CN102786570B - Macrolides compound, its preparation method, application and intermediate - Google Patents
Macrolides compound, its preparation method, application and intermediate Download PDFInfo
- Publication number
- CN102786570B CN102786570B CN201110129340.0A CN201110129340A CN102786570B CN 102786570 B CN102786570 B CN 102786570B CN 201110129340 A CN201110129340 A CN 201110129340A CN 102786570 B CN102786570 B CN 102786570B
- Authority
- CN
- China
- Prior art keywords
- compound
- hydrazone
- clarithromycin
- alkyl
- organic phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@@](C)([C@@]([C@@](C)[C@](C)([C@@]1C)O[Rh])O[C@@]2O[C@](C)C[C@]([*+]C)[C@@]2OC(*)=O)O*)=NNC(*)=O)O)N=O)OC1=O Chemical compound CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@@](C)([C@@]([C@@](C)[C@](C)([C@@]1C)O[Rh])O[C@@]2O[C@](C)C[C@]([*+]C)[C@@]2OC(*)=O)O*)=NNC(*)=O)O)N=O)OC1=O 0.000 description 3
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a class such as formula the macrolides compound shown in I, its preparation method, application and intermediate.Macrolides compound of the present invention is to the tested G of major part
+bacterium has very strong activity, and wherein the specific activity Azythromycin of two compounds to part gram-positive microorganism is higher.
Description
Technical field
The present invention is specifically related to a kind of macrolides compound, its preparation method, application and intermediate.
Background technology
Macrolide antibiotics is applied to the anti-infective history having had more than 50 year of clinical departments, has the advantages such as security is high, cheap, oral absorption is good, plays an important role in the treatment of infectious diseases.
To the work of macrolide antibiotics modifying for chemical structure based on mechanism of drug action research, experienced by three developmental stage.Main ester class, the salt of being transformed into is to improve bitter taste in early days, enhanced stability, improves bioavailability.20 century 70s, the acid deactivation mechanism of Erythromycin A is illustrated, after this to the transformation of Erythromycin A mainly for the avtive spot participating in acid degradation, the s-generation macrolides compound that to obtain with clarithromycin, Azythromycin be representative, improve acid acceptance, pharmacokinetic property improves.Day by day serious along with resistant organism problem in world wide, s-generation macrolide antibiotics demonstrates its weakness to resistant organism poor activity.To the nineties, research finds that cladinose is the essential groups that Induction of bacterial produces resistance, transform for this position, obtain ketone lactone, 4 "-carbamate, acyl lactone, 2; third generation macrolide antibiotics such as 3-dehydration alkene lactone; overcome the in-ductive drug-tolerance of bacterium are active strong to resistant organism.
The development of prospect macrolide antibiotics, finds the focus and emphasis effective macrolide antibiotics of resistant organism being still to research.
Summary of the invention
Technical problem to be solved by this invention there is provided a class and the diverse macrolides compound of prior art, its preparation method, application and intermediate.Macrolides compound of the present invention is to the tested G of major part
+bacterium has very strong activity, and wherein the specific activity Azythromycin of two compounds to part gram-positive microorganism is higher.
Therefore, the present invention relates to a class such as formula the macrolides compound shown in I;
Wherein, R is C
1~ C
3alkyl, or H; R
afor
3
represent singly-bound or double bond, when it is double bond, R
bdo not exist, when it is singly-bound, R
bfor
R
cfor substituted or unsubstituted C
1~ C
3alkyl (preferable methyl, ethyl or sec.-propyl), substituted or unsubstituted C
6~ C
10aryl or substituted or unsubstituted C
2~ C
4thiazolinyl (preferred vinyl); Wherein, the C of replacement
6~ C
10substituting group in aryl is nitro or halogen (the preferred C1 of halogen), and the substituting group in aryl can be ortho position, contraposition or a position; The C replaced
1~ C
3substituting group in alkyl is C
6~ C
10aryl, or C
4~ C
8heteroaryl (preferred 2-thienyl or 3-indyl), wherein heteroatoms is N, O or S; The C replaced
2~ C
4substituting group in thiazolinyl is C
6~ C
10aryl;
X
1and X
2be independently halogen, as fluorine, chlorine, bromine or iodine, X
1and X
2position can be 2 ' position and 5 ' position; Preferably, X
1and X
2identical;
R
dand R
ebe independently C
1~ C
3alkyl (preferred ethyl);
N is 1 ~ 3 (preferably 2).
In the present invention, described Compound I is preferably following arbitrary structure:
Wherein, described in the definition of Ra and Rc all ditto.
In the present invention, what described Compound I was better is following arbitrary compound:
In Ia, R
cfor methyl, phenyl, p-nitrophenyl, rubigan, benzyl, styroyl, styryl, thiophene-2-methyl, indoles-3-methyl or indoles-3-propyl group;
In Ib, R
cfor phenyl, p-nitrophenyl, rubigan, benzyl, styroyl, styryl or sec.-propyl;
In Ic, R
afor
For the preparation of Compound I of the present invention, those skilled in the art all can carry out with reference to state of the art, can obtain corresponding target product.
The invention further relates to the preparation method of above-claimed cpd I, it is any one in following method:
(1) when in target compound I, R
afor
r is C
1~ C
3during alkyl, Compound II per is carried out the reaction of the acyl protecting groups sloughing hydroxyl;
R
c1for R
cor the substituting group on the acyl protecting groups of this area routine;
(2) when in target compound I, R
afor
r is H or C
1~ C
3during alkyl, by Compound II per ' and R
ax carries out nucleophilic substitution reaction as follows;
Wherein, X is leavings group conventional in this type of nucleophilic substitution reaction of this area, as halogen (preferred chlorine, bromine or iodine).
In above-mentioned two kinds of methods, the method for the reaction related to and condition all can be ordinary method in the reaction of this area respective classes and condition; Described in the definition of each group is all the same unless otherwise indicated.
Compound I in the present invention according to prior art, can adopt the methodology of organic synthesis preparation of any suitable.Below by the present invention, the preferred preparation method of Compound I illustrates:
(1) preparation of Compound I a series, reaction scheme is as follows:
Take clarithromycin as starting raw material, react with hydrazine acetate and generate 9-hydrazone clarithromycin, more two acidylate, de-2 ' position acidylate protects to obtain target compound.
Wherein each group definition ditto described in.Those skilled in the art, with reference to above-mentioned reaction scheme, conventionally and Conventional wisdom, can obtain Compound I a.
(2) preparation of compounds ib series, reaction scheme is as follows:
Take clarithromycin as starting raw material, react with hydrazine acetate and generate 9-hydrazone clarithromycin, more two acidylate, descladinosylation, oxidation, deacylation, obtains target compound.
Wherein each group definition ditto described in.Those skilled in the art, with reference to above-mentioned reaction scheme, conventionally and Conventional wisdom, can obtain compounds ib.
(3) preparation of Compound I c series, synthetic route is as follows:
With Matachrom A for raw material, obtain target compound through becoming hydrazone, desulfurization cyanate radical, alkylation three-step reaction.
Wherein each group definition ditto described in.Those skilled in the art, with reference to above-mentioned reaction scheme, conventionally and Conventional wisdom, can obtain Compound I c.
Therefore, the invention further relates to midbody compound IIa, IIb or IIIb of preparing above-claimed cpd I:
Wherein, described in the definition of each group all ditto.
The invention still further relates to above-claimed cpd I and prepare the application in antibiotic medicine.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: macrolides compound of the present invention is to the tested G of major part
+bacterium has very strong activity, and wherein the specific activity Azythromycin of two compounds to part gram-positive microorganism is higher.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
The particular compound related in the embodiment of the present invention is as follows:
Table 1Ia series compound
Table 2Ib series compound
compound 18
compound 19
Preparation embodiment:
In following embodiment:
Thin-layer chromatography (TLC): silica gel H SGF254 (Yantai City's Zhifu Huang business silica gel develop sequence factory)
Colour developing: UV-light (254nm, 365nm) and developer (1g cerous sulfate, 2.5g Sodium orthomolybdate and 10% sulphuric acid soln are made into 100ml) colour developing
Column chromatography silica gel: tlc silica gel H (Qingdao Marine Chemical Co., Ltd.'s product)
NMR:Varian-Inova-400 type nuclear magnetic resonance analyser
MS:MAT212 magnetic-type mass spectrograph
IR:NEXUS-670 type infrared spectrometer, pellet technique
HPLC:Agilentl100GC and UV absorbance detection instrument
English abbreviation explanation
Embodiment 1 hydrazine acetate (intermediate 1)
In 100ml round-bottomed flask, add 85% hydrazine hydrate (28.5ml, 0.5mol), ice bath stirs, and slowly drip glacial acetic acid (28.6ml, 0.5mol), control temperature is at 0-10 DEG C.Dropwise, stirring at room temperature reaction 40min.Underpressure distillation is removed after moisture content, adds chloroform: ethanolic soln (1: 1,20ml), ice bath stirred crystallization in remaining liq, after be placed in 4 DEG C of further crystallizations of refrigerator again, evaporated under reduced pressure, obtain white solid (41.6g, 90.5%).
Embodiment 29-hydrazone clarithromycin (intermediate 2)
Get hydrazine acetate (37g, 0.4mol) and clarithromycin (10g, 13.36mmol) in round-bottomed flask, add methyl alcohol (80ml), reflux 46h.Underpressure distillation, after add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white solid (9.68g, 95.1%).
Embodiment 32 '-O-ethanoyl-9-ethanoyl hydrazone clarithromycin (intermediate 3)
9-hydrazone clarithromycin (3.00g, 3.94mmol) is dissolved in methylene dichloride (15mL), adds diacetyl oxide (1.12mL, 11.85mmol), normal-temperature reaction 2h, adds water, 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filters, filtrate decompression evaporate to dryness, obtain white foaming material (3.28g, 98.5%).(small trials is crossed with diacetyl oxide identical with reaction product with 9-hydrazone clarithromycin reaction process with acetic acid+DCC, therefore diacetyl oxide and the reaction of 9-hydrazone clarithromycin during iodine, more convenient)
MS(ESI
+，m/e)：846.52[M+H]
+
Embodiment 49-ethanoyl hydrazone clarithromycin (compound 1)
2 '-O-ethanoyl-9-ethanoyl hydrazone clarithromycin (intermediate 3) (1.00g; 1.18mmol) be dissolved in methyl alcohol (5mL); reflux 6h; evaporated under reduced pressure; add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, separates organic phase; aqueous phase methylene dichloride extracting three times; merge organic phase, through washing, saturated common salt is washed; dried over anhydrous sodium carbonate; filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 12: 1)]; obtain faint yellow solid (0.41g, 43.2%).
MS(ESI
+，m/e)：804.51[M+H]
+
1HNMR(400MHz，CDCl
3)δ(ppm)：8.58(s，1H，9＝N-NH-)，2.19(s，3H，9-CO-CH
3)
13CNMR(400MHz，CDCl
3)δ(ppm)：172.56(9-NH-CO-)，166.92(9＞C＝N-)
Embodiment 52 '-O-benzoyl-9-benzoyl hydrazone clarithromycin (intermediate 4)
Benzene phenylformic acid (4.00g, 32.75mmol) and DCC (7.00g, 33.93mmol) are dissolved in methylene dichloride (50mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (5.00g, 6.56mmol), normal-temperature reaction 60h.Filter, removing insolubles, filtrate adds water, 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white crude (9.35g, containing part dicyclohexylurea (DCU), lower same).
MS(ESI
+，m/e)：970.56[M+H]
+
Embodiment 69-benzoyl hydrazone clarithromycin (compound 2)
Above-mentioned 2 '-O-benzoyl-9-benzoyl hydrazone clarithromycin crude product (intermediate 4, 1.50g, 1.05mmol) be dissolved in methyl alcohol (6mL), reflux 2.5h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 7: 0.6)], obtain white foaming material (0.40g, from intermediate 2 to intermediate 4, the total recovery finally arriving compound 2 is 44.0%).
MS(ESI
+，m/e)：866.47[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.69 (s, 1H, 9=N-NH-), 7.40-7.90 (m, 5H, 9 phenyl ring)
13cNMR (400MHz, CDCl
3) δ (ppm): 166.41 (9-NH-CO-), 163.30 (9 > C=N-), 127.21-134.38 (6 carbon on 9 phenyl ring)
Embodiment 72 '-O-benzoyl-3-O-descladinosylation-3-hydroxyl-9-benzoyl hydrazone clarithromycin (intermediate 5)
Above-mentioned 2 '-O-benzoyl-9-benzoyl hydrazone clarithromycin crude product (intermediate 4,2.00g, 1.40mmol) is dissolved in 1% ethanol solution hydrochloride (20mL); normal-temperature reaction 12h, adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains white solid (1.66g).
MS(ESI
+，m/e)：812.46[M+H]
+
Embodiment 82 '-O-benzoyl-3-O-descladinosylation-3-oxo-9-benzoyl hydrazone clarithromycin (intermediate 6)
Above-mentioned 2 '-O-benzoyl-3-O-descladinosylation-3-hydroxyl-9-benzoyl hydrazone clarithromycin crude product (intermediate 5; 1.66g; 1.40mmol) with EDCHCl (2.63g; 13.71mmol) be dissolved in anhydrous methylene chloride (17mL); add DMSO (2.62mL, 36.84mmol), slowly drip TFAPy (1.31g; dichloromethane solution 6.75mmol), N
2the lower normal-temperature reaction 1h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white solid (1.66g).
MS(ESI
+，m/e)：810.45[M+H]
+
Embodiment 93-O-descladinosylation-3-oxo-9-benzoyl hydrazone clarithromycin (compound 11)
Above-mentioned 2 '-O-benzoyl-3-O-descladinosylation-3-oxo-9-benzoyl hydrazone clarithromycin crude product (intermediate 6, 1.66g, 1.40mmol) be dissolved in methyl alcohol (9mL), reflux 2h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain faint yellow foaming material (0.56g, from intermediate 2, to intermediate 4, 5, 6, the total recovery finally arriving compound 11 is 56.6%).
MS(ESI
+，m/e)：706.57[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.63 (s, 1H, 9=N-NH), 7.41-7.86 (m, 5H, 9 phenyl ring)
13cNMR (400MHz, CDCl
3) δ (ppm): 202.32.72 (3 > C=O), 165.34 (9-NH-CO-), 163.32 (9 > C=N-), 104.39-134.23 (6 carbon in 9 side-chain benzene ring)
Embodiment 102 '-O-p-nitrophenyl formyl radical-9-p-nitrophenyl formyl radical hydrazone clarithromycin (intermediate 7)
P-nitrobenzoic acid (3.29g, 19.69mmol) and DCC (4.22g, 20.45mmol) are dissolved in methylene dichloride (30mL),, normal-temperature reaction 30min, adds 9-hydrazone clarithromycin (3.00g, 3.94mmol), normal-temperature reaction 1h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellowish crude product (4.54g).
MS(ESI
+，m/e)：1060.53[M+H]
+
Embodiment 119-p-nitrophenyl formyl radical hydrazone clarithromycin (compound 3)
Above-mentioned 2 '-O-p-nitrophenyl formyl radical-9-p-nitrophenyl formyl radical hydrazone clarithromycin crude product (intermediate 7, 1.30g, 1.13mmol) be dissolved in methyl alcohol (6.50mL), reflux 1h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 4: 0.4)], obtain yellow foaming material (0.27g, from intermediate 2, to intermediate 7, the total recovery finally arriving compound 3 is 26.5%).
MS(ESI
+，m/e)：911.20[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.24 (s, 1H, 9=N-NH), 8.02-8.29 (m, 4H, 9 phenyl ring)
13cNMR (400MHz, CDCl
3) δ (ppm): 149.24 (9-NH-CO-), 128.64 (9 > C=N-), 123.20-123.70 (6 carbon in 9 side-chain benzene ring)
Embodiment 122 '-O-p-nitrophenyl formyl radical-3-O-descladinosylation-3-hydroxyl-9-p-nitrophenyl formyl radical hydrazone clarithromycin (intermediate 8)
Above-mentioned 2 '-O-p-nitrophenyl formyl radical-9-p-nitrophenyl formyl radical hydrazone clarithromycin crude product (intermediate 7,2.00g, 1.73mmol) is dissolved in 1% ethanol solution hydrochloride (20mL); normal-temperature reaction 7h, adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains yellow solid (1.70g).
MS(ESI
+，m/e)：902.43[M+H]
+
Embodiment 132 '-O-p-nitrophenyl formyl radical-3-O-descladinosylation-3-oxo-9-p-nitrophenyl formyl radical hydrazone clarithromycin (intermediate 9)
Above-mentioned 2 '-O-p-nitrophenyl formyl radical-3-O-descladinosylation-3-hydroxyl-9-p-nitrophenyl formyl radical hydrazone clarithromycin crude product (intermediate 8; 1.70g; 1.73mmol) with EDCHCl (2.42g; 12.64mmol) be dissolved in anhydrous methylene chloride (17mL); add DMSO (2.42mL, 34.02mmol), slowly drip TFAPy (1.20g; dichloromethane solution 6.24mmol), N
2the lower normal-temperature reaction 1h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellow solid (1.69g).
MS(ESI
+，m/e)：900.42[M+H]
+
Embodiment 143-O-descladinosylation-3-oxo-9-p-nitrophenyl formyl radical hydrazone clarithromycin (compound 12)
Above-mentioned 2 '-O-p-nitrophenyl formyl radical-3-O-descladinosylation-3-oxo-9-p-nitrophenyl formyl radical hydrazone clarithromycin crude product (intermediate 9, 1.69g, 1.73mmol) be dissolved in methyl alcohol (9mL), reflux 2h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [methyl alcohol: chloroform (1: 3)], obtain brown color foaming material (0.32g, from intermediate 2, to intermediate 7, 8, 9, the total recovery finally arriving compound 12 is 24.6%).
MS(ESI
+，m/e)：751.31[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.90 (s, 1H, 9=N-NH), 7.98-8.25 (m, 4H, 9 phenyl ring)
13cNMR (400MHz, CDCl
3) δ (ppm): 202.2 (3 > C=O), 168.0 (9-NH-CO-), 160.3 (9 > C=N-), 123.39-149.56 (6 carbon in 9 side-chain benzene ring)
Embodiment 152 '-O-to chlorobenzene formacyl-9-to chlorobenzene formacyl hydrazone clarithromycin (intermediate 10)
Chlorodracylic acid (3.08g, 19.67mmol) and DCC (4.22g, 20.45mmol) are dissolved in methylene dichloride (30mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol), normal-temperature reaction 24h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white crude (6.02g).
MS(ESI
+，m/e)：1038.48[M+H]
+
Embodiment 169-is to chlorobenzene formacyl hydrazone clarithromycin (compound 4)
Above-mentioned 2 '-O-to chlorobenzene formacyl-9-to chlorobenzene formacyl hydrazone clarithromycin crude product (intermediate 10, 2.00g, 1.31mmol) be dissolved in methyl alcohol (10mL), reflux 5h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 7.5: 0.6)], obtain faint yellow solid (0.45g, from intermediate 2, to intermediate 10, the total recovery finally arriving compound 4 is 38.4%).
MS(ESI
+，m/e)：900.40[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.74 (s, 1H, 9=N-NH), 7.80 (d, J=8Hz, 2H, 9 phenyl ring 3,5-H), 7.39 (d, J=8.4Hz, 2H, 9 phenyl ring 2,6-H)
13cNMR (400MHz, CDCl
3) δ (ppm): 167.06 (9-NH-CO-), 162.25 (9 > C=N-), 128.63-156.93 (6 carbon in 9 side-chain benzene ring)
Embodiment 172 '-O-to chlorobenzene formacyl-3-O-descladinosylation-3-hydroxyl-9-to chlorobenzene formacyl hydrazone clarithromycin (intermediate 11)
Above-mentioned 2 '-O-is dissolved in 1% ethanol solution hydrochloride (20mL) to chlorobenzene formacyl-9-to chlorobenzene formacyl hydrazone clarithromycin crude product (intermediate 10,2.00g, 1.31mmol); normal-temperature reaction 17h, adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains white solid (1.68g).
MS(ESI
+，m/e)：880.38[M+H]
+
Embodiment 182 '-O-to chlorobenzene formacyl-3-O-descladinosylation-3-oxo-9-to chlorobenzene formacyl hydrazone clarithromycin (intermediate 12)
Above-mentioned 2 '-O-to chlorobenzene formacyl-3-O-descladinosylation-3-hydroxyl-9-to chlorobenzene formacyl hydrazone clarithromycin crude product (intermediate 11; 1.68g; 1.31mmol) with EDCHCl (2.45g; 12.79mmol) be dissolved in anhydrous methylene chloride (17mL); add DMSO (2.44mL, 34.38mmol), slowly drip TFAPy (1.22g; dichloromethane solution 6.30mmol), N
2the lower normal-temperature reaction 1h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white solid (1.66g).
MS(ESI
+，m/e)：878.37[M+H]
+
Embodiment 193-O-descladinosylation-3-oxo-9-is to chlorobenzene formacyl hydrazone clarithromycin (compound 13)
Above-mentioned 2 '-O-to chlorobenzene formacyl-3-O-descladinosylation-3-oxo-9-to chlorobenzene formacyl hydrazone clarithromycin crude product (intermediate 12, 1.66g, 1.31mmol) be dissolved in methyl alcohol (9mL), reflux 2h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [methyl alcohol: chloroform (1: 16)], obtain yellow solid (0.19g, from intermediate 2, to intermediate 10, 11, 12, the total recovery finally arriving compound 13 is 19.6%).
MS(ESI
+，m/e)：740.33[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.7 (s, 1H, 9=N-NH), 7.37-7.78 (m, 4H, 9 phenyl ring)
13cNMR (400MHz, CDCl
3) δ (ppm): 202.51 (3=O), 172.52 (9-NH-CO-), 170.14 (9 > C=N-), 103.92-137.55 (6 carbon in 9 side-chain benzene ring)
Embodiment 202 '-O-phenylacetyl-9-phenylacetyl hydrazone clarithromycin (intermediate 13)
Toluylic acid (5.36g, 39.37mmol) and DCC (8.93g, 43.28mmol) are dissolved in methylene dichloride (60mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), normal-temperature reaction 1h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains faint yellow crude product (9.96g).
MS(ESI
+，m/e)：998.59[M+H]
+
Embodiment 219-phenylacetyl hydrazone clarithromycin (compound 5)
Above-mentioned 2 '-O-phenylacetyl-9-phenylacetyl hydrazone clarithromycin crude product (intermediate 13, 4.50g, 3.56mmol) be dissolved in methyl alcohol (23mL), reflux 2.5h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtain 4.45g, get 1.3g column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain faint yellow foaming material (0.45g, from intermediate 2, to intermediate 13, the total recovery finally arriving compound 5 is 50.0%).
MS(ESI
+，m/e)：880.51[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.58 (s, 1H, 9=N-NH), 7.22-7.36 (m, 5H, 9 phenyl ring), 4.54 (s, 2H, 9-CO-CH
2-)
13cNMR (400MHz, CDCl
3) δ (ppm): 172.56 (9-NH-CO-); 166.92 (9 > C=N-); 126.74-129.30 (6 carbon in 9 side-chain benzene ring), 32.75 (9 carbon between side chain acyl group and phenyl ring)
Embodiment 222 '-O-phenylacetyl-3-O-descladinosylation-3-hydroxyl-9-phenylacetyl hydrazone clarithromycin (intermediate 14)
Above-mentioned 2 '-O-phenylacetyl-9-phenylacetyl hydrazone clarithromycin crude product (intermediate 13,1.73g, 1.37mmol) is dissolved in 1% ethanol solution hydrochloride (17mL); normal-temperature reaction 21h, adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains white foaming material (1.44g).
MS(ESI
+，m/e)：840.49[M+H]
+
Embodiment 232 '-O-phenylacetyl-3-O-descladinosylation-3-oxo-9-phenylacetyl hydrazone clarithromycin (intermediate 15)
Above-mentioned 2 '-O-phenylacetyl-3-O-descladinosylation-3-hydroxyl-9-phenylacetyl hydrazone clarithromycin crude product (intermediate 14; 1.44g; 1.37mmol) with EDCHCl (2.20g; 11.50mmol) be dissolved in anhydrous methylene chloride (15mL); add DMSO (2.19mL, 30.89mmol), slowly drip TFAPy (1.09g; dichloromethane solution 5.66mmol), N
2the lower normal-temperature reaction 1h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellow solid (1.30g).
MS(ESI
+，m/e)：838.48[M+H]
+
Embodiment 243-O-descladinosylation-3-oxo-9-phenylacetyl hydrazone clarithromycin (compound 14)
Above-mentioned 2 '-O-phenylacetyl-3-O-descladinosylation-3-oxo-9-phenylacetyl hydrazone clarithromycin crude product (intermediate 15, 1.30g, 1.37mmol) be dissolved in methyl alcohol (8mL), reflux 3h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain faint yellow foaming material (0.40g, from intermediate 2, to intermediate 13, 14, 15, the total recovery finally arriving compound 14 is 32.0%).
MS(ESI
+，m/e)：720.41[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 10.66 (s, 1H, 9=N-N-H), 7.21-7.30 (m, 5H, 9 phenyl ring), 2.55 (s, 2H, 9-CO-CH
2-Ph)
13cNMR (400MHz, CDCl
3) δ (ppm): 205.79 (3=O); 172.33 (9-NH-CO-); 167.18 (9 > C=N-); 104.30-134.40 (6 carbon in 9 side-chain benzene ring), 38.29 (9 carbon between side chain acyl group and phenyl ring)
Embodiment 252 '-O-β-hydrocinnamoyl-9-β-hydrocinnamoyl hydrazone clarithromycin (intermediate 16)
Beta-phenylpropionic acid (5.90g, 39.29mmol) and DCC (8.45g, 40.95mmol) are dissolved in methylene dichloride (60mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), normal-temperature reaction 24h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains faint yellow crude product (10.29g).
MS(ESI
+，m/e)：1026.62[M+H]
+
Embodiment 269-β-hydrocinnamoyl hydrazone clarithromycin (compound 6)
Above-mentioned 2 '-O-β-hydrocinnamoyl-9-β-hydrocinnamoyl hydrazone clarithromycin crude product (intermediate 16, 2.19g, 1.67mmol) be dissolved in methyl alcohol (10mL), reflux 5h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 10: 0.6)], obtain faint yellow foaming material (0.61g, from intermediate 2, to intermediate 16, the total recovery finally arriving compound 6 is 40.7%).
MS(ESI
+，m/e)：894.27[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.60 (s, 1H, 9=N-NH), 7.15-7.29 (m, 5H, 9 phenyl ring), 2.7-3.1,2.2-2.5 (m, 4H, 9-CO-CH
2cH
2-Ph)
13cNMR (400MHz, CDCl
3) δ (ppm): 174.03 (9-NH-CO-); 167.08 (9 > C=N-); 126.01-140.93 (6 carbon in 9 side-chain benzene ring), 33.36,30.44 (two alkyl carbon between 9 acyl group structures and phenyl ring)
Embodiment 272 '-O-β-hydrocinnamoyl-3-O-descladinosylation-3-hydroxyl-9-β-hydrocinnamoyl hydrazone clarithromycin (intermediate 17)
Above-mentioned 2 '-O-β-hydrocinnamoyl-9-β-hydrocinnamoyl hydrazone clarithromycin crude product (intermediate 16,2.20g, 1.68mmol) is dissolved in 1% ethanol solution hydrochloride (22mL); normal-temperature reaction 24h, filtrate adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains yellow sticky shape solid (1.83g).
MS(ESI
+，m/e)：868.52[M+H]
+
Embodiment 282 '-O-β-hydrocinnamoyl-3-O-descladinosylation-3-oxo-9-β-hydrocinnamoyl hydrazone clarithromycin (intermediate 18)
Above-mentioned 2 '-O-β-hydrocinnamoyl-3-O-descladinosylation-3-hydroxyl-9-β-hydrocinnamoyl hydrazone clarithromycin crude product (intermediate 17; 1.83g; 1.68mmol) with EDCHCl (2.71g; 14.14mmol) be dissolved in anhydrous methylene chloride (18mL); add DMSO (2.70mL, 37.99mmol), slowly drip TFAPy (1.35g; dichloromethane solution 6.97mmol), N
2the lower normal-temperature reaction 0.5h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellow sticky shape solid (1.82g).
MS(ESI
+，m/e)：866.51[M+H]
+
Embodiment 293-O-descladinosylation-3-oxo-9-β-hydrocinnamoyl hydrazone clarithromycin (compound 15)
Above-mentioned 2 '-O-hydrocinnamoyl-3-O-descladinosylation-3-oxo-9-β-hydrocinnamoyl hydrazone clarithromycin crude product (intermediate 18, 1.82g, 1.68mmol) be dissolved in methyl alcohol (9mL), reflux 3h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain faint yellow foaming material (0.56g, from intermediate 2, to intermediate 16, 17, 18, the total recovery finally arriving compound 15 is 45.5%).
MS(ESI
+，m/e)：734.05[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.80 (s, 1H, 9=N-NH), 7.14-7.27 (m, 5H, 9 phenyl ring), 2.50-2.90,3.0-3.3 (m, 4H, 9-CO-CH
2cH
2-Ph)
13cNMR (400MHz, CDCl
3) δ (ppm): 205.81 (3 > C=O); 169.86 (9-NH-CO-); 166.64 (9 > C=N-); 126.05-140.89 (6 carbon in 9 side-chain benzene ring), 34.29,28.36 (two alkyl carbon between 9 acyl group structures and phenyl ring)
Embodiment 302 '-O-cinnamoyl-9-cinnamoyl hydrazone clarithromycin (middle 19)
Styracin (5.83g, 39.35mmol) and DCC (8.93g, 43.28mmol) are dissolved in methylene dichloride (60mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (6.00g, 7.87mmol), normal-temperature reaction 48h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains faint yellow crude product (11.14g).
MS(ESI
+，m/e)：1022.59[M+H]
+
Embodiment 319-cinnamoyl hydrazone clarithromycin (compound 7)
Above-mentioned 2 '-O-cinnamoyl-9-cinnamoyl hydrazone clarithromycin crude product (middle 19, 1.20g, 0.85mmol), be dissolved in methyl alcohol (6mL), reflux 16h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 8: O.6)], obtain yellow foaming material (0.67g, from intermediate 2, to intermediate 19, the total recovery finally arriving compound 7 is 88.7%).
MS(ESI
+，m/e)：892.45[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.35 (s, 1H, 9=N-N-H), 7.25-7.80 (m, 5H, 9 phenyl ring), 7.17 (d, J=15.6Hz, 1H, 9=CH-Ph), 6.34 (d, J=15.6Hz, 1H, 9-CO-CH=)
13cNMR (400MHz, CDCl
3) δ (ppm): 177.85 (9-NH-CO-), 167.06 (9 > C=N-), 144.06 (9=CH-Ph), 117.41 (9-CO-CH=), 103.14-135.83 (6 carbon in 9 side-chain benzene ring)
Embodiment 322 '-O-cinnamoyl-3-O-descladinosylation-3-hydroxyl-9-cinnamoyl hydrazone clarithromycin (intermediate 20)
Above-mentioned 2 '-O-cinnamoyl-9-cinnamoyl hydrazone clarithromycin crude product (middle 19,2.00g, 1.41mmol) is dissolved in 1% ethanol solution hydrochloride (20mL); normal-temperature reaction 24h, filtrate adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains yellow foaming material (1.68g).
MS(ESI
+，m/e)：864.49[M+H]
+
Embodiment 332 '-O-cinnamoyl-3-O-descladinosylation-3-oxo-9-cinnamoyl hydrazone clarithromycin (intermediate 21)
Above-mentioned 2 '-O-cinnamoyl-3-O-descladinosylation-3-hydroxyl-9-cinnamoyl hydrazone clarithromycin crude product (intermediate 20; 1.61g; 1.41mmol) with EDCHCl (2.47g; 12.50mmol) be dissolved in anhydrous methylene chloride (16mL); add DMSO (2.46mL, 33.58mmol), slowly drip TFAPy (1.19g; dichloromethane solution 6.16mmol), N
2the lower normal-temperature reaction 0.5h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellow sticky shape solid (1.61g).
MS(ESI
+，m/e)：862.48[M+H]
+
Embodiment 343-O-descladinosylation-3-oxo-9-cinnamoyl hydrazone clarithromycin (compound 16)
Above-mentioned 2 '-O-cinnamoyl-3-O-descladinosylation-3-oxo-9-cinnamoyl hydrazone clarithromycin crude product (intermediate 21, 1.61g, 1.41mmol) be dissolved in methyl alcohol (8mL), reflux 3h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain yellow foaming material (0.35g, from intermediate 2, to intermediate 19, 20, 21, the total recovery finally arriving compound 16 is 33.9%)
MS(ESI
+，m/e)：732.41[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 11.32 (s, 1H, 9=N-N-H), 7.73 (t, J=17.6Hz, 1H, 9 phenyl ring 4-H), 7.33-7.59 (m, 4H, 9 phenyl ring 2,3,5,6-H, 1H, 9=CH-Ph), 6.34 (d, J=15.6Hz, 1H, 9-CO-CH=)
13cNMR (400MHz, CDCl
3) δ (ppm): 202.85 (3 > C=O), 167.06 (9-NH-CO-), 161.91 (9 > C=N-), 142.14 (9=CH-Ph), 117.25 (9-CO-CH=), 120.23-135.81 (6 carbon in 9 side-chain benzene ring)
Embodiment 352 '-O-(2-thiophene acetyl)-9-(2-thiophene acetyl) hydrazone clarithromycin (intermediate 22)
2-thiophene acetic acid (2.80g, 19.69mmol) and DCC (4.22g, 20.45mmol) are dissolved in methylene dichloride (30mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol), normal-temperature reaction 24h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains brown crude product (5.19g).
MS(ESI
+，m/e)：1010.50[M+H]
+
Embodiment 369-(2-thiophene acetyl) hydrazone clarithromycin (compound 8)
Above-mentioned 2 '-O-(2-thiophene acetyl)-9-(2-thiophene acetyl) hydrazone clarithromycin crude product (intermediate 22, 1.60g, 1.21mmol) be dissolved in methyl alcohol (8mL), reflux 2h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 8: 0.6)], obtain brown foaming material (0.61g, from intermediate 2, to intermediate 22, the total recovery finally arriving compound 8 is 57.0%).
MS(ESI
+，m/e)：886.31[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.57 (s, 1H, 9=N-NH), 6.92-7.26 (m, 3H, 9 thiphene ring), 4.46 (s, 2H, 9-CO-CH
2-)
13cNMR (400MHz, CDCl
3) δ (ppm): 171.41 (9-NH-CO-); 168.21 (9 > C=N-); 124.72-135.57 (4 carbon in 9 side chain thiphene ring), 33.88 (the alkyl carbon between 9 acyl group structures and thiphene ring)
Embodiment 372 '-O-(3-indoles ethanoyl)-9-(3-indoles ethanoyl) hydrazone clarithromycin (intermediate 23)
3-indolyl acetic acid (3.45g, 19.69mmol) and DCC (4.22g, 20.45mmol) are dissolved in methylene dichloride (30mL), solutions turbid, normal-temperature reaction 30min, adds 9-hydrazone clarithromycin (3.00g, 3.94mmol), normal-temperature reaction 18h.Filter, removing insolubles, filtrate adds water, and 3MNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains brown color crude product (4.45g).
MS(ESI
+，m/e)：1076.61[M+H]
+
Embodiment 389-(3-indoles ethanoyl) hydrazone clarithromycin (compound 9)
Above-mentioned 2 '-O-(3-indoles ethanoyl)-9-(3-indoles ethanoyl) hydrazone clarithromycin crude product (intermediate 23, 1.30g, 1.15mmol) be dissolved in methyl alcohol (6.50mL), reflux 5h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (7: 5: 0.55)], obtain brown color foaming material (0.41g, from intermediate 2, to intermediate 23, the total recovery finally arriving compound 9 is 39.0%).
MS(ESI
+，m/e)：919.51[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.71 (s, 1H, 9 indole ring NH), 8.48 (s, 1H, 9=N-NH), 7.64 (d, 1H, the 4-H of 9 indole rings), 7.33 (d, 1H, the 7-H of 9 indole rings), 7.11-7.20 (m, 3H, 2,5,6-H of 9 indole rings), 3.50 (s, 2H, 9-CO-CH
2-)
13cNMR (400MHz, CDCl
3) δ (ppm): 171.59 (9-NH-CO-); 166.57 (9 > C=N-); 121.81-136.59 (8 carbon on 9 side chain indole rings), 29.78 (the alkyl carbon between 9 acyl group structures and indole ring)
Embodiment 392 '-O-(3-indoles butyryl radicals)-9-(3-indoles butyryl radicals) hydrazone clarithromycin (intermediate 24)
3-indolebutyric acid (4.00g, 19.68mmol) and DCC (4.22g, 20.45mmol) are dissolved in methylene dichloride (30mL), normal-temperature reaction 30min, add 9-hydrazone clarithromycin (3.00g, 3.94mmol), normal-temperature reaction 45h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains yellow-brown solid crude product (6.05g).
MS(ESI
+，m/e)：1132.67[M+H]
+
Embodiment 409-(3-indoles butyryl radicals) hydrazone clarithromycin (compound 10)
Above-mentioned 2 '-O-(3-indoles butyryl radicals)-9-(3-indoles butyryl radicals) hydrazone clarithromycin crude product (intermediate 24, 1.40g, 0.91mmol) be dissolved in methyl alcohol (7mL), reflux 8h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography [ethyl acetate: sherwood oil: diethylamine (5: 6: 0.5)], obtain yellow foaming material (0.47g, from intermediate 2, to intermediate 24, the total recovery finally arriving compound 10 is 54.4%)
MS(ESI
+，m/e)：947.51[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 8.56 (s, 1H, 9 indole ring NH) 8.45 (s, 1H, 9=N-NH), 7.59 (d, J=7.6Hz, 1H, the 4-H of 9 indole rings), 7.30 (d, J=8.4Hz, 1H, the 7-H of 9 indole rings), 6.99-7.16 (m, 3H, 2 of 9 indole rings, 5,6-H), 2.85 (t, J=7.0Hz, 2H, 9-CH
2-indole ring), 2.0-2.63 (m, 4H, two CH of 9 contiguous acyl group structures
2)
13cNMR (400MHz, CDCl
3) δ (ppm): 174.92 (9-NH-CO-); 166.46 (9 > C=N-); 111.02-136.56 (8 carbon on 9 side chain indole rings), 35.08,31.97,24.56 (3 alkyl carbon between 9 acyl group structures and indole ring)
Embodiment 412 '-O-isobutyryl-9-isobutyryl hydrazone clarithromycin (middle 25)
Isopropylformic acid (2.33ml, 25mmol) and DCC (4.38g, 21.25mmol) are dissolved in methylene dichloride (38mL), solutions turbid, normal-temperature reaction 30min, adds 9-hydrazone clarithromycin (3.81g, 5.00mmol), normal-temperature reaction 72h.Filter, removing insolubles, filtrate adds water, and 3NNaOH adjusts pH to 9.7, separates organic phase, aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white crude (4.10g).
MS(ESI
+，m/e)：902.59[M+H]
+
Embodiment 422 '-O-isobutyryl-3-O-descladinosylation-3-hydroxyl-9-isobutyryl hydrazone clarithromycin (intermediate 26)
Above-mentioned 2 '-O-isobutyryl-9-isobutyryl hydrazone clarithromycin (middle 25,4.10g, 5.00mmol) is dissolved in 1% ethanol solution hydrochloride (20mL); normal-temperature reaction 24h, adds water and methylene dichloride, and 3NNaOH adjusts pH to 9.7; separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase; through washing; saturated common salt is washed, dried over anhydrous sodium carbonate, filters; filtrate decompression evaporate to dryness, obtains white solid (3.74g).
MS(ESI
+，m/e)：744.49[M+H]
+
Embodiment 432 '-O-isobutyryl-3-O-descladinosylation-3-oxo-9-isobutyryl hydrazone clarithromycin (intermediate 27)
Above-mentioned 2 '-O-isobutyryl-3-O-descladinosylation-3-hydroxyl-9-isobutyryl hydrazone clarithromycin crude product (intermediate 26; 3.24g; 4.33mmol) with EDCHCl (4.33g; 22.60mmol) be dissolved in anhydrous methylene chloride (30ml); add DMSO (3.54mL, 45.30mmol), slowly drip TFAPy (2.61g; dichloromethane solution 22.6mmol), N
2the lower normal-temperature reaction 24h of protection, adds water, stirs 10min, separate organic phase; aqueous phase methylene dichloride extracting three times, merges organic phase, and through washing, saturated common salt is washed; dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, obtains white solid (2.22g).
MS(ESI
+，m/e)：742.48[M+H]
+
Embodiment 443-O-descladinosylation-3-oxo-9-isobutyryl hydrazone clarithromycin (compound 17)
Above-mentioned 2 '-O-isobutyryl-3-O-descladinosylation-3-oxo-9-isobutyryl hydrazone clarithromycin crude product (intermediate 27, 2.22g, 4.33mmol) be dissolved in methyl alcohol (20mL), reflux 3h, evaporated under reduced pressure, add water and methylene dichloride, 3NNaOH adjusts pH to 9.7, stir 10min, separate organic phase, aqueous phase methylene dichloride extracting three times, merge organic phase, through washing, saturated common salt is washed, dried over anhydrous sodium carbonate, filter, filtrate decompression evaporate to dryness, column chromatography for separation [methyl alcohol: chloroform (1: 10)], obtain white foaming material (0.45g, from intermediate 2, to intermediate 25, 26, 27, the total recovery finally arriving compound 17 is 15.5%).
MS(ESI
+，m/e)：672.44[M+H]
+
Embodiment 459-hydrazone Matachrom A (intermediate 25)
Matachrom A (20g, 0.0252mol) is dissolved in methyl alcohol (20mL), adds 85% hydrazine hydrate (2.2mL, 0.0378mol), cool after reflux 18h, separate out solid, filter, white solid (13.3g, 65.0%) washed to obtain by filter cake.
9-hydrazone Erythromycin A (intermediate 26)
9-hydrazone Matachrom A (intermediate 25) (4.00g, 0.0050mol) be dissolved in methylene dichloride (90mL)-water (80mL), pH9.7 is adjusted to 3mol/L sodium hydroxide solution, separate organic phase, washing, anhydrous sodium sulfate drying, filter, evaporated under reduced pressure, white foaming material (3.352g, 90.4%).
Embodiment 46N-[4-(2,5-dichlorophenoxy)-crotyl]-9-hydrazone Erythromycin A (compound 18)
9-hydrazone Erythromycin A (intermediate 26) (2.00g, 0.0025mol) be dissolved in DMF (20mL), add Anhydrous potassium carbonate (0.69g, 0.0050mol) 4-(2, 5-dichlorophenoxy)-2-butylene-1-bromine (0.96g, 0.0033mol) add water (50mL) after stirred at ambient temperature 16h, methylene dichloride (30mL), stratification, separate organic phase, aqueous phase methylene dichloride extracting, merge organic phase, through washing, anhydrous sodium sulfate drying, filter, filtrate decompression evaporate to dryness, pillar layer separation [eluent: methanol dichloromethane (1: 13)], obtain white solid (0.604g, 25.1%).
MS(ESI
+，m/z)：962[M+H]
+
1hNMR (400MHz, CDCl
3) δ (ppm): 7.47 (d, J=8.4,1H, 9-phenyl ring 3-H), 7.26 (d, J=2Hz, 1H, 9-phenyl ring 6-H), 7.05 (dd, 1H, 9-phenyl ring 4-H), 6.09-δ 6.32 (m, 2H, 9-CH=CH-), 5.06-5.10 (dd, 1H, 1 '-CH-).
13cNMR (400MHz, CDCl
3) δ (ppm): 174.7 (1-CO), 165.7 (9-C=N-), 154.1 (9-phenyl ring 1-C), 137.8 (3-
ch=CH-), 132.5 (9-phenyl ring 5-C), 131.1 (9-phenyl ring 3-C), 121.8 (9-phenyl ring 4-C), 120.8 (9-phenyl ring 6-C), 114.8 (9-phenyl ring 6-C), 100.9 (1 '-CH), 95.9 (3-O-CH), 82.7 (5-CH), 78.8 (3-CH), 77.3 (4 "-CH); 76.1 (13-CH); 74.1 (12-C), 73.8 (6-C), 71.1 (2 '-CH); 70.7 (5 "-CH), 68.5 (3-O-CH
2), 65.7 (3 '-CH), 65.2 (3-CH=CH-
ch
2), 44.1 (2-CH), 38.0 (7-CH
2), 35.1 (4 '-CH
2), 21.1 (6-CH
3), 21.0 (13-
ch
2-CH
3), 18.7 (8-CH
3), 16.2 (12-CH
3), 14.6 (10-CH
3), 10.6 (13-CH
2-
ch
3), 9.6 (4-CH
3).
Embodiment 47N-(2-diethyllaminoethyl)-9-hydrazone Erythromycin A (compound 19)
9-hydrazone Erythromycin A (intermediate 26) (1.30g, 0.0016mol) be dissolved in dehydrated alcohol (7mL), add diethylin monochloroethane hydrochloride (0.3053g, 0.0018mol), reflux stirs 7h, add methylene dichloride (25mL), water (20mL), pH is adjusted to 9.3 stratification, separate organic phase, aqueous phase methylene dichloride extracting, merge organic phase, through washing, anhydrous sodium sulfate drying, filter, filtrate decompression evaporate to dryness, pillar layer separation [eluent: ethyl acetate-light petrol-diethylamine (5: 16: 1)] obtains white foaming material, white foaming material (0.055g is obtained again through pillar layer separation [eluent: methanol dichloromethane-ammoniacal liquor (1: 25: 0.5)], 4.1%).
MS(ESI
+，m/z)：847[M+H]
+
1HNMR(400MHz，DMSO)δ(ppm)：5.57(s，1H，9-N-NH-)，5.08-5.11(dd，1H，1′-CH-)，2.32-2.64(m，8H，9-NH-
CH 2 CH 2 N(
CH 2 CH
3)
2)。
13CNMR(400MHz，DMSO)δ(ppm)：174.7(1-CO)，δ165.7(9-C＝N-)，102.9(1′-CH)，96.4(3-O-CH)，83.7(5-CH)，80.4(3-CH)，78.1(4″-CH)，77.3(12-C)，77.0(6-C)，76.8(13-CH)，76.7(5″-CH)，71.5(2′-CH)，65.5(3′-CH)，51.6(9-NH-CH
2 CH
2N)，48.0(9-NH-CH
2CH
2N)，45.6(9-NH-CH
2CH
2N(
CH 2 CH
3)
2)，44.7(2-CH)，40.3(3′-N(
CH
3)
2)，38.7(7-CH
2)，35.2(6″-CH)，32.6(4-CH)，28.9(4′-CH
2)，21.5(6-CH
3)，21.1(13-
CH
2-CH
3)，18.6(8-CH
3)，16.0(12-CH
3)，14.3(10-CH
3)，10.5(13-CH
2-
CH
3)，9.2(4-CH
3)。
Effect example
Anti-microbial activity is tested:
Antibacterial activity in vitro test is carried out to the compound 1 ~ 19 of above-mentioned synthesis, sample is first used anhydrous alcohol solution respectively, then be diluted to 125 μ g/mL with sterilized water, then two-fold dilution successively.By 20 strain G
+and G
-tested bacterial classification is seeded in meat soup respectively, 37 DEG C of overnight incubation.With agar plate dilution method, quantitative with multiple spot inoculation instrument, inoculate often 10
5cFU.After having inoculated bacterial classification, be placed in 37 DEG C of incubators and cultivate 18h observations, draw the minimum inhibitory concentration (MIC value) of compound to tested bacterium.
Tested bacterium comprises G
+bacterium 6 strain: streptococcus aureus 26003, staphylococcus epidermidis 26069, Staphylococcus albus 26101, pneumococcus 31002, faecalis 32220 and gamma streptococcus 32206, G
-bacterium 14 strain: intestinal bacteria 44102, Pseudomonas aeruginosa 10124, pneumobacillus 46101, Corynebacterium diphtheriae 50097, gas bacillus 45102, citrobacter 48017, proteus vulgaris 49085, Proteus mirabilis 49005, Morgan Bacillus proteus 49086, Salmonella enteritidis 50041, serratia marcescens 41002, Song Shi Shigellae 51081, Shigella bogdii 51313, shigella flexneri 51573.
Test result is in table 3 and table 4.
Table 3
Table 4
Conclusion: the 9-substituted acyl hydrazone clarithomycin derivative (compound 1-10) of synthesis has very strong anti-microbial activity to Staphylococcus albus, pneumococcus, faecalis; compound 1 and compound 9 pairs of S. aureus L-forms have stronger anti-microbial activity; compound 1,2,3; 4; 5,6,8; 9,10 pairs of gamma streptococcus have stronger anti-microbial activity.Wherein compound Isosorbide-5-Nitrae, the anti-microbial activity of 9 pairs of S. aureus L-forms is better than Azythromycin, and compound 1-10 is all better than Azythromycin to enterococcal anti-microbial activity.
3-O-descladinosylation-3-the oxo-9-substituted acyl hydrazone clarithomycin derivative (compound 11-17) of synthesis has very strong anti-microbial activity to S. aureus L-forms, Staphylococcus albus, pneumococcus, gamma streptococcus; part of compounds (compound 11; 12; 16,17) very strong anti-microbial activity is had to faecalis.The anti-microbial activity of all compounds to S. aureus L-forms is better than Azythromycin (compound 11-17).4 compounds (compound 11,12,14,16) are had to be better than Azythromycin to gamma streptococcus activity; 4 compounds (compound 11,12,16,17) are better than Azythromycin to enterococcal anti-microbial activity.
Claims (14)
1. a class is such as formula the macrolides compound shown in I;
Wherein, R is C
1~ C
3alkyl, or H; R
afor
3
represent singly-bound or double bond, when it is double bond, R
bdo not exist, when it is singly-bound, R
bfor
R
cfor substituted or unsubstituted C
1~ C
3alkyl, substituted or unsubstituted C
6~ C
10aryl or substituted or unsubstituted C
2~ C
4thiazolinyl; Wherein, the C of replacement
6~ C
10substituting group in aryl is nitro or halogen, and the substituting group in aryl is ortho position, contraposition or a position; The C replaced
1~ C
3substituting group in alkyl is C
6~ C
10aryl, or C
4~ C
8heteroaryl, wherein heteroatoms is N, O or S; The C replaced
2~ C
4substituting group in thiazolinyl is C
6~ C
10aryl;
X
1and X
2it is independently halogen;
R
dand R
ebe independently C
1~ C
3alkyl;
N is 1 ~ 3.
2. macrolides compound as claimed in claim 1, is characterized in that: work as R
cfor substituted or unsubstituted C
1~ C
3during alkyl, described C
1~ C
3alkyl is methyl, ethyl or sec.-propyl.
3. macrolides compound as claimed in claim 1, is characterized in that: R
cin, the C of described replacement
6~ C
10when substituting group in aryl is halogen, described halogen is Cl.
4. macrolides compound as claimed in claim 1, is characterized in that: R
cin, the C of replacement
1~ C
3substituting group in alkyl is C
4~ C
8during heteroaryl, described C
4~ C
8heteroaryl is 2-thienyl or 3-indyl.
5. macrolides compound as claimed in claim 1, is characterized in that: work as X
1and X
2when being independently halogen, described halogen is fluorine, chlorine, bromine or iodine.
6. macrolides compound as claimed in claim 1, is characterized in that: described X
1and X
2position be 2 ' position and 5 ' position.
7. macrolides compound as claimed in claim 1, is characterized in that: described X
1and X
2identical.
8. macrolides compound as claimed in claim 1, is characterized in that: work as R
dand R
ebe independently C
1~ C
3during alkyl, described C
1~ C
3alkyl is ethyl.
9. macrolides compound as claimed in claim 1, is characterized in that: described n is 2.
10. the macrolides compound as described in any one of claim 1 ~ 9, is characterized in that: described Compound I is following arbitrary structure:
Wherein, R
aand R
cdefinition with described in any one of claim 1 ~ 9.
11. macrolides compounds as described in any one of claim 1 ~ 9, is characterized in that: described Compound I is following arbitrary compound:
In Ia, R
cfor methyl, phenyl, p-nitrophenyl, rubigan, benzyl, styroyl, styryl, thiophene-2-methyl, indoles-3-methyl, indoles-3-propyl group;
In Ib, R
cfor phenyl, p-nitrophenyl, rubigan, benzyl, styroyl, styryl or sec.-propyl;
In Ic, R
afor
The preparation method of 12. macrolides compounds as described in any one of claim 1 ~ 9, is characterized in that: it is any one in following method:
(1) when in target compound I, R
afor
time, R is C
1~ C
3during alkyl, Compound II per is carried out the reaction of the acyl protecting groups sloughing hydroxyl;
R
c1for R
c, each group definition except specified otherwise all with described in any one of claim 1 ~ 9;
(2) when in target compound I, R
afor
r is H or C
1~ C
3during alkyl, by Compound II per ' and R
ax carries out nucleophilic substitution reaction as follows;
Wherein, X is chlorine, bromine or iodine, each group definition except specified otherwise all with described in any one of claim 1 ~ 9.
Midbody compound IIa, IIb or the IIIb of Compound I described in 13. any one of preparation claim 1 ~ 9:
Wherein, the definition of each group is with described in any one of claim 1 ~ 9.
14. Compound I as described in any one of claim 1 ~ 9 are preparing the application in antibiotic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110129340.0A CN102786570B (en) | 2011-05-18 | 2011-05-18 | Macrolides compound, its preparation method, application and intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110129340.0A CN102786570B (en) | 2011-05-18 | 2011-05-18 | Macrolides compound, its preparation method, application and intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102786570A CN102786570A (en) | 2012-11-21 |
| CN102786570B true CN102786570B (en) | 2016-02-10 |
Family
ID=47152175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110129340.0A Expired - Fee Related CN102786570B (en) | 2011-05-18 | 2011-05-18 | Macrolides compound, its preparation method, application and intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102786570B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015014261A1 (en) * | 2013-07-30 | 2015-02-05 | 上海医药工业研究院 | Macrolide compound or salt thereof, synthesis method, pharmaceutical composition, and application thereof |
| CN104337826B (en) * | 2013-07-30 | 2018-02-13 | 上海医药工业研究院 | The application of macrolides compound or its salt and the pharmaceutical composition containing it |
| CN105646624B (en) * | 2014-12-04 | 2019-01-18 | 湖南九典制药股份有限公司 | A kind of preparation process of macrolides compound key intermediate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3780020A (en) * | 1970-09-30 | 1973-12-18 | Lilly Industries Ltd | Erythromycin azine derivatives |
| EP0307176A2 (en) * | 1987-09-09 | 1989-03-15 | Beecham Group Plc | Erythromycin derivatives |
| WO1999040097A1 (en) * | 1998-02-04 | 1999-08-12 | Teva Pharmaceutical Industries Ltd. | Process for making clarithromycin |
| EP0955307A1 (en) * | 1998-04-14 | 1999-11-10 | Chemagis Ltd. | Erythromycin a derivatives and methods for the preparation thereof |
| WO2005108984A2 (en) * | 2004-05-06 | 2005-11-17 | Chiron Corporation | Methods and systems for detection, identification and quantitation of macrolides and their impurities |
| CN101792473A (en) * | 2010-03-30 | 2010-08-04 | 暨南大学 | Novel ketolide compound and preparation method and application thereof |
-
2011
- 2011-05-18 CN CN201110129340.0A patent/CN102786570B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3780020A (en) * | 1970-09-30 | 1973-12-18 | Lilly Industries Ltd | Erythromycin azine derivatives |
| EP0307176A2 (en) * | 1987-09-09 | 1989-03-15 | Beecham Group Plc | Erythromycin derivatives |
| WO1999040097A1 (en) * | 1998-02-04 | 1999-08-12 | Teva Pharmaceutical Industries Ltd. | Process for making clarithromycin |
| EP0955307A1 (en) * | 1998-04-14 | 1999-11-10 | Chemagis Ltd. | Erythromycin a derivatives and methods for the preparation thereof |
| WO2005108984A2 (en) * | 2004-05-06 | 2005-11-17 | Chiron Corporation | Methods and systems for detection, identification and quantitation of macrolides and their impurities |
| CN101792473A (en) * | 2010-03-30 | 2010-08-04 | 暨南大学 | Novel ketolide compound and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 氮杂内酯类抗生素研究现状;张涛，等;《药学进展》;20060430;第30卷(第4期);第150-157页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102786570A (en) | 2012-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2207403B1 (en) | PREPARATION OF AZITHROMYCIN IN ITS FORM CRYSTAL DIHYDRATE. | |
| RU2330856C2 (en) | Macrolide compounds with antiinflammatory effect | |
| Fajdetić et al. | 4 ″-O-(ω-Quinolylamino-alkylamino) propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens | |
| CN102786570B (en) | Macrolides compound, its preparation method, application and intermediate | |
| NO161497B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 9A-AZA-9A-HOMOERYTROMYCIN DERIVATIVES. | |
| JP2008519787A (en) | Macrolone compounds | |
| CN102382157B (en) | Erythromycin A derivative and preparation method thereof | |
| JPS5896097A (en) | Erythromycin b derivative | |
| CN107129514B (en) | erythromycin A ketolide antibiotic derivative, and preparation method and application thereof | |
| US20190211003A1 (en) | Novel 16-member triamilide derivatives and uses thereof | |
| AP739A (en) | Erythromycin A 9-0-oxime derivatives endowed with antibiotic activity. | |
| Ma et al. | Novel C-4 ″modified azithromycin analogs with remarkably enhanced activity against erythromycin-resistant Streptococcus pneumoniae: The synthesis and antimicrobial evaluation | |
| ES2835828T3 (en) | Process to produce α-halo-tetraacylglucose | |
| Pandey et al. | Synthesis and antimicrobial activity of erythromycin-A oxime analogs | |
| CN103130852B (en) | A kind of erythromycin A derivant, its preparation method, intermediate and application | |
| US4918058A (en) | Macrolide compounds | |
| JP2007501268A (en) | Novel 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A 3-decladinosyl 9a-N-carbamoyl and 9a-N-thiocarbamoyl derivatives | |
| CA2217417C (en) | 9-n-ethenyl derivatives of 9(s)-erythromycylamine | |
| KR100804439B1 (en) | Methods utilizing aryl thioimines in synthesis of erythromycin derivatives | |
| JP2004536075A (en) | Arylation method for functionalizing O-allyl erythromycin derivatives | |
| JP2009518396A (en) | Method for demethylating the 3'-dimethylamino group of an erythromycin compound | |
| RU2205185C2 (en) | β, β-DISUBSTITUTED DERIVATIVES OF 9-DEOXO-9A-N-ETHENYL-9A-AZA-9A- HOMOERYTHROMYCIN A | |
| CN104788519B (en) | Sixteen-ring triamine lactone derivatives and its application | |
| CN110330539B (en) | Azithromycin compound and preparation method and application thereof | |
| JP2004331632A (en) | 2-fluoro-6-o-substituted ketoride derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160210 Termination date: 20200518 |