to claim 1;
3. the preparation method of rosmarinic acid verivate as claimed in claim 1 is characterized in that, this method comprises the following steps that reaction formula is following:
(1) compound IV 3-(3,4-dialkoxy phenyl)-2-hydroxyl or amino or thiohydracrylic acid are under acid catalysis, and esterification obtains compound V3-(3,4-dialkoxy phenyl)-2 hydroxyls or amino or mercaptopropionic acid ester;
(2) compound V and various different substituted cinnamic acid VI generation condensation reactions obtain the esterified derivative VII of (±)-rosmarinic acid;
The esterified derivative VII of (3) (±)-rosmarinic acid is sloughed the protection of allyl group or methyl through catalysis and is obtained corresponding (±)-rosmarinic acid verivate VIII;
(4) (±)-rosmarinic acid verivate VIII and oxammonium hydrochloride; Condensation in the presence of condensing agent; Make (±)-rosmarinic acid hydroxamic acid derivatives IX (±)-2-substitutional crylic acid (sulphur) ester or acrylamido-3-(3,4-dimethoxy or dihydroxyl) phenyl propyl hydroximic acid;
(5) (±)-rosmarinic acid verivate VIII gets rosmarinic acid derivative compound X (±)-2-substitutional crylic acid (sulphur) ester or acrylamido-3-(3, the 4-dihydroxyl) phenylpropionic acid through the catalysis demethylating;
(6) chirality of rosmarinic acid verivate R-type and S-type isomer preparation
Get compound VIII, IX or X, the selective solvent dissolving splits the post fractionation through chirality and is prepared into R-type and S-type isomer
4. according to the said method of claim 3, it is characterized in that, said step (1) esterification be the compound IV under acid catalysis, back flow reaction in appropriate solvent; Said acid is tosic acid, methanesulfonic, phospho-molybdic acid, molecular sieve or acid zeyssatite, preferred molecular sieve, acid zeyssatite, tosic acid or methanesulfonic, preferred especially tosic acid; Said solvent is benzene,toluene,xylene, normal hexane, hexanaphthene or octane-iso solvent, preferred toluene, normal hexane or hexanaphthene, preferred especially toluene; Said compound IV is 1:10 with the consumption mol ratio of acid, preferred 1:6, preferred especially 1:3; The reaction times of esterification is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (2) condensation reaction is compound V and condensing agent, in solvent, reacts; Said condensing agent is N; N-dicyclohexyl carbon imide, benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 3-(diethoxy phosphoryl oxy)-1; 2; 3-phentriazine-4-ketone, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus or 1-hydroxyl-benzo-triazole; Preferred N, N-dicyclohexyl carbon imide, 1-hydroxyl-benzo-triazole or 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, preferred especially 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate; Said solvent is ETHYLE ACETATE, methylene dichloride, chloroform, THF, dioxane, N, dinethylformamide or methyl-sulphoxide, ethyl acetate, methylene dichloride or THF, preferred especially methylene dichloride; The temperature of condensation reaction is-20-50 ℃, and preferred 0-50 ℃, preferred 20-35 ℃ especially; The consumption mol ratio of said compound V and condensing agent is 1:10, preferred 1:6, preferred especially 1:3; The time of said step (2) condensation reaction is 8-72 hour, preferred 12-36 hour, and preferred 12-24 hour especially;
Said step (3) deprotection reaction be the esterified derivative VII of (±)-rosmarinic acid under catalyst action, in solvent, carry out; Said catalyzer is palladium carbon, tetrakis triphenylphosphine palladium, Palladous chloride, three (triphenylphosphine) or rhodium chloride, preferred three (triphenylphosphine) rhodium chloride or tetrakis triphenylphosphine palladiums, preferred especially tetrakis triphenylphosphine palladium; Said solvent is methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, THF or N, dinethylformamide, ethyl acetate, methylene dichloride or THF, preferred especially THF; The temperature of reaction of deprotection reaction is 0-90 ℃, preferred 20-50 ℃, and preferred 25-30 ℃ especially; The esterified derivative VII of said (±)-rosmarinic acid and catalyst consumption mol ratio are 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (3) deprotection reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (4) condensation reaction is compound VIII and condensing agent, in solvent, reacts; Said condensing agent is N; N-dicyclohexyl carbon imide, benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 3-(diethoxy phosphoryl oxy)-1; 2; 3-phentriazine-4-ketone, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus or 1-hydroxyl-benzo-triazole; Preferred N, N-dicyclohexyl carbon imide, 1-hydroxyl-benzo-triazole or 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, preferred especially 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate; Said solvent is ETHYLE ACETATE, methylene dichloride, chloroform, THF, dioxane, N, dinethylformamide or methyl-sulphoxide, ethyl acetate, methylene dichloride or THF, preferred especially methylene dichloride; The temperature of reaction of condensation reaction is-20-50 ℃, and preferred 0-50 ℃, preferred 20-35 ℃ especially; The consumption mol ratio of said compound VIII and condensing agent is 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (4) condensation reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
Said step (5) deprotection reaction be the compound VIII under catalyst action, in solvent, carry out; Said catalyzer is palladium carbon, tetrakis triphenylphosphine palladium, Palladous chloride, three (triphenylphosphine) or rhodium chloride, preferred three (triphenylphosphine) rhodium chloride or tetrakis triphenylphosphine palladiums, preferred especially tetrakis triphenylphosphine palladium; Said solvent is methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, THF or N, dinethylformamide, ethyl acetate, methylene dichloride or THF, preferred especially THF; The temperature of reaction of deprotection reaction is 0-90 ℃, preferred 20-50 ℃, and preferred 25-30 ℃ especially; Said compound VIII and catalyst consumption mol ratio are 1:10, preferred 1:6, preferred especially 1:3; The reaction times of said step (5) deprotection reaction is 12-72 hour, preferred 12-48 hour, and preferred 12-24 hour especially;
The chiral method for preparing of said step (6) rosmarinic acid verivate R-type and S-type isomer is: get compound VIII, IX or X, dissolution with solvents, through chirality split post R-type and S-type isomer; Said solvent is a methylene dichloride, chloroform, THF; Normal hexane, MTBE, ETHYLE ACETATE; Ethanol, Virahol, acetonitrile; One or more mixed solvents in acetone or the acetic acid, one or more mixed solvents in preferred normal hexane, methylene dichloride, Virahol and the acetic acid, it is preferred especially that normal hexane/methylene dichloride/Virahol/acetic acid ratio is 65/20/15/0.1 mixed solvent; Said chiral separation temperature is 0-60 ℃, preferred 20-50 ℃, and preferred 30-35 ℃ especially; Said chiral separation post is a polysaccharide derivates class chiral column; Preferred bonding type polysaccharide derivates chiral column, Daicel CHIRALPAK IA type, CHIRALPAK IB type or CHIRALPAK IC type, preferred especially Daicel CHIRALPAK IC type; Packing material size is 3 μ m or 5 μ m, preferred 5 μ m.
5. according to the said method of claim 3, it is characterized in that the preparation method of said compound IV comprises the following steps that reaction formula is following:
(1) be starting raw material with the substituted benzaldehyde I, in the presence of alkali and diacetyl oxide with acetyl-glycine through cyclization De Dao the azolactone compound ii;
(2) compound ii hydrolysis under acidic conditions obtains the compound III;
(3) the compound III obtains the compound IV through reduction.
6. according to the said method of claim 5; It is characterized in that; The alkali of said step (1) cyclization is sodium hydride, sodium methylate, sodium ethylate, sodium isopropylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium-acetate, Potassium ethanoate, triethylamine or Trimethylamine 99 etc.; Preferred sodium-acetate, Potassium ethanoate, sodium ethylate, sodium hydroxide, Pottasium Hydroxide or triethylamine, preferred especially sodium-acetate or Potassium ethanoate; Temperature of reaction is 80-150 ℃, and preferred temperature is 100-130 ℃, and preferred especially temperature is 110-115 ℃;
The acid of said step (2) acidic hydrolysis is sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, hydroiodic acid HI, acetate or formic acid etc., preferably sulfuric acid, hydrochloric acid, Hydrogen bromide or hydroiodic acid HI, special preferably sulfuric acid or hydrochloric acid; The concentration of said acid is 2M-10M, preferred 3M-6M, preferred especially 3-4M; Temperature of reaction is 70-110 ℃, and preferred temperature is 80-100 ℃, and preferred especially temperature is 90-95 ℃;
Said step (3) is used reductive agent or catalytic hydrogenation reduction; Said reductive agent is iron, zinc or tin/hydrochloric acid, sodium sulphite, vat powder, Raney Ni/Hydrazine Hydrate 80, tetrahydrochysene lithium aluminium or Peng Qinghuana; Preferred tetrahydrochysene lithium aluminium, Peng Qinghuana or catalytic hydrogenation reduction, preferred especially sodium borohydride reduction.
7. the application of rosmarinic acid verivate as claimed in claim 1 in preparation anti-mycobacterium tuberculosis medicine.
8. application according to claim 7 is characterized in that, described rosmarinic acid verivate is compound 1-47; Be preferably compound 5,15,19,26,33 or 41; Compound 26 or 33 more preferably.
9. according to the described application of claim 7-8, it is characterized in that described rosmarinic acid verivate comprises its R-type isomer or S-type isomer.
10. according to the said application of claim 7, it is characterized in that said medicine is the pharmaceutical composition of being made up of as activeconstituents and pharmaceutical carrier the rosmarinic acid verivate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109843896A (en) * | 2016-10-14 | 2019-06-04 | 波尔图大学 | Hydroxy cinnamic acid derivative, method and application thereof |
| CN115385819A (en) * | 2022-09-22 | 2022-11-25 | 贵州中医药大学 | Rosmarinic acid bioelectronic isostere and preparation method and application thereof |
| CN117488458A (en) * | 2023-10-25 | 2024-02-02 | 普宁市新栩纺织有限公司 | Antibacterial breathable fabric |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315863A (en) * | 1998-05-16 | 2001-10-03 | 财团法人牧岩生命工学研究所 | Use of rosmarinic acid and derivatives thereof as immunosuppressant or inhibitor of SHz-mediated process |
-
2012
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315863A (en) * | 1998-05-16 | 2001-10-03 | 财团法人牧岩生命工学研究所 | Use of rosmarinic acid and derivatives thereof as immunosuppressant or inhibitor of SHz-mediated process |
Non-Patent Citations (4)
| Title |
|---|
| CHARLES J.KELLEY ET AL: "Polyphenolic Acids of Lithospermum ruderale Dougl.ex Lehm.(Boraginaceae).1.Isolation and Structure Determination of Lighospermic Acid", 《J.ORG.CHEM.》 * |
| THEOPHIL EICHER ET AL: "Bryophyte Constituents：New Synthesis of (+)-Rosmarinic Acid and Related Compounds", 《SYNTHESIS》 * |
| 刘伟，丁海杰: "HPLC测定夏枯草中熊果酸、齐墩果酸、迷迭香酸的含量", 《中成药》 * |
| 邓喜玲等: "丹参素的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109843896A (en) * | 2016-10-14 | 2019-06-04 | 波尔图大学 | Hydroxy cinnamic acid derivative, method and application thereof |
| CN109843896B (en) * | 2016-10-14 | 2022-12-20 | 波尔图大学 | Hydroxycinnamic acid derivatives, methods and uses thereof |
| CN115385819A (en) * | 2022-09-22 | 2022-11-25 | 贵州中医药大学 | Rosmarinic acid bioelectronic isostere and preparation method and application thereof |
| CN117488458A (en) * | 2023-10-25 | 2024-02-02 | 普宁市新栩纺织有限公司 | Antibacterial breathable fabric |
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