CN103319437B - There is pleuromutilin analog derivative of thiadiazoles skeleton and preparation method thereof, application - Google Patents
There is pleuromutilin analog derivative of thiadiazoles skeleton and preparation method thereof, application Download PDFInfo
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Abstract
The invention discloses a kind of pleuromutilin analog derivative with thiadiazoles skeleton and preparation method thereof, comprise the steps: step 1,22-O-(4-tosyl) oxygen acetyl group nurse body woods synthetic; Step 2,14-O-(iodoacetyl) nurse body woods synthetic; Step 3,14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods synthetic; Synthesizing of step 4, end-product. Such compou nd synthesis method raw material is easy to get, cheap, simple to operate, product easily separates, purifying, yield is high, total recovery is 32～40%.
Description
Technical field
The present invention relates to a kind of pleuromutilin analog derivative and preparation method thereof, belong to chemicals field.
Background technology
Antibiotic discovery and use have very important meaning in human history. But over the past 30 years,The antibiotic even abuse that is widely used, causes that numerous bacteriums have produced day by day serious drug resistance. Due to the generation of drug resistance,Cause the good curative effect of medication of original curative effect reduce or lost efficacy. Especially cause the staphylococcus aureus of breathing problem(Staphylococcusaureus), streptococcus pneumonia (Staphylococcuspneumoniae) and Much's bacillus(Mycobacteriumtuberculosis) drug-fast bacteria such as, causes more than 200 ten thousand people's death every year, serious harm peopleThe health of class.
Pleuromutilin (chemical structural formula is as follows) is the natural antibiotics of finding the fifties in last century, and research shows, is somebody's turn to doCompound and some derivative thereof gram-positive bacteria and the mycoplasma to resistance has obvious antibacterial activity and good medicineFor kinetic property, and with the characteristic of other antibiotic without crossing drug resistant. At present, the pleuromulins medicine having gone on the market has threeKind: be respectively Thailand second rhzomorph (tianmulin), valnemulin (Valnemulin), Retapamulin (Retapmulin). WhereinTwo kinds of medicines, as veterinary drug, are mainly used in treatment or the prevention of animal breath tract disease clinically, and rear one is people's skinSkinfeel is dyed medicine. In addition, BC-7013 and BC-3205 are people's medicines of exploitation recent years, infect for bacteriumTreatment, especially, for the infection of drug-fast bacteria, these two kinds of medicines have completed I phase clinical trial at present.
Pleuromutilin molecular structural formula
The side chain of pleuromutilin C14 is the main site of carrying out chemical modification. But its ester group structure is that brachymemma is picked up the earsThe essential group that element is active, if be hydroxyl by hydrolysis of ester group, antibacterial activity disappears. Therefore, both at home and abroad to pleuromutilinThe structural modification study general of the side chain of C14 is to retain under the prerequisite of ester group structure, transforming in C22 position, like this canGreatly improve its bacteriostatic activity and bioavilability. Structure-activity relationship shows, C-14 position side chain connects neutral group or acid groupCompound antibacterial activity extremely low, its activity of derivative that connects two basic center side chains is also lower. And connect a basic centerThioether group side chain, will there is conclusive improvement in its derivatives active. In the side chain of thioether group, branched derivativeActivity is stronger than unbranched activity, as the antibacterial activity of fertile Buddhist nun woods second is obviously better than safe second rhzomorph.
Pleuromutilin and derivative thereof are mainly to make protein biosynthesis block by the activity of peptide for inhibiting based transferase,Thereby reach bacteriostasis. This compounds is to be positioned in the ribosomal peptidyl transferase of 50S subunit by its tricyclic ring heartThe heart, and the ledge of the tricyclic ring heart has covered the site of combination, has directly suppressed thus the formation of peptide bond. Just because of brachymemmaThe action principle of this uniqueness of pleurin, thus between this class medicine and other drug, there will not be cross resistance, especiallyStaphylococcus aureus, streptococcus pneumonia and Much's bacillus etc. to resistance have good inhibitory action. Therefore, such changeThe development tool of compound is of great significance.
Most compounds taking thiadiazoles as skeleton have biologically active widely, as antibacterial, antitumor, depressionDeng. If infer in pleuromutilin analog derivative and contain thiadiazoles group, its biologically active likely can improve. ThereforeDesign and synthesize out a series of pleuromulins new derivatives with thiadiazoles skeleton, by synthetic these derivatives, withPhase filters out the reasonable pleuromulins noval chemical compound of biologically active.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, and good absorbing is provided, anti-oxidant eutherapeutic anti-The combined extracts of free radical is removed in oxidation.
Object of the present invention is carried out specific implementation by the following technical programs:
Have the pleuromutilin analog derivative of thiadiazoles skeleton, chemical structural formula is as I or II:
（I）
Or
（II）
Wherein: R in formula (I)1=Cl、OCH3Or NH2; In formula (II)=、、、、Or。
The preparation method of the above-mentioned pleuromutilin analog derivative with thiadiazoles skeleton, comprises the steps:
Step 1,22-O-(4-tosyl) oxygen acetyl group nurse body woods (intermediate 1) synthetic
Pleuromutilin and paratoluensulfonyl chloride are dissolved in to methyl tertiary butyl ether(MTBE) and H2In O mixture, then slowly dripConcentration is the sodium hydroxide solution of 30-50wt%, heating reflux reaction 20-80min, and the white product of generation is filtered while hot, thenThe white product of washing respectively gained with methyl tertiary butyl ether(MTBE) and water, is dried and obtains white powder, is 22-O-(4-toluene sulphurAcyl group) oxygen acetyl group nurse body woods, without purifying, be directly used in next step;
Step 2,14-O-(iodoacetyl) nurse body woods (intermediate 2) synthetic
Be dissolved in acetone soln at step 1 gained white powder, add slightly excessive KI, reflux, then filter, filtrate existsFlaxen intermediate 14-O-(iodoacetyl is directly recrystallized out under room temperature) nurse body woods;
Step 3,14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] the closing of nurse body woods (intermediate 3)Become
By 2-amino-5-sulfydryl-1,3,4, in the NaOH that-thiadiazoles is dissolved in, and dropwise add the synthetic 14-O-of step 2In the THF solution of (iodoacetyl) nurse body woods, mixture is 0oUnder C, stir 2-3h, after evaporated under reduced pressure, add ethyl acetate moltenSeparate, and use NH4Cl washes away after residual alkali with distilled water extraction, uses anhydrous Na after separating organic phase2SO4Dried overnight, after filtrationFiltrate separates and obtains intermediate 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base with silicagel column) mercapto acetyl group] nurse body woods;
Synthesizing of step 4, end-product
The first situation: derivative (structural formula as I) synthetic that contains benzene ring structure in pleuromutilin side chain
By intermediate 14-O-[(2-amino-1 synthetic in step 3,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurseBody woods and chloride, methoxyl group or amino benzoic acid, the EDC hydrochloride replacing(EDCI) and I-hydroxybenzotriazole (HOBt) be dissolved in carrene (DCM), stirring reaction 15-18h under room temperature, mixed after reactionThe first water of compound washes away EDCI, then uses saturated NaHCO3Solution washing, removes unreacted carboxylic acid completely, through anhydrous MgSO4After dry, remove DCM under reduced pressure, target compound obtains after being separated by silicagel column;
The second situation: derivative (structural formula as I I) synthetic that contains tertiary amine in pleuromutilin side chain
First use intermediate 14-O-[(2-amino-1 synthetic in step 3,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurseBody woods reacts in DCM with chloracetyl chloride, N-methylmorpholine, generates intermediate 14-O-[(2-chloracetyl-1, and 3,4 ,-thiophene twoAzoles-5 base) mercapto acetyl group] nurse body woods, after evaporate to dryness DCM, add oxolane (THF), then add secondary amine and triethylamine or N-Methyl morpholine reacts under the condition of 45 DEG C, and evaporate to dryness THF after reaction adds after AcOEt with saturated NH4Cl solution washing, thenWater extraction three times, separates organic layer and uses anhydrous MgSO4Dried overnight, after filtering, filtrate is carried out column chromatography for separation, must cutThe derivative that contains tertiary amine in short pleurin side chain,
Wherein, described secondary amine is selected dimethylamine agueous solution, diethylamine, piperidines, pyrrolidines, morpholine or 4 methyl of 40wt%Piperazine.
Further, the first situation in described step 4, contains spreading out of benzene ring structure in described pleuromutilin side chainSubstituent R on biological phenyl ring1During for amino, structural formula is as follows,
，
Described substituted benzoic acid is selected amino substituted benzoic acid, first amino substituted benzoic acid is carried out to amido protecting, by ammoniaCarboxylic acid and 14-O-[(2-amino-1 of base protection, 3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods, molten with DCI and HOBtIn a certain amount of DCM, under room temperature, stir 15-18h, after reaction, the first water of mixture washes away EDCI, then uses saturated NaHCO3Solution washing, removes unreacted carboxylic acid completely, after anhydrous MgSO4 is dry, removes DCM under reduced pressure, gained mixture silicagel columnSeparate, in the compound the obtaining TFA that separation is obtained and the mixed solution of DCM, stir 30min, then use respectively distilled waterWith saturated MH4Cl solution washing, separates two-phase, after organic phase is dry, obtains target product.
Above-mentioned amido protecting, concrete operations are as follows,
Amino substituted benzoic acid is dissolved in the mixed solvent by THF and distilled water, adds NaOH solution, in stirring at room temperatureCondition under slowly drip and the BOC of amino substituted benzoic acid equimolar amounts2O, continues reaction about 8h after dripping, after reactionUnder reduced pressure, by THF evaporate to dryness, add ethyl acetate washing, separate two-phase, in water, add 5% citric acid acidifying to pH3-4, now produce a large amount of white precipitates, filter and wash with water 2-3 time, the dry substituted benzoic acid that obtains amido protecting,
Wherein, described amino substituted benzoic acid: the mixed solution of THF: water: NaOH: ethyl acetate: TFA and DCM is1mmol：8-10mL：4-5mL：1-1.5mmol：4-6mL：5-8mL。
Preferably, in described step 1, pleuromutilin: t-butyl methyl ether: water: NaOH solution is 1mmol:0.8-2mL:0.15-0.25mL:0.25-0.5mL, is preferably 1mmol:1mL:0.2mL:0.3mL; The preferred 40wt% of concentration of NaOH solution.
Preferably, in described step 2,22-O-(4-tosyl) oxygen acetyl group nurse body woods: KI: acetone is 1mmol:1.0-1.2mmol:12-18mL, be preferably 1mmol:1.1mmol:15mL.
Preferably, in described step 3,14-O-(iodoacetyl) nurse body woods: 2-amino-5-sulfydryl-1,3,4 ,-thiophene twoAzoles: NaOH:THF solution: ethyl acetate is 1mmol:1.1-1.2mmol:1.8-2.2mmol:10-12mL:10-20mL,Be preferably 1mmol:1.1mmol:2mmol:10mL:15mL.
Described silicagel column separates the silicagel column that adopts benzinum: ethyl acetate=1:2.
Preferably, the first situation in described step 4,
14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloride, methoxyl group or amino are gotThe benzoic acid in generation: EDCI:HOBt:DCM is 1mmol:1.1-1.3mmol:1.1-1.3mmol:1.1-1.3mmol:15-25mL, is preferably 1mmol:1.1mmol:1.2mmol:1.2mmol:20mL.
Described silicagel column separates the silicagel column that adopts benzinum: ethyl acetate=1:0.5-2.
Preferably, the second situation in described step 4,
Described 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloracetyl chloride: N-methylMorpholine: DCM is 1mmol:1.3-1.8mmol:1.8-2.4mmol:6-10mL, is preferably 1mmol:1.5mmol:2mmol:8mL. The N-methylmorpholine of indication is intermediate 14-O-[(2-chloracetyl-1 herein, 3,4, and-thiadiazoles-5 base) mercapto acetyl group]When nurse body woods is synthetic as the N-methylmorpholine of reactant, the N-methylmorpholine that difference adds below, after described in add three secondAmine or N-methylmorpholine, just as acid binding agent, do not participate in reaction.
Described 14-O-[(2-chloracetyl 1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: secondary amine: triethylamineOr N-methylmorpholine: THF is 1mmol:1.3-1.8mmol:1.8-2.4mmol:15-25mL, is preferably 1mmol:1.5mmol：5mmol：20mL。
Described silicagel column separates the silicagel column that adopts ethyl acetate: ethanol=20:1.
The above-mentioned pleuromutilin derivative with thiadiazoles skeleton is in the application of preparing in antibacterials.
Above-mentioned pleuromutilin new derivative 14-O-[(2-amino-1 taking thiadiazoles as skeleton that the present invention synthesizes, 3,4 ,-thiadiazoles-5 base) mercapto acetyl group] derivative that contains benzene ring structure in nurse body woods (intermediate 3), pleuromutilin side chain(structural formula as I), R1The derivative that contains benzene ring structure in pleuromutilin side chain during for amino and pleuromutilin side chainIn contain tertiary amine derivative (structural formula as I I), adopt staphylococcus aureus and the epidermis ball of agar dilution to resistanceThe minimal inhibitory concentration (MIC) of bacterium, Escherichia coli and Streptococcusagalactiae is measured, and control drug is pleuromutilin and safe wonderful bacteriumElement, its result is respectively in table 1 and table 2. In table, 16 synthetic pleuromutilin derivatives are antibacterial dense to the minimum of these four kinds of bacteriumDegree is respectively 8-0.25 μ g/mL, 8-0.5 μ g/mL, 64-8 μ g/mL, 8-0.5 μ g/mL. From minimal inhibitory concentration and antibacterialTest can find out, in these derivatives, compound 4,7b and 9c are to showing good bacteriostatic activity, especially to MRSAAnd MRSE. Compound 4,7b and 9c have exceeded control drug pleuromutilin and Tiamulin to the bacteriostatic activity of these four kinds of bacterium.All the other compounds have also shown medium antibacterial activity, and bacteriostatic activity has exceeded pleuromutilin, and especially phenyl ring adjacency pair position hasCompound 5d and the 5e of methoxyl group.
。
。
Can find out pleuromutilin side chain terminal, the phenyl base that meta-substituent group is Cl and NH2 from upper table 1 and table 2The antibacterial activity of group is better than the antibacterial activity of the phenyl group with ortho position or para-orientating group group. And meta-substituent group isThe antibacterial activity that the antibacterial activity of the phenyl group of methoxyl group does not but have at ortho position or para-orientating group is rolled into a ball is good.
On the other hand, no matter compound 9 is MIC or bacteriostatic test research, all has good antibacterial activity in vitro. AndWith the bacteriostatic activity of the similar compound 9d of this compound structure a little less than.
Such compou nd synthesis method raw material is easy to get, cheap, simple to operate, product easily separates, purifying, yieldHeight, total recovery is 32～40%.
Detailed description of the invention
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only usesIn description and interpretation the present invention, be not intended to limit the present invention.
Have the pleuromutilin analog derivative of thiadiazoles skeleton, chemical structural formula is as I or II:
（I）
Or
（II）
Wherein: R in formula (I)1=Cl、OCH3Or NH2; In formula (II)=、、、、Or。
Prepare a method for above-claimed cpd, first synthetic intermediate-14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 bases) mercapto acetyl group] nurse body woods (compound 4), then taking this intermediate as raw material, synthetic above-claimed cpd 5a-f, 7a-c respectivelyAnd 9a-f. Reaction scheme is as follows:
R=Cl or OCH in formula3。
R=NH in formula2。
Embodiment 1:22-O-(4-tosyl) oxygen acetyl group nurse body woods (2) synthetic
By 75.7g(0.2mol) pleuromutilin, the paratoluensulfonyl chloride of 42g (0.22mol) be dissolved in the methyl of 200mlIn tertbutyl ether, mixture slowly stirs and splashes into the NaOH solution 50ml that concentration is 0.01mol/ml. Then be heated to reflux,Vigorous stirring simultaneously, has a large amount of whitenesses to generate, then stirs 20-40min after 10-20min. By Buchner funnel mistake while hotFilter, and then uses respectively methyl tertiary butyl ether(MTBE) (MTBE) and distilled water flushing, obtains white powder product after natural drying(2), yield 97.8%.
mp147～148oC;IR(KBr):3446,2924,2863,1732,1633,1597,1456,1371,1297,1233,1117,1035,832,664,560cm-1;1HNMR(400MHz,CDCl3)δ0.63(d,3H,J=6.8Hz),0.87(d,3H,J=6.8Hz),1.11–1.15(m,1H),1.22-1.26(s,5H),1.33–1.36(m,1H),1.41–1.44(m,1H),1.46-1.50(m,5H),1.63-1.65(dd,2H,J1=10Hz,J2=7.2Hz),2.01–2.08(m,3H),2.21–2.29(m,3H),2.45(s,3H),3.34(d,1H,J=6.4Hz),4.48(s,2H),5.17-5.21(d,1H,J=8.8Hz),5.31-5.34(d,1H,J=6.4Hz),5.75-5.78(d,1H,J=4.2Hz),6.43(q,1H,J=17.2Hz,10.8Hz);7.35-7.37(d,2H,J=4.0Hz),7.80-7.82(d,2H,J=4.0Hz);13CNMR(100MHz,CDCl3)δ216.7,164.8,145.2,138.6,132.5,129.9,127.9,117.2,74.4,70.2,64.9,57.9,45.3,44.4,43.9,41.7,36.4,35.9,34.3,30.2,26.7,26.3,24.7,21.6,16.4,14.6,11.4.。
Synthesizing of embodiment 2:14-O-(iodoacetyl) nurse body woods (3)
The 22-O-(4-tosyl of 7.2g) oxygen acetyl group nurse body woods (13.5mmol), be dissolved in the acetone of 200mL,Add the KI(14mmol of 2.3g), cessation reaction after backflow 1h. Reactant mixture removes by filter insoluble salt, and filtrate is concentratedTo 20-30mL, filter the filtrate flaxen target compound 5.36g that is at room temperature directly recrystallized out.
Pale yellow powder, yield is 81%, mp:117-119oC; IR (KBr): 3307,2979,2933,1736,1712,1456,1417,1279,1084,1023,985,967cm-1；1HNMR(400MHz,CDCl3)δ7.26(s,1H),6.41(dd,J=17.4,11.0Hz,1H),5.70(d,J=8.5Hz,1H),5.34(d,J=11.0Hz,1H),5.20(dd,J=17.4,1.1Hz,1H),3.65(d,J=10.4Hz,1H),3.57(d,J=10.5Hz,1H),3.35(s,1H),2.36–2.28(m,1H),2.26–2.14(m,2H),2.07(dd,J=16.0,8.5Hz,2H),1.79–1.60(m,4H),1.57–1.47(m,2H),1.47–1.42(m,4H),1.35(dd,J=26.4,9.7Hz,2H),1.17(s,3H),1.12(d,J=4.3Hz,1H),0.87(d,J=7.0Hz,3H),0.73(d,J=6.9Hz,3H)；13CNMR(100MHz,CDCl3)δ216.76,166.88,138.57,117.28,74.71,70.49,58.20,45.48,44.20,43.93,41.98,36.71,35.86,34.31,30.10,26.78,26.42,24.80,16.75,14.78,11.46。
Embodiment 3:14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] the closing of nurse body woods (intermediate 3)Become
The 14-O-of 2.45g (iodoacetyl) nurse body woods (5mmol) is dissolved in the THF of 60mL, by the 2-ammonia of 0.73gBase-5-sulfydryl-1,3,4 ,-thiadiazoles (5.5mmol) is dissolved in the NaOH of 5mL10%, and dropwise adds in above-mentioned solution. MixThing is 0oUnder C, stir 2h, then evaporated under reduced pressure, adds the ethyl acetate of 100mL. Saturated NH for the mixture of gained4Cl washesWash, and with distilled water extraction 3 times, after separation organic phase, use anhydrous Na2SO4Dried overnight, after filtering, filtrate separates with silicagel column(benzinum: ethyl acetate=1:2) mixture, obtains 2.3g target compound.
White powder, yield 92%, mp74-75oC.；IR(KBr):3419,3330,2931,1731,1616,1507,1456,1417,1373,1282,1190,1152,1117,1019,980,953,938,916cm-1；1HNMR(400MHz,DMSO)δ7.28(s,2H),6.08(dd,J=17.8,11.2Hz,1H),5.52(d,J=8.1Hz,1H),5.03(dd,J=21.0,14.7Hz,2H),4.51(d,J=5.9Hz,1H),4.02(q,J=7.1Hz,1H),3.90(q,J=16.0Hz,2H),3.45–3.32(m,2H),2.39(s,1H),2.19(dd,J=18.8,10.8Hz,1H),2.11–1.97(m,4H),1.64(dd,J=18.4,9.5Hz,2H),1.54–1.42(m,1H),1.36–1.21(m,6H),1.16(d,J=7.1Hz,1H),1.08–0.94(m,4H),0.82(d,J=6.7Hz,3H),0.59(d,J=6.7Hz,3H)；13CNMR(100MHz,DMSO)δ217.08,169.73,166.70,148.89,140.68,115.39,72.63,70.27,59.75,57.23,44.95,44.14,41.51,36.33,34.00,30.10,28.70,26.60,24.47,20.75,16.09,14.51,14.08,11.5。
Embodiment 4: the conventional method that compound 5a-f is synthetic
14-O-[(2-amino-1 of 3.6mmol substituted benzoic acid, 1.48g, 3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurseThe EDCI(3.6mmol of body woods (3mmol), 0.69g), the HOBt (3.6mol) of 0.51g is dissolved in the DCM of 60mL, under room temperature, stirMix 36-48h. Reaction finishes the rear saturated NaHCO that uses3With distilled water washing, organic phase anhydrous Na after separating2SO4Dry, filterThe rear post of crossing separates (benzinum: ethyl acetate=1:1), obtains pure compound 11a-f.
1,14-O-[(2-chlorobenzene formacyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (5a)
White solid, yield 75%, mp:74-76oC；IR(KBr):3446,2932,1731,1683,1539,1456,1374,1305,1248,1189,1152,1117,1046,1017,980,938,916,895,746cm-1；1HNMR(400MHz,CDCl3)δ=7.79(s,1H),7.57–7.34(m,3H),6.38(dd,J=17.4,11.0,1H),5.73(d,J=8.4,1H),5.27(d,J=11.0,1H),5.13(d,J=17.4,1H),3.94–3.77(m,2H),3.32(d,J=6.1,1H),2.32–2.09(m,3H),2.09–1.96(m,3H),1.78–1.68(m,1H),1.65–1.47(m,3H),1.45–1.29(m,5H),1.23(dd,J=12.2,5.1,2H),1.10(d,J=8.5,4H),0.84(d,J=7.0,3H),0.67(d,J=6.9,3H)；13CNMR(100MHz,CDCl3)δ=216.79,166.40,164.40,160.13,158.44,138.71,130.84,130.47,127.08,117.20,74.48,70.36,60.28,57.98,45.33,44.62,43.84,41.77,36.57,35.85,34.33,30.28,26.73,26.35,24.73,16.64,14.75,14.10,11.37。
2,14-O-[(3-chlorobenzene formacyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (5b)
White solid, yield 75%, 62%, mp:115-118oC；IR(KBr):3427,2928,1731,1673,1538,1454,1411,1309,1250,1188,1152,1116,1019,980,914,805,733cm-1；1HNMR(400MHz,CDCl3)δ8.13(d,J=6.5Hz,2H),7.60(d,J=6.6Hz,1H),7.51(dd,J=9.9,5.3Hz,1H),6.40–6.29(m,1H),5.72(d,J=5.3Hz,1H),5.27–5.19(m,1H),5.09(dd,J=17.4,1.8Hz,1H),4.05–3.92(m,2H),3.31(s,1H),2.30–2.11(m,3H),2.04(s,2H),1.97(dd,J=14.6,6.9Hz,1H),1.73(d,J=14.3Hz,1H),1.61(d,J=10.1Hz,2H),1.46(dd,J=16.4,13.0Hz,2H),1.34(t,J=13.3Hz,4H),1.28–1.16(m,3H),1.09(t,J=10.4Hz,4H),0.84(d,J=4.8Hz,3H),0.65(d,J=3.2Hz,3H)；13CNMR(100MHz,CDCl3)δ=166.20,163.91,161.20,158.54,138.37,133.00,132.35,129.84,128.48,126.62,116.93,74.21,70.06,60.04,57.71,45.06,44.25,43.53,41.47,36.29,35.58,34.07,30.00,26.43,25.99,24.46,20.71,16.35,14.44,13.85,11.12。
3,14-O-[(4-chlorobenzene formacyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (5c)
White solid, yield 75%, 64%, mp:101-103oC；IR(KBr):3420,2927,1731,1670,1594,1539,1493,1456,1409,1310,1152,1116,1014,980,891,846,749cm-1；1HNMR(400MHz,CDCl3)δ8.19(d,J=8.6Hz,2H),7.54(d,J=8.3Hz,2H),6.38(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.23(d,J=10.9Hz,1H),5.10(d,J=17.3Hz,1H),3.98(s,2H),3.31(d,J=6.4Hz,1H),2.29–2.15(m,3H),2.05–1.94(m,2H),1.73(d,J=14.3Hz,1H),1.61(d,J=10.4Hz,2H),1.50–1.37(m,5H),1.33–1.20(m,3H),1.08(s,4H),0.84(d,J=6.9Hz,4H),0.68(d,J=6.9Hz,3H)；13CNMR(100MHz,CDCl3)δ216.88,166.48,164.44,161.65,158.79,139.91,138.71,130.18,129.18,128.85,117.26,74.53,70.44,58.03,45.38,44.59,43.85,41.80,36.62,35.87,34.39,30.33,26.75,26.28,24.77,16.69,14.78,11.44。
4,14-O-[(2-methoxybenzoyl base-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods(5d)
White solid, yield 68%, mp:89-92oC；IR(KBr):3304,2934,1732,1662,1601,1527,1487,1466,1398,1373,1288,1242,1184,1163,1118,1044,1017,980,938,916,895,756,666cm-1；1HNMR(400MHz,CDCl3)δ=11.18(s,1H),8.20(dd,J=7.9,1.7,1H),7.58–7.53(m,1H),7.11(t,J=7.6,1H),7.05(d,J=8.4,1H),6.38(dd,J=17.4,11.0,1H),5.72(d,J=8.4,1H),5.29–5.23(m,1H),5.14(dd,J=17.4,1.2,1H),4.12–4.00(m,6H),3.97(t,J=10.2,2H),3.32(d,J=6.0,1H),2.29–2.24(m,1H),2.16(dd,J=11.4,6.3,2H),2.07–1.97(m,5H),1.71(dd,J=14.4,2.4,2H),1.64–1.53(m,4H),1.52–1.45(m,1H),1.43–1.27(m,9H),1.21(t,J=7.1,2H),1.14–1.06(m,5H),0.82(s,3H),0.70(d,J=6.9,3H)；13CNMR(100MHz,CDCl3)δ216.91,166.77,162.45,159.06,158.51,157.98,138.83,135.12,132.74,121.81,118.16,117.20,111.76,74.55,70.38,60.34,58.08,56.44,45.40,44.59,43.96,41.83,36.69,35.99,34.42,30.37,26.82,26.45,24.80,16.74,14.79,11.46。
5,14-O-[(3-methoxybenzoyl base-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods(5e)
White solid, yield 68%62%, mp:142-145oC；IR(KBr):32894,2934,1728,1678,1585,1557,1489,1456,1407,1310,1273,1226,1186,1153,1114,1042,1009,979,922,736,675cm-1；1HNMR(400MHz,CDCl3)δ7.81(d,J=8.1Hz,1H),7.65–7.62(m,1H),7.44(t,J=8.0Hz,1H),7.15(dd,J=8.1,2.2Hz,1H),6.35(dd,J=17.4,11.0Hz,1H),5.72(d,J=8.4Hz,1H),5.22(dd,J=11.0,1.1Hz,1H),5.08(dd,J=17.4,1.2Hz,1H),4.00(dd,J=36.4,16.1Hz,2H),3.84(s,3H),3.35–3.27(m,1H),2.29–2.10(m,3H),2.03(d,J=5.7Hz,1H),1.96(dd,J=16.0,8.5Hz,1H),1.72(dd,J=14.4,2.2Hz,1H),1.63–1.47(m,3H),1.41–1.30(m,4H),1.25–1.19(m,1H),1.06(s,4H),0.83(d,J=7.0Hz,3H),0.65(d,J=7.0Hz,3H)；13CNMR(100MHz,CDCl3)δ216.39,166.05,164.73,160.88,159.22,157.88,138.12,131.64,129.29,120.30,119.08,116.68,112.92,73.98,69.78,57.47,54.89,44.82,43.99,43.28,41.22,36.06,35.40,35.11,33.84,29.77,26.19,25.75,24.22,16.11,14.20,10.90。
6,14-O-[(4-methoxybenzoyl base-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods(5f)
White solid, yield 66%, mp:131-133oC；IR(KBr):3426,2933,1731,1666,1606,1537,1513,1456,1416,1374,1299,1256,1176,1117,1027,980,938,892,845,759,691,649,609cm-1；1HNMR(400MHz,CDCl3)δ8.20(d,J=8.8Hz,2H),7.02(d,J=8.4Hz,2H),6.35(dd,J=17.3,11.0Hz,1H),5.72(d,J=8.4Hz,1H),5.21(d,J=11.0Hz,1H),5.08(d,J=17.4Hz,1H),4.11(q,J=7.1Hz,1H),3.98(t,J=9.3Hz,2H),3.87(d,J=18.7Hz,3H),3.30(dd,J=10.1,6.6Hz,1H),2.29–2.11(m,3H),2.03(s,2H),1.95(dd,J=16.0,8.5Hz,1H),1.72(d,J=14.2Hz,1H),1.60(dd,J=21.1,11.3Hz,2H),1.54–1.40(m,3H),1.37–1.29(m,4H),1.24(t,J=7.1Hz,2H),1.15–1.02(m,4H),0.84(d,J=6.9Hz,3H),0.66(d,J=6.9Hz,3H)；13CNMR(100MHz,CDCl3)δ216.99,166.64,164.82,163.89,158.25,138.77,130.95,123.07,117.34,114.19,74.62,70.47,60.46,58.12,55.64,45.47,44.62,43.93,41.89,36.72,36.05,34.49,30.43,26.85,26.37,24.87,21.12,16.75,14.82,14.27,11.54。
Embodiment 5: the conventional method that compound 7a-c is synthetic
The amino acid of 0.015mol is dissolved in by the THF of 150ml and the mixed solvent of 50ml distilled water, adds 10mlThe NaOH solution of 2N slowly drips 3.27g(0.015mol under the condition of stirring at room temperature) (BOC)2O. After dripping, continue anti-Answer 8h left and right. Then cessation reaction, by adding the washing of 80ml ethyl acetate after THF evaporate to dryness, separates two-phase under reduced pressure. WaterIn add 5% citric acid acidifying to pH3-4. Now produce a large amount of white precipitates, filter and wash with water 2-3 time, kept dryFor subsequent use.
Utilize (BOC)2The compound 6a-c that O first synthesizing amino has been protected, under need not separation and purification directly carrying out after syntheticSingle step reaction. Take compound 10a-c, 1.48g14-O-[(2-amino-1 that 3.6mol is protected by BOC, 3,4 ,-thiadiazoles-5 bases) mercapto acetyl group] EDCI(3.6mmol of nurse body woods (3mmol), 0.69g), the HOBt (3.6mol) of 0.51g is dissolved in 60mLDCM in, under room temperature, stir 36-48h. Reaction finishes the rear saturated NaHCO that uses3With distilled water washing, after separating, organic phase is usedMixed solution (the V of the TFA of 20mL and DCMTFA：VDCM=1:1) the middle 30min that stirs, then uses respectively distilled water and saturatedNaHCO3Solution washing, removes excessive TFA. Remove DCM under reduced pressure, gained mixture separates (benzinum: acetic acid second with silicagel columnEster=1:2).
1,14-O-[(2-amino benzoyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (7a)
White solid, yield 61%, mp:146-149oC；R(KBr):3473,3367,2931,1731,1651,1617,1557,1525,1455,1385,1297,1241,1161,1117,1017,980,937,896,751,696,670cm-1；1HNMR(400MHz,CDCl3)δ7.91(d,J=8.2Hz,1H),7.29(dd,J=15.0,7.4Hz,1H),6.72(t,J=6.9Hz,2H),6.38(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.26(d,J=11.0Hz,1H),5.12(d,J=17.4Hz,1H),3.99(q,J=16.1Hz,2H),3.33(d,J=5.9Hz,1H),2.35–2.10(m,4H),2.09–1.91(m,3H),1.73(d,J=15.4Hz,1H),1.57(ddd,J=27.7,23.3,12.8Hz,3H),1.48–1.28(m,6H),1.25(t,J=7.1Hz,1H),1.19–0.99(m,4H),0.95(t,J=7.4Hz,1H),0.85(d,J=6.9Hz,3H),0.69(d,J=6.9Hz,3H)；13CNMR(100MHz,CDCl3)δ217.14,166.84,166.65,161.15,158.06,150.56,138.82,134.51,129.17,117.50,116.83,111.52,74.71,70.48,58.21,45.53,44.69,44.01,41.95,36.81,36.09,34.56,30.49,26.91,26.45,24.93,16.84,14.94,11.60。
2,14-O-[(3-amino benzoyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (7b)
White solid, yield 61%, mp:135-138oC；IR(KBr):3432,3370,2927,1729,1667,1626,1587,1531,1456,1410,1374,1305,1189,1152,1117,1049,1017,980,939,847,743,677cm-1；1HNMR(400MHz,CDCl3)δ7.59(d,J=1.4Hz,1H),7.49(d,J=7.4Hz,1H),7.31–7.25(m,1H),6.89(d,J=7.9Hz,1H),6.41–6.31(m,1H),5.73(d,J=8.0Hz,1H),5.25(d,J=10.9Hz,1H),5.10(d,J=17.4Hz,1H),4.11(q,J=7.1Hz,1H),3.93(dd,J=20.6,4.6Hz,2H),3.31(s,1H),2.32–2.10(m,3H),2.01(dt,J=26.7,8.0Hz,3H),1.72(d,J=14.4Hz,1H),1.60(dd,J=20.2,10.1Hz,2H),1.52–1.29(m,6H),1.28–1.18(m,3H),1.10(d,J=14.2Hz,4H),0.84(d,J=6.7Hz,3H),0.66(d,J=6.6Hz,3H)；13CNMR(100MHz,CDCl3)δ216.90,166.70,165.57,162.01,158.11,147.14,138.68,131.50,129.71,119.66,118.47,117.28,114.54,74.51,70.41,60.34,58.01,45.35,44.58,43.84,41.76,36.56,35.94,34.37,30.31,26.7426.26,24.75,21.00,16.68,14.75,14.15,11.44。
3,14-O-[(4-amino benzoyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (7c)
White solid, yield 58%, mp:151-153oC；IR(KBr):3441,3371,2930,1728,1627,1603,1568,1518,1455,1374,1296,1261,1183,1117,1049,980,938,890,842,760,693,609cm-1；1HNMR(400MHz,CDCl3)δ8.06–7.96(m,2H),6.69(d,J=8.6Hz,2H),6.35(dd,J=17.4,11.0Hz,1H),5.71(d,J=8.1Hz,1H),5.15(dd,J=49.9,14.1Hz,2H),4.35–4.23(m,2H),4.01(t,J=9.9Hz,2H),3.35–3.26(m,1H),2.20(ddd,J=23.9,11.0,4.8Hz,3H),2.07–1.81(m,3H),1.72(d,J=14.2Hz,1H),1.67–1.53(m,3H),1.49–1.30(m,5H),1.28–1.18(m,2H),1.06(s,4H),0.83(d,J=6.7Hz,3H),0.67(d,J=6.8Hz,3H)；13CNMR(100MHz,CDCl3)δ216.92,166.790,164.770,161.78,157.81,151.60,138.73,130.82,119.69,117.28,114.06,74.55,70.48,60.41,58.04,45.40,44.52,43.89,41.83,36.65,35.91,34.43,30.34,26.56,24.79,16.73,14.78,11.47。
Embodiment 6:14-O-[(2-chloracetyl-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (8)Synthetic
1.48g14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods (3mmol), 0.61gN-methylmorpholine (4-Methylmorpholine, NMM; 6mmol) be dissolved in the DCM of 20mL the chloracetyl chloride of 0.51g(4.5mmol) be dissolved in the DCM of 10mL and 0oC drips in said mixture. Reactant mixture at room temperature stirs after 1hComplete, reactant liquor is first used saturated NH4Cl washs once, then water extraction three times, separates organic layer and uses anhydrous MgSO4Dry, mistakeAfter filter, filtrate is carried out column chromatography for separation (benzinum: ethyl acetate=1:1), obtains target compound 1.47g.
White powder, yield 86%, mp:82-84oC；IR(KBr):3446,2936,1731,1652,1558,1540,1456,1405,1286,1189,1153,1117,1056,1017,980,668cm-1；1HNMR(400MHz,CDCl3)δ6.47–6.32(m,1H),5.72(s,1H),5.33–5.20(m,1H),5.13(d,J=13.6Hz,1H),4.38(s,2H),4.14–4.03(m,1H),3.98(s,2H),3.33(d,J=5.6Hz,1H),2.23(d,J=33.3Hz,3H),2.03(t,J=11.2Hz,3H),1.73(d,J=13.6Hz,1H),1.62(d,J=7.5Hz,2H),1.42(t,J=17.2Hz,6H),1.10(d,J=4.0Hz,4H),0.84(d,J=3.4Hz,3H),0.69(d,J=6.8Hz,3H)；13CNMR(100MHz,CDCl3)δ216.94,171.07,166.43,164.90,159.41,138.80,117.24,74.47,70.46,60.43,57.97,45.46,44.55,43.87,41.94,41.79,36.48,35.89,34.31,30.28,26.75,26.34,24.60,16.71,14.74,11.41。
Embodiment 7: the conventional method that compound 9a-f is synthetic
Respectively the secondary amine of 4.5mmol is added to 14-O-[(2-amino-1 of containing 1.76g, 3,4 ,-thiadiazoles-5 base)Mercapto acetyl group] TEA(6mmol of nurse body woods (3mmol) and 0.61g) THF(60mL) in, in 45oUnder the condition of C, stir 2H. Evaporate to dryness THF after reaction, adds after the AcOEt of 50mL with saturated NH4Cl solution washing, then water extraction three times, separation hasMachine layer is also used anhydrous MgSO4Dried overnight, after filtering, filtrate is carried out column chromatography for separation (ethyl acetate: ethanol=20:1), obtains orderMark compound 9a-f.
1,14-O-[(2-diformazan ammonia acetyl group-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9a)
White solid, yield 69%, mp:74-76oC；IR(KBr):3444,2937,1731,1557,1519,1403,1284,1152,1117,1047,1017,980,953,916,864,665cm-1；1HNMR(400MHz,Acetone)δ6.36(dd,J=17.8,11.2Hz,1H),5.83(d,J=8.6Hz,1H),5.22(dd,J=35.5,14.5Hz,2H),4.17(dt,J=14.2,5.8Hz,4H),3.70(d,J=5.4Hz,1H),3.40(s,2H),2.48(s,7H),2.35(dd,J=18.0,11.0Hz,2H),2.25–2.10(m,14H),2.06(d,J=1.4Hz,9H),1.92–1.75(m,2H),1.68(dd,J=34.3,21.7Hz,2H),1.56–1.34(m,6H),1.30(t,J=7.1Hz,3H),1.21(d,J=16.0Hz,4H),1.04(d,J=7.0Hz,3H),0.81(d,J=6.7Hz,3H)；13CNMR(100MHz,Acetone)δ216.84,168.83,168.65,141.35,141.31,141.22,116.02,74.47,70.36,70.86,58.43,57.97,46.11,45.31,45.20,44.94,44.79,42.73,36.63,35.83,34.69,30.48,29.95,29.71,29.34,28.60,28.01,27.74,25.41。
2,14-O-[(2-diethylamino acetyl group-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9b)
White solid, yield 64%, mp:70-73oC；IR(KBr):3444,2971,2932,1732,1698,1519,1455,1403,1285,1202,1152,1117,1065,1018,980,953,938,916,724,665cm-1；1HNMR(400MHz,Acetone)δ6.25(t,J=14.0Hz,1H),5.72(s,1H),5.11(dd,J=32.6,14.1Hz,2H),4.18–4.02(m,2H),3.59(s,1H),3.38(s,2H),3.11(s,1H),2.69(d,J=5.3Hz,3H),2.37(s,1H),2.28–2.03(m,4H),1.73(dd,J=27.5,12.4Hz,2H),1.63–1.49(m,2H),1.39(d,J=20.0Hz,5H),1.30(d,J=13.1Hz,1H),1.11(dd,J=25.5,14.0Hz,12H),0.93(s,3H),0.70(s,3H)；13CNMR(100MHz,Acetone)δ217.09,171.44,167.44,159.08,141.33,116.42,74.70,71.63,58.52,57.46,49.35,46.34,45.18,42.88,37.65,36.86,34.94,31.24,30.56,30.07,28.74,27.82,27.38,25.65,16.88,15.12,12.51,11.81。
3,14-O-[(2-piperidines acetyl group-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9c)
White solid, yield 62%, mp:49-51oC；IR(KBr):3434,2932,1731,1557,1519,1455,1403,1286,1188,1152,1117,1019,980,954,939,916,667cm-1；1HNMR(400MHz,Acetone)δ6.26(dd,J=17.7,11.2Hz,1H),5.72(d,J=8.4Hz,1H),5.12(dd,J=32.7,14.4Hz,2H),4.16–4.03(m,2H),3.60(d,J=5.9Hz,1H),3.30(s,2H),2.57(s,3H),2.38(s,1H),2.31–2.23(m,1H),2.19–2.08(m,2H),1.96(s,6H),1.77(d,J=16.7Hz,1H),1.69–1.51(m,6H),1.50–1.35(m,7H),1.31(d,J=15.8Hz,1H),1.21–1.09(m,4H),0.94(d,J=7.0Hz,3H),0.71(d,J=6.6Hz,3H)；13CNMR(100MHz,Acetone)δ217.24,172.50,170.26,167.42,159.22,141.30,116.40,74.68,71.60,62.29,58.48,55.44,46.31,45.14,42.85,37.62,36.81,34.90,28.67,27.45,27.83,26.69,25.61,24.46,20.62,16.96,15.25,11.88。
4,14-O-[(2-pyrrolidines acetyl group-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9d)
White solid, yield 71%, mp:82-84oC；IR(KBr):3418,2937,1732,1519,1456,1402,1374,1289,1167,1149,1117,1013,981,954,940,918,835,671cm-1；1HNMR(400MHz,Acetone)δ6.27(dd,J=17.7,11.2Hz,1H),5.74(d,J=8.4Hz,1H),5.22–5.05(m,2H),4.11(s,1H),4.06(d,J=7.1Hz,1H),3.50(d,J=1.8Hz,2H),2.74(d,J=6.5Hz,3H),2.26(dd,J=12.7,5.8Hz,1H),2.11–2.04(m,8H),1.98(s,4H),1.83(d,J=14.1Hz,4H),1.74(dd,J=19.5,6.0Hz,1H),1.63–1.53(m,1H),1.44(s,4H),1.32(d,J=14.0Hz,1H),1.21(t,J=7.1Hz,3H),1.14(s,3H),0.95(d,J=7.1Hz,3H),0.72(d,J=6.8Hz,3H).13CNMR(100MHz,CDCl3)δ216.92,169.25,139.04,117.15,74.39,58.62,58.25,48.72,46.88,45.16,43.38,42.89,36.90,35.39,31.25,30.61,26.89,26.45,26.17,24.27,17.97,17.48,16.79,14.39,11.44。
5,14-O-[(2-morpholine acetyl group-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9e)
White solid, yield 73%, mp:69-71oC；IR(KBr):3438,2927,2892,1731,1519,1454,1403,1295,1190,1152,1116,1015,981,954,912,897,668cm-1；1HNMR(400MHz,Acetone)δ6.26(dd,J=17.7,11.2Hz,1H),5.72(d,J=8.4Hz,1H),5.12(ddd,J=14.5,12.5,1.4Hz,2H),4.12–4.03(m,2H),3.74–3.67(m,4H),3.59(d,J=6.0Hz,1H),3.38(s,2H),2.67–2.59(m,4H),2.38(s,1H),2.29–2.21(m,1H),2.18–2.03(m,5H),1.97(s,2H),1.81–1.64(m,2H),1.56(ddd,J=16.2,10.3,4.1Hz,2H),1.47–1.35(m,5H),1.36–1.27(m,1H),1.20(t,J=7.1Hz,1H),1.17–1.06(m,4H),0.94(d,J=7.1Hz,3H),0.71(d,J=6.7Hz,3H)；13CNMR(100MHz,Acetone)δ216.16,168.81,166.46,158.32,158.10,140.33,115.46,73.65,70.65,66.36,60.98,57.52,53.54,45.34,44.18,41.89,36.66,35.84,33.95,30.22,27.75,26.86,24.65,19.97,19.66,16.01,14.31,10.93。
6,14-O-[(2-4 methyl piperazine-1,3,4-thiadiazoles-5-yl) mercapto acetyl group] nurse body woods (9f)
White solid, yield 79%, mp:70-71oC；IR(KBr):3435,2935,1731,1556,1519,1455,1403,1284,1189,1153,1117,1018,981,955,916,863,665cm-1；1HNMR(400MHz,Acetone)δ6.27(dd,J=17.7,11.2Hz,1H),5.74(d,J=8.4Hz,1H),5.22–5.05(m,2H),4.11(d,J=3.5Hz,1H),4.06(d,J=7.1Hz,2H),3.61(s,1H),3.36(s,2H),2.65(s,3H),2.43(d,J=24.2Hz,4H),2.30–2.16(m,5H),2.14–2.05(m,6H),1.98(s,4H),1.83–1.66(m,2H),1.56(dt,J=26.2,10.6Hz,2H),1.47–1.37(m,5H),1.32(d,J=14.3Hz,1H),1.21(t,J=7.1Hz,4H),1.16–1.01(m,5H),0.95(d,J=7.1Hz,3H),0.72(d,J=6.8Hz,3H)；13CNMR(100MHz,Acetone)δ216.92,169.37,166.46,138.32,117.16,74.65,70.65,57.55,53.57,44.18,41.89,36.06,35.84,33.92,30.22,27.75,26.86,24.65,19.97,19.66,16.61,11.44。
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to aforementioned realityExecute example the present invention is had been described in detail, for a person skilled in the art, it still can be to aforementioned each enforcementThe technical scheme recorded of example is modified, or part technical characterictic is wherein equal to replacement. All in essence of the present inventionWithin god and principle, any amendment of doing, be equal to replacement, improvement etc., within protection scope of the present invention all should be included in.
Claims (14)
1. a preparation method with the pleuromutilin analog derivative of thiadiazoles skeleton, is characterized in that:
The described pleuromutilin analog derivative with thiadiazoles skeleton, chemical structural formula is as I or II:
Wherein: R in formula I1＝Cl、OCH3Or NH2; In formula II
Its method comprises the steps:
Synthesizing of step 1, intermediate 22-O-(4-tosyl) oxygen acetyl group nurse body woods
Pleuromutilin and paratoluensulfonyl chloride are dissolved in to methyl tertiary butyl ether(MTBE) and H2In O mixture, then slowly drip concentration and beThe sodium hydroxide solution of 30-50wt%, heating reflux reaction 20-80min, the white product of generation is filtered while hot, then uses firstBase tertbutyl ether and water wash respectively the white product of gained, are dried and obtain white powder, are 22-O-(4-tosylBase) oxygen acetyl group nurse body woods;
Synthesizing of step 2, intermediate 14-O-(iodoacetyl) nurse body woods
Be dissolved in acetone soln at step 1 gained white powder, add excessive KI, reflux, then filter, filtrate at room temperatureFlaxen intermediate 14-O-(iodoacetyl) nurse body woods is directly recrystallized out;
Step 3, intermediate 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods synthetic
By 2-amino-5-sulfydryl-1,3,4 ,-thiadiazoles is dissolved in NaOH, and dropwise adds the synthetic 14-O-of step 2 (iodine secondAcyl group) in the THF solution of nurse body woods, mixture stirs 2-3h at 0 DEG C, after evaporated under reduced pressure, adds acetic acid ethyl dissolution, and usesNH4Cl washes away after residual alkali with distilled water extraction, uses anhydrous Na after separating organic phase2SO4Dried overnight, after filtering, filtrate is usedSilicagel column separates and obtains intermediate 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods;
Synthesizing of step 4, end-product
The first situation: the derivative that contains benzene ring structure in the pleuromutilin side chain of structural formula I synthetic
By intermediate 14-O-[(2-amino-1 synthetic in step 3,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods withChloride, methoxyl group or the amino benzoic acid replacing, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) andI-hydroxybenzotriazole (HOBt) is dissolved in carrene (DCM), stirring reaction 15-18h under room temperature, and after reaction, mixture is first usedEDCI is removed in washing, then uses saturated NaHCO3Solution washing, removes unreacted carboxylic acid completely, after anhydrous MgSO4 is dry, subtractsPress and steam except DCM, target compound obtains after being separated by silicagel column;
The second situation: the derivative that contains tertiary amine in the pleuromutilin side chain of formula II synthetic
First use intermediate 14-O-[(2-amino-1 synthetic in step 3,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods withChloracetyl chloride, N-methylmorpholine react in DCM, generate intermediate 14-O-[(2-chloracetyl-1, and 3,4 ,-thiadiazoles-5 base)Mercapto acetyl group] nurse body woods, after evaporate to dryness DCM, add oxolane (THF), then add secondary amine and triethylamine or N-methylQuinoline reacts under the condition of 45 DEG C, and evaporate to dryness THF after reaction adds after AcOEt with saturated NH4Cl solution washing, then water extractionGet three times, separate organic layer and use anhydrous MgSO4Dried overnight, after filtering, filtrate is carried out column chromatography for separation, obtains brachymemma and picks up the earsThe derivative that contains tertiary amine in element side chain,
Wherein, described secondary amine is selected dimethylamine agueous solution, diethylamine, piperidines, pyrrolidines, morpholine or the 4 methyl piperazines of 40wt%Piperazine.
2. the preparation method of the pleuromutilin analog derivative with thiadiazoles skeleton according to claim 1, its featureBe: the first situation in described step 4, on the phenyl ring of the derivative that contains benzene ring structure in described pleuromutilin side chainSubstituent R1During for amino, structural formula is as follows,
Described substituted benzoic acid is selected amino substituted benzoic acid, first amino substituted benzoic acid is carried out to amido protecting, and amino is protectedThe carboxylic acid protecting and 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods, be dissolved in one with EDCI and HOBtIn quantitative DCM, under room temperature, stir 15-18h, after reaction, the first water of mixture washes away EDCI, then uses saturated NaHCO3SolutionWashing, removes unreacted carboxylic acid completely, after anhydrous MgSO4 is dry, removes DCM under reduced pressure, and gained mixture divides with silicagel columnFrom, in the compound the obtaining TFA that separation is obtained and the mixed solution of DCM, stir 30min, then use respectively distilled water andSaturated MH4Cl solution washing, separates two-phase, after organic phase is dry, obtains target product,
Wherein, described amido protecting, concrete operations are as follows,
Amino substituted benzoic acid is dissolved in the mixed solvent by THF and distilled water, adds NaOH solution, at the bar of stirring at room temperatureUnder part, slowly drip the BOC with amino substituted benzoic acid equimolar amounts2O, continues reaction 8h left and right after dropping, after reaction, reducing pressureUnder condition, by THF evaporate to dryness, add ethyl acetate washing, separate two-phase, in water, add 5% citric acid acidifying to pH3-4,Now produce a large amount of white precipitates, filter and wash with water 2-3 time, after being dried, obtain the substituted benzoic acid of amido protecting.
3. the preparation method of the pleuromutilin analog derivative with thiadiazoles skeleton according to claim 2, its featureBe:
Described amino substituted benzoic acid: the mixed solution of THF: water: NaOH: ethyl acetate: TFA and DCM is 1mmol:8-10mL:4-5mL：1-1.5mmol：4-6mL：5-8mL。
4. according to the preparation method of pleuromutilin derivative described in claim 2 or 3, it is characterized in that: in described step 1,Pleuromutilin: t-butyl methyl ether: water: NaOH solution is 1mmol:0.8-2mL:0.15-0.25mL:0.25-0.5mL.
5. the preparation method of pleuromutilin derivative according to claim 4, is characterized in that: pleuromutilin: tertiary fourthBase methyl ether: water: NaOH solution is 1mmol:1mL:0.2mL:0.3mL; The concentration of NaOH solution is 40wt%.
6. according to the preparation method of pleuromutilin derivative described in claim 2 or 3, it is characterized in that: in described step 2,22-O-(4-tosyl) oxygen acetyl group nurse body woods: KI: acetone is 1mmol:1.0-1.2mmol:12-18mL.
7. the preparation method of pleuromutilin derivative according to claim 6, is characterized in that: in described step 2, and 22-O-(4-tosyl) oxygen acetyl group nurse body woods: KI: acetone is 1mmol:1.1mmol:15mL.
8. according to the preparation method of pleuromutilin derivative described in claim 2 or 3, it is characterized in that: in described step 3,
14-O-(iodoacetyl) nurse body woods: 2-amino-5-sulfydryl-1,3,4 ,-thiadiazoles: NaOH:THF solution: ethyl acetate is1mmol：1.1-1.2mmol：1.8-2.2mmol：8-12mL:10-20mL。
9. the preparation method of pleuromutilin derivative according to claim 8, is characterized in that: 14-O-(iodoacetyl)Nurse body woods: 2-amino-5-sulfydryl-1,3,4 ,-thiadiazoles: NaOH:THF solution: ethyl acetate is mmol:1.1mmol:2mmol:10mL:15mL；
Described silicagel column separates the silicagel column that adopts benzinum: ethyl acetate=1:2.
10. according to the preparation method of pleuromutilin derivative described in claim 2 or 3, it is characterized in that: in described step 4The first situation,
14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloride, methoxyl group or the amino benzene replacingFormic acid: EDCI:HOBt:DCM is 1mmol:1.1-1.3mmol:1.1-1.3mmol:1.1-1.3mmol:15-25mL.
11. preparation methods of pleuromutilin derivative according to claim 10, is characterized in that: 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloride, methoxyl group or the amino benzoic acid replacing: EDCI:HOBt:DCMFor 1mmol:1.1mmol:1.2mmol:1.2mmol:20mL,
Described silicagel column separates the silicagel column that adopts benzinum: ethyl acetate=1:0.5-2.
12. according to the preparation method of pleuromutilin derivative described in claim 2 or 3, it is characterized in that: in described step 4The second situation,
Described 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloracetyl chloride: N-methylmorpholine:DCM is 1mmol:1.3-1.8mmol:1.8-2.4mmol:6-10mL;
Described 14-O-[(2-chloracetyl-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: secondary amine: triethylamine or N-Methyl morpholine: THF is 1mmol:1.3-1.8mmol:1.8-2.4mmol:15-25mL;
Described silicagel column separates the silicagel column that adopts ethyl acetate: ethanol=20:1.
13. according to the preparation method of pleuromutilin derivative described in claim 12, it is characterized in that: in described step 4The second situation, described 14-O-[(2-amino-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: chloracetyl chloride: N-firstBase morpholine: DCM is 1mmol:1.5mmol:2mmol:8mL;
Described 14-O-[(2-chloracetyl-1,3,4 ,-thiadiazoles-5 base) mercapto acetyl group] nurse body woods: secondary amine: triethylamine or N-Methyl morpholine: THF is 1mmol:1.5mmol:5mmol:20mL.
14. pleuromutilin derivatives with thiadiazoles skeleton according to claim 1 are in preparation antibacterialsApplication.
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