CN101906123B - 4''-aralkyl carbamic acid ester clarithomycin derivative and preparation method and application thereof - Google Patents
4''-aralkyl carbamic acid ester clarithomycin derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a 4''-aralkyl carbamic acid ester clarithomycin derivative with the general formula (I) or (II), and a preparation method and application thereof. R1 represents hydrogen, acetyl or benzoyl, and R2 represents fatty alkyl, substituted aryl radical or substituted aromatic heterocyclic alkyl. The invention also relates to a prepared intermediate product and a preparation method thereof and application of the 4''-aralkyl carbamic acid ester clarithomycin derivative to mainly resisting bacterial infection.
Description
Technical field
The present invention relates to clarithomycin derivative and its preparation method and application, " ''-aralkyl carbamic acid ester clarithomycin derivative and preparation method and application belong to technical field of chemistry to relate in particular to 4.
Background technology
Macrolide antibiotics is as the important anti-infectives of a class, because of its anti-microbial activity good, without anaphylaxis, side effect is little, safe, development through nearly 50 years has become the second largest class anti-infectives that clinical application is only second to β-lactam antibitics, has consequence at clinical treatment.Erythromycin once was widely used in the infection that treatment streptococcus aureus, streptococcus pneumoniae, Streptococcus hemolyticus and mycoplasma pneumoniae etc. cause as first-generation macrolide antibiotic, was particularly useful for penicillin anaphylaxis person.Yet owing to, bioavailability low etc. unstable to acid medium causes its application to be restricted.S-generation macrolide antibiotic take clarithromycin as representative has solved this problem, and very big improvement is being arranged aspect drug effect and the pharmacokinetics.
(chemical name: CAMA A) another name clarithromycin is a kind of semi-synthetic macrolide antibiotic to clarithromycin.Generally adopt at present Erythromycin A 9-9 oxime derivate to prepare as intermediate.It is erythromycin through oximate, protect oximido, slough the oximido protecting group and go the polystep reactions such as oximate to prepare clarithromycin and (see European patent EP 0158467; EP0195960; EP0269938 and EP0272110 and world patent WO9736912 and WO9736913), be the product of Erythromycin C-6 HM.Its outstanding feature is: stable to acidic medium, tissue permeability is good, plasma half-life is long, clinical indication is wide, evident in efficacy and untoward reaction is few.Particularly clarithromycin has widely antimicrobial spectrum, anti-microbial effect and erythromycin quite or 2～4 times to erythromycin.Clarithromycin has the activity that suppresses multiple anaerobism and aerobic gram-positive cocci, mycoplasma, chlamydozoan and legionella pneumophilia, especially the activity of some important gram negative bacillis such as Haemophilus influenzae and Mycobacterium intracellulare-mycobacterium avium complex body obviously is better than erythromycin, remedied the deficiency of macrolide antibiotic aspect anti-gram-negative bacteria.But, along with antibiotic widespread use, particularly lasting, improper use, bacterium has almost produced resistance to the microbiotic of all clinical uses, has brought very big difficulty to clinical treatment.Therefore, for this Tough questions of reply drug-fast bacteria infection, to the macrolide antibiotics further investigation, exploitation anti-microbial activity novel macrocyclic lactone microbiotic strong, has a broad antifungal spectrum has become the study hotspot of anti infection region.
4 " the ''-aralkyl carbamic acid ester macrolides compound is the novel derivative of macrolides of a class of report in 1998.This compounds is the C-4 of C-3 position cladinose in macrolide structure, and " position is introduced the carboxylamine ester side chain and is made, and anti-microbial activity is similar to ketolide and acylide, and is not subjected to resistant organism to carry the impact of gene kind.At present, 4 " ''-aralkyl carbamic acid ester macrolide derivatives (US Patent No. 6025350, the US20080249033 that reported; World patent WO2004101589, WO2005108413, WO2006050941, WO2006050942, WO2006050943, WO2008014221; Chinese patent: CN1980945 etc.) better performance is arranged all aspect antimicrobial agent, the research of this compounds is subject to extensive concern." position is the very potential decorating site of macrolide antibiotic to C-4, and introducing different carboxylamine ester side chains in this site is the effective ways of exploitation antimicrobial agent macrolide antibiotic.
The mixing resistance streptococcus pneumoniae of the resistance streptococcus pneumoniae of the Antimicrobial Streptococcus Pneumoniae of erm gene mediated, mef gene mediated and erm and mef gene mediated is three kinds of main respiratory tract pathogenic bacterium.The invention provides series of novel 4 " ''-aralkyl carbamic acid ester clarithomycin derivative has significant antibacterial activity in vitro to above three kinds of resistant organisms.
According to known and definite prior art, this class 4 " ''-aralkyl carbamic acid ester clarithomycin derivative, the intermediate product that relates to its preparation and method were not described also up to now.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, 4 " ''-aralkyl carbamic acid ester clarithomycin derivatives and its preparation method and application are provided.
Technical scheme of the present invention is as follows:
One, 4 " ''-aralkyl carbamic acid ester clarithomycin derivatives
Of the present invention 4 " ''-aralkyl carbamic acid ester clarithomycin derivative has following general formula (I) or (II):
Wherein, R
1Represent hydrogen, acetyl or benzoyl base, R
2Represent aliphatic group, substituted aroma alkyl or replace aromatic heterocyclic alkyl; N is 3 or 5.
Preferably, R
2Benzyl, 4-luorobenzyl, 4-methoxy-benzyl, 4-leptodactyline, 2-chlorobenzene ethyl, styroyl, 3,4-methylenedioxy benzene ethyl, cyclohexyl, sec.-propyl, n-propyl, allyl group, normal-butyl or n-pentyl.
Preferably, above-claimed cpd (I) or (II) be one of following:
(1) 4 " O-(benzyl) formamyl clarithromycin,
(2) 4 " O-(4-luorobenzyl) formamyl clarithromycin,
(3) 4 " O-(4-methoxy-benzyl) formamyl clarithromycin,
(4) 4 " O-(4-leptodactyline) formamyl clarithromycin,
(5) 4 " O-(2-chlorobenzene ethyl) formamyl clarithromycin,
(6) 4 " O-(styroyl) formamyl clarithromycin,
(7) 4 " O-(3,4-methylenedioxy benzene ethyl) formamyl clarithromycin,
(8) 4 " O-(n-propyl) formamyl clarithromycin,
(9) 4 " O-(allyl group) formamyl clarithromycin,
(10) 4 " O-(normal-butyl) formamyl clarithromycin,
(11) 4 " O-(n-pentyl) formamyl clarithromycin,
(12) 4 " O-(((benzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(13) 4 " O-(((4-luorobenzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(14) 4 " O-(((4-methoxy-benzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(15) 4 " O-(((4-leptodactyline) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(16) 4 " O-(((2-chlorobenzene ethyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(17) 4 " O-(((cyclohexyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(18) 4 " O-(((sec.-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(19) 4 " O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(20) 4 " O-(((allyl group) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(21) 4 " O-(((normal-butyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(22) 4 " O-(((n-pentyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(23) 4 " O-(((benzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(24) 4 " O-(((4-luorobenzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(25) 4 " O-(((4-methoxy-benzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(26) 4 " O-(((4-leptodactyline) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(27) 4 " O-(((2-chlorobenzene ethyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(28) 4 " O-(((cyclohexyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(29) 4 " O-(((sec.-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(30) 4 " O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(31) 4 " O-(((allyl group) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(32) 4 " O-(((normal-butyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(33) 4 " O-(((n-pentyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin.
Two, 4 " ''-aralkyl carbamic acid ester clarithomycin derivative prepares used intermediate and alkyl aryl ammonium formyl radical fatty amine hydrochloride
The first intermediate has following general formula (III): R wherein
1Represent the acetyl or benzoyl base.
The second intermediate has following general formula (IV): R wherein
1Represent the acetyl or benzoyl base.
Alkyl aryl ammonium formyl radical fatty amine hydrochloride has following logical formula V: R wherein
3Represent benzyl, 4-luorobenzyl, 4-methoxy-benzyl, 4-leptodactyline, 2-chlorobenzene ethyl, cyclohexyl, sec.-propyl, n-propyl, allyl group, normal-butyl or n-pentyl; N is 3 or 5.
Three, 4 " ''-aralkyl carbamic acid ester clarithomycin derivatives
Of the present invention 4 " preparation method of ''-aralkyl carbamic acid ester clarithomycin derivative, step is as follows:
Synthetic route one:
Step 1: with 2 '-OH acidylate protection of the clarithromycin of general formula (VI), acylating reagent aceticanhydride, acetic acid, Acetyl Chloride 98Min., benzoyl oxide, phenylformic acid or Benzoyl chloride, in the presence of inorganic or organic bases,, react under 0～40 ℃ temperature as solvent with acetone, ethyl acetate, tetrahydrofuran (THF) or methylene dichloride, generate the compound with above-mentioned general formula (III);
Step 2: will have the compound of general formula (III) in inert solvent, in the presence of inorganic or organic bases, with N, N '-carbonyl dimidazoles (CDI) generates the compound with general formula (IV) in 0～110 ℃ of reaction 2～72h;
Step 3: the compound of above-mentioned general formula (IV) and aliphatic amide, substituted aromatic amine or replacement aromatic heterocycle amine etc., at N, react in one of dinethylformamide, tetrahydrofuran (THF), acetonitrile or acetonitrile-water or the mixed solvent, catalyzer is 1.8-diazabicylo (5.4.0) hendecene-7 (DBU), in 0～65 ℃ of reaction 2～24h, generate general formula (I) or compound (II);
Step 4: when the R1 in above-mentioned general formula (I) or the compound (II) was the acetyl or benzoyl base, further acyl group on 2 '-position was sloughed in alcoholysis in the lower alcohols solvent, produced general formula (VII) or compound (VII); Wherein R2 represents aliphatic group, substituted aroma alkyl or replaces aromatic heterocyclic alkyl.
In the above-mentioned steps 1: the mol ratio of acylating reagent and clarithromycin 1: 1～5, preferred 1: 2.
In the above-mentioned steps 1: preferred acylating reagent is aceticanhydride.
In the above-mentioned steps 1: described inorganic or organic bases is selected from sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, pyridine or DMAP, preferred triethylamine.
In the above-mentioned steps 1: preferred solvent is methylene dichloride.
In the above-mentioned steps 1: preferably under 25 ℃ of conditions, react 3～24h.
Preferably, treatment process is as follows after in the above-mentioned steps 1: in alkaline media, the preferably time extraction in pH8.0～10.0 comes separated product by separating organic layer and solvent evaporated; Perhaps after the extraction, again by the acetone-water recrystallization or use the silica gel column chromatography of 15: 1 methylene chloride-methanol system to carry out purifying, can produce purity and reach the R that has more than 95%
fValue is the compound of 0.42 general formula (III).
In the above-mentioned steps 2: compound and the N of general formula (III), the mol ratio 1: 1～6 of N '-carbonyl dimidazoles (CDI), preferred molar ratio 1: 2, by the acetone-water recrystallization or use the silica gel column chromatography of 15: 1 methylene chloride-methanol system to carry out purifying, can produce the R of purity more than 90%
fValue is the compound of 0.45 general formula (IV).
In the above-mentioned steps 2: preferably under 55 ℃ of conditions, react 24h, can produce the compound of the general formula (IV) more than 90%.
In the above-mentioned steps 2: inert solvent is selected from methylene dichloride, tetrahydrofuran (THF) or toluene, preferred toluene.
In the above-mentioned steps 2: described inorganic or organic bases is selected from sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, pyridine or DMAP, preferred triethylamine.
In the above-mentioned steps 3: the preferred DMF of reaction solvent.
In the above-mentioned steps 4: lower alcohol particular methanol, temperature of reaction are 55 ℃, and the reaction times is 24h.
Four, the preparation method of alkyl aryl ammonium formyl radical fatty amine hydrochloride
The preparation method of alkyl aryl ammonium formyl radical fatty amine hydrochloride of the present invention, step is as follows:
Synthetic route two:
Step 1: with γ-aminobutyric acid or 6-aminocaprolc acid raw material, make alkali with the 1mol/L sodium hydroxide solution, with tert-Butyl dicarbonate ((BOC)
2O) amino in the raw material is protected obtain the having general formula compound of (IX);
Step 2: have the compound of general formula (IX) at N-hydroxy benzo triazole (HOBt) and N, N '-dicyclohexyl carbodiimide (DCC) effect is lower, (THF) makes solvent with tetrahydrofuran (THF), with the reaction of corresponding aralkylamine, obtain the having general formula compound of (X);
Step 3: the compound that will have general formula (X) places the anhydrous ethyl acetate solution of saturated hydrogen chloride gas, sloughs the BOC protecting group, obtains having the alkyl aryl ammonium formyl radical fatty amine hydrochloride of logical formula V.
Five, the pharmaceutical composition that contains the compounds of this invention
The present invention comprises the medicine that contains the therapeutic dose the compounds of this invention, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.
Six, the 4 " anti-microbial activity of ''-aralkyl carbamic acid ester clarithomycin derivative
4 " ''-aralkyl carbamic acid ester clarithomycin derivative is mainly used in the purposes of bacterial-infection resisting.
Adopt the test tube doubling dilution to measure the part target compound to responsive streptococcus aureus ATCC25923, responsive streptococcus pneumoniae ATCC49619, MLS
BType Antimicrobial Streptococcus Pneumoniae B1 (erm), M type Antimicrobial Streptococcus Pneumoniae A22072 (mef) and MLS
BThe antibacterial activity in vitro of+M type Antimicrobial Streptococcus Pneumoniae (erm+mef).Measurement result sees Table 1:
Table 14 " ''-aralkyl carbamic acid ester clarithomycin derivative and the anti-microbial activity MIC value that has main macrolide antibiotic now
(μg/mL)
Wherein, the compound that (1)～(33) represent successively is consistent with the compound that number (1)～(33) during above-claimed cpd is preferred.
As shown in Table 1: 1～33 pair of responsive streptococcus aureus of listed target compound and responsive streptococcus pneumoniae show stronger anti-microbial activity; Compare with control drug erythromycin, clarithromycin, Azythromycin, the majority of compounds in the listed target compound 1～33 shows the inhibition activity of obvious enhancing to the Antimicrobial Streptococcus Pneumoniae of different drug resistant genes (erm or mef gene) mediation.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited to this.
Terminological interpretation:
CDI:N, N '-carbonyl dimidazoles.
DBU:1.8-diazabicylo (5.4.0) hendecene-7.
The DMAP:4-Dimethylamino pyridine.
DMF:N, dinethylformamide.
(BOC)
2O: tert-Butyl dicarbonate.
The HOBt:N-hydroxy benzo triazole.
DCC:N, N '-dicyclohexyl carbodiimide.
THF: tetrahydrofuran (THF).
Embodiment 1.
The preparation of 2 '-O-ethanoyl-clarithromycin
Clarithromycin (2.0g, 2.67mmol) is dissolved in anhydrous methylene chloride (20mL), adds aceticanhydride (0.50mL, 5.34mmol) and triethylamine (1.48mL, 10.68mmol), stirring at room 24h.React complete after, add equal-volume 5% sodium hydrogen carbonate solution, separatory, dichloromethane extraction (10mL * 2) merges organic layer, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets white foam shape solid 1.82g, yield 85.4%.Fusing point 167-170 ℃, R
f=0.42 (developping agent: methylene dichloride: methyl alcohol=15: 1).
Embodiment 2.
4 " preparation of O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-clarithromycin
A) 2 '-O-ethanoyl-clarithromycin (1.5g, 1.90mmol) is dissolved in dry toluene (20mL), adds triethylamine (0.60mL, 4.33mmol) and CDI (0.67g, 3.80mmol), 55 ℃ of heated and stirred 24h.React complete after, add saturated sodium bicarbonate solution (20mL), separatory, methylbenzene extraction (10mL * 2) merges organic layer, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets white foam shape solid 1.56g, yield 92.9%.Fusing point 147-150 ℃, R
f=0.45 (developping agent: methylene dichloride: methyl alcohol=10: 1).
B) 2 '-O-ethanoyl-clarithromycin (5.0g, 6.40mmol) is dissolved in anhydrous methylene chloride (30ml), adds successively DMAP (1.8ml, 12.8mmol) and CDI (2.0g, 12.3mmol), stirring at room 36 hours.React complete after, add saturated sodium bicarbonate solution (40mL), separatory, methylene dichloride (20mL * 2) merges organic phase, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure, acetonitrile: water=3: 1. recrystallization gets white solid 4.40g, yield 79.0%.R
f=0.68 (developping agent: ethyl acetate: methyl alcohol=5: 1).
Embodiment 3.
A): 4 " the preparation of O-(benzyl) formamyl-2 '-O-ethanoyl-clarithromycin
" (2.0g; 2.30mmol) be dissolved among the DMF (20mL) adds DBU (0.5mL, 3.41mmol) and benzylamine (1.26mL; 11.5mmol), stirring at room 7h to O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-clarithromycin with 4.React complete after, add entry (40mL), ethyl acetate (20mL * 3) extraction merges organic layer, saturated aqueous common salt (20mL * 3) washing, anhydrous sodium sulfate drying.Filter, evaporated under reduced pressure gets faint yellow solid 1.46g, yield 68.8%.
B): 4 " the preparation of O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl-2 '-O-ethanoyl-clarithromycin
" O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-clarithromycin (1.5g; 1.70mmol) be dissolved among the DMF (15mL); add DBU (0.5mL; 3.41mmol), triethylamine (1.50mL; 10.8mmol) and gamma-amino butyryl-Tri N-Propyl Amine hydrochloride (1.09g; 6.67mmol) (voluntarily preparation), stirring at room 24h with 4.React complete after, add entry (30mL), ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.45g, yield 88.9%.R
f=0.40 (developping agent is methylene dichloride: methyl alcohol=15: 1).
C): 4 " the preparation of O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl-2 '-O-ethanoyl-clarithromycin
" O-(1-H-imidazoles-1-carbonyl)-2 '-O-ethanoyl-clarithromycin (1.5g; 1.70mmol) be dissolved among the DMF (15mL); add DBU (0.5mL; 3.41mmol), triethylamine (1.50mL; 10.8mmol) and the amino hexanoyl of 6--Tri N-Propyl Amine hydrochloride (1.19g; 6.67mmol) (voluntarily preparation), stirring at room 24h with 4.React complete after, add entry 30mL, ethyl acetate (15mL * 3) extraction merges organic layer, saturated aqueous common salt (15mL * 3) washing, anhydrous sodium sulfate drying, evaporated under reduced pressure gets white solid foam 1.40g.
Other embodiment adopts the method identical with embodiment 3, but with other aliphatic amide, substituted aroma aliphatic amide, replace the assorted aliphatic amide replacement of virtue embodiment 3a) in benzyl, 3b) in gamma-amino butyryl-Tri N-Propyl Amine salt acid amide, 3c) in 6-amino hexanoyl-Tri N-Propyl Amine hydrochloride.
Embodiment 4:
A): 4 " the preparation of O-(benzyl) formamyl clarithromycin (target compound (1))
" O-(benzyl) formamyl-2 '-O-ethanoyl clarithromycin (1.46g) is dissolved in the methyl alcohol (30mL), and 45 ℃ are stirred 12h, and evaporated under reduced pressure gets white foam shape solid with 4.(eluent is methylene dichloride to silica gel column chromatography: methyl alcohol=25: 1), get white foam shape solid.Yield 64.6%, mp 228-231 ℃, TLC R
f=0.346 (chloroform/methanol, 5: 1); IR (KBr): 3450,2974,2938,2883,2832,2786,1732,1639,1498,1456,1378,1339,1279,1266,1242,1171,1110,1073,1052,1033,1012cm
-1,
1HNMR (600MHz, CDCl
3): δ 7.33-7.29 (m, 2H), 7.28-7.26 (m, 2H), 5.07-4.97 (d, J=1.5,1H), 4.97-4.96 (d, J=4.9,1H), (4.60-4.58 d, J=4.1,1H), 4.42-4.41 (m, 2H), (4.30 m, 1H), 3.99-3.98 (m, 1H), 3.78-3.75 (m, 2H), 3.67-3.65 (d, J=7.2,1H), (3.49 m, 1H), 3.36 (s, 1H), (3.30 s, 3H), 3.18-3.04 (m, 2H), (3.04 s, 3H), 2.99-2.95 (m, 1H), (2.90 m, 1H), 2.57 (m, 1H), (2.43-2.41 m, 1H), 2.28 (s, 3H), (2.19-2.18 m, 4H), 1.94-1.90 (m, 3H), (1.68-1.61 m, 4H), 1.48-1.39 (m, 1H), (1.38 s, 3H), 1.23-1.16 (m, 12H), (1.13-1.09 m, 15H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
46H
76N
2O
14880.5; Found (M+H)
+882.0.
Compound 2-11 adopts and embodiment 4a) identical method, but replace embodiment 4a with target product among other corresponding embodiment 4) in 4 " O-(benzyl) formamyl clarithromycin is with corresponding amine replacement embodiment 4a) middle benzylamine.
4 " O-(4-luorobenzyl) formamyl clarithromycin (target compound (2)) white solid, yield 65.6%, mp205-208 ℃, TLC R
f=0.395 (chloroform/methanol, 5: 1); IR (KBr): 3658,3447,2976,2938,2876,2834,2788,1732,1687,1607,1547,1511,1458,1378,1349,1332,1268,1228,1171,1128,1110,1082,1051,1033,1011cm
-1 1HNMR (600MHz, CDCl
3): δ 7.26-7.25 (s, 1H), 7.03-7.00 (t, 2H), (5.07-5.06 m, 2H), 4.98-4.96 (m, 1H), (4.58-4.57 d, J=9.7,1H), 4.50-4.49 (d, J=7.0,1H), 4.39-4.34 (m, 2H), (4.31-4.29 m, 1H), 4.00-3.99 (m, 1H), (3.77-3.75 m, 3H), 3.66-3.65 (d, J=7.2,1H), 3.42-3.40 (m, 1H), 3.30 (m, 3H), 3.20-3.19 (m, 2H), 3.04 (s, 3H), 2.99-2.98 (m, 2H), 2.31 (s, 6H), 1.94-1.90 (m, 3H), (1.70-1.62 m, 4H) .1.48-1.47 (m, 1H), 1.39 (s, 3H), (1.20-1.17 m, 12H), 1.13-1.09 (m, 15H), 0.84-0.83 (t, 3H); MS (ESI) m/z calcd.for C
46H
75FN
2O
14898.5; Found (M+H)
+900.1.
4 " O-(4-methoxy-benzyl) formamyl clarithromycin (target compound (3)) white solid, yield 66.7%, mp145-148 ℃, TLC R
f=0.400 (chloroform/methanol, 5: 1); IR (KBr): 3454,2973,2938,2884,2833,2786,1731,1613,1586,1514,1458,1378,1340,1247,1172,1109,1071,1033,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 7.20-7.19 (d, J=8.4,2H), 6.87-6.85 (d, J=8.6,2H), 5.07 (dd, J=10.9, J=1.5,1H), (4.97-4.96 m, 1H), 4.58-4.56 (d, J=9.7,1H), (4.51-4.50 d, J=6.8,1H), 4.34-4.33 (d, J=6.1,2H), 4.30-4.29 (m, 1H), 3.98 (s, 1H), 3.80 (s, 3H), 3.77-3.75 (m, 2H), 3.67-3.65 (m, 1H), 3.63-3.62 (m, 1H), 3.30 (s, 3H), 3.18 (m, 2H), 3.04 (s, 3H), 3.00-2.99 (m, 1H), 2.89-2.88 (m, 1H), 2.43-2.40 (m, 2H), 2.32 (s, 5H), 1.94-1.82 (m, 2H), 1.69-1.66 (m, 3H), 1.65-1.63 (m, 2H), 1.38 (s, 3H), 1.20-1.18 (m, 12H), 1.17-1.09 (m, 15H) 0.84-0.83 (t, 3H); MS (ESI) m/z calcd.forC
47H
78N
2O
15910.5; Found (M+H)
+912.1.
4 " O-(4-leptodactyline) formamyl clarithromycin (target compound (4)) white solid, yield 54.9%, mp145-148 ℃, TLC R
f=0.311 (chloroform/methanol, 5: 1); IR (KBr): 3438,2974,2938,2884,2832,2787,1732,1615,1595,1516,1458,1378,1344,1245,1171,1110,1070,1054,1033,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 7.01-6.99 (m, 2H), 6.88-6.76 (m, 2H), (5.07-5.05 d, J=11.0,1H), 4.96-4.95 (d, J=4.0,1H), 4.53-4.52 (d, J=6.6,1H), 4.47-4.45 (d, J=9.7,1H), (4.43-4.41 m, 1H), 4, (13-4.11 m, 1H), 3.96 (s, 1H), 3.80-3.76 (m, 1H), (3.75-3.73 m, 1H), 3.64-3.63 (m, 1H), 3.50-3.48 (m, 2H), (3.39-3.37 m, 3H), 3.30 (s, 3H), 3.18-3.02 (m, 1H), (3.02 s, 3H), 2.99-2.97 (m, 1H), 2.87-2.84 (m, 2H), (2.77-2.73 m, 3H), 2.71 (s, 4H), 2.59-2.56 (m, 1H), (2.42-2.37 m, 2H), 2.08-2.06 (m, 1H), 1.94-1.88 (m, 3H), (1.63-1.61 m, 2H), 1.65-1.57 (m, 2H), 1.33 (s, 3H), (1.29-1.27 m, 3H), 1.21 (d, J=6.9,3H), 1.18-1.16 (m, 2H), 1.12-1.11 (m, 11H), (1.08-1.06 m, 3H), 0.92-0.90 (m, 3H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
47H
78N
2O
15910.5; Found (M+H)
+912.1.
4 " O-(2-chlorobenzene ethyl) formamyl clarithromycin (target compound (5)) white solid, yield 62.2%, mp180-185 ℃, TLC R
f=0.368 (chloroform/methanol, 5: 1); IR (KBr): 3450,2973,2937,2884,2832,2785,1732,1057,1458,1378,1342,1267,1245,1171,1110,1071,1051,1034,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 7.36-7.35 (m, 1H), 7.20 (m, 3H), (5.07 dd, J=11.1, J=1.9,1H), (4.96-4.95 d, J=5.0,1H), 4.83 (m, 1H), 4.55-4.53 (d, J=2.0,2H), (4.25 m, 1H), 3.98 (s, 1H), 3.75-3.65 (m, 2H), (3.64-3.62 d, J=7.1,1H), (3.62-3.60 m, 1H), 3.57-3.55 (m, 1H), 3.55-3.50 (m, 1H), (3.29 s, 2H), 3.18 (m, 1H), 3.04-3.00 (s, 2H), (2.99-2.96 m, 3H), 2.89-2.87 (m, 1H), 2.59-2.57 (m, 2H), (2.41 s, 4H), 2.05 (m, 1H), 1.94-1.90 (m, 2H), (1.83-1.81 m, 2H), 1.68-1.62 (m, 3H), 1.48-1.47 (m, 2H), (1.38 s, 3H), 1.27-1.24 (m, 2H), 1.20-1.19 (m, 3H), (1.19-1.09 m, 24H) 0.84-0.83 (t, 3H);
13CNMR (600MHz, CDCl
3): δ 221.0,175.7, and 156.2,136.3,134.2,131.1,129.6,128.1,126.9,96.2,80.5,79.0,78.3,77.2,77.0,76.8,76.6,74.3,73.0,71.1,69.0,65.1,63.3,50.7,49.5,45.3,44.9,40.5,39.3,37.2,35.3,33.7,21.6,21.0,20.9,19.7,18.3,18.1,16.0,15.9,12.4,10.6,9.2; MS (ESI) m/z calcd.for C
47H
77ClN
2O
14928.5; Found (M+H)
+930.2.
4 " O-(styroyl) formamyl clarithromycin (target compound (6)) white solid, yield 61.8%, mp136-139 ℃, TLC R
f=0.380 (chloroform/methanol, 5: 1); IR (KBr): 3450,2974,2938,2884,2831,2785,1731,1634,1498,1456,1378,1342,1267,1245,1171,1110,1071,1052,1033,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 7.30-7.28 (m, 2H), 7.20 (m, 1H), (7.19-7.17 m, 2H), 5.06 (d, J=1.5,1H), 4.96-4.95 (d, J=4.9,1H), (4.79 m, 1H), 4.53-4.49 (m, 2H), (4.23-4.21 m, 1H), 3.98 (s, 1H), (3.76-3.74 m, 2H), 3.64-3.63 (d, J=7.3,1H), 3.57-3.53 (m, 2H), 3.45-3.44 (m, 1H), (3.29 s, 3H), 3.22-3.18 (m, 2H), 3.04 (s, 3H), (2.99-2.97 m, 1H), 2.86-2.82 (m, 3H), 2.58-2.56 (m, 2H), (2.39 m, 6H), 1.94-1.90 (m, 3H), 1.86-1.76 (m, 2H), (1.65-1.62 m, 3H), 1.48-1.45 (m, 1H), 1.38 (s, 3H), (1.25-1.19 m, 4H), 1.18-1.16 (m, 6H), 1.13-1.11 (m, 9H), (1.09-1.07 d, 3H), 1.05-1.03 (d, 3H), 0.85-0.82 (m, 3H); MS (ESI) m/z calcd.for C
47H
78N
2O
14894.6; Found (M+H)
+896.1.
4 " O-(3,4-methylenedioxy benzene ethyl) formamyl clarithromycin (target compound (7)) white solid, yield 67.1%, mp 235-237 ℃, TLC R
f=0.311 (chloroform/methanol, 5: 1); IR (KBr): 3447,2974,2938,2884,2832,2784,1731,1631,1054,1491,1457,1378,1339,1247,1171,1109,1071,1035,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 6.74-6.73 (d, J=7.7,1H), 6.67 (s, 1H), 6.63-6.62 (d, J=7.7,1H), (5.94-5.92 d, J=3.5,2H), 5.07-5.05 (d, J=11.0,1H), 4.98-4.96 (m, 1H), (4.58-4.51 d, J=4.7,2H), 4.21-4.20 (m, 1H), 3.98 (s, 1H), 3.76-3.74 (m, 2H), 3.66 (m, 2H), 3.50-3.48 (m, 1H), 3.41-3.38 (m, 1H), (3.28 s, 4H), 3.18 (m, 1H), 3.03 (s, 3H), (3.00-2.98 m, 1H), 2.89-2.86 (m, 1H), 2.76-2.74 (m, 2H), (2.60-2.56 m, 2H), 2.38-2.35 (m, 2H), 2.17 (s, 1H), (1.94-1.91 m, 2H), 1.63-1.58 (m, 10H), 1.48-1.46 (m, 1H), (1.37 s, 3H), 1.25-1.21 (m, 4H), 1.20 (m, 6H), (1.17-1.09 m, 9H), 1.08-1.04 (m, 6H), 0.86-0.82 (t, 3H); MS (ESI) m/z calcd.for C
48H
78N
2O
16938.5; Found (M+H)
+940.1.
4 " O-(n-propyl) formamyl clarithromycin (target compound (8)) white solid, yield 57.8%, mp:220-223 ℃, TLC R
f=0.445 (chloroform/methanol, 5: 1); IR (KBr): 3458,2972,2938,2878,2832,2785,1732,1638,1508,1459,1378,1340,1265,1245,1171,1110,1083,1051,1013cm
-1 1HNMR (600MHz, CDCl
3): δ 5.07-5.04 (d, J=10.1,1H), 4.99-4.95 (m, 1H), 4.78-4.77 (m, 1H), 4.55-4.53 (m, 2H), 4.27-4.26 (m, 1H), 3.98 (s, 1H), 3.77-3.75 (m, 2H), 3.68-3.66 (m, 2H), 3.32 (s, 3H), 3.20-3.13 (m, 4H), 3.04 (s, 3H), 3.01-2.95 (m, 1H), 2.89-2.86 (m, 1H), 2.42-2.40 (m, 3H), 1.94-1.91 (m, 2H), 1.69-1.61 (m, 9H), 1.56-1.49 (m, 3H), 1.39 (s, 3H), 1.25-1.21 (m, 3H), 1.20-1.18 (m, 12H), 1.15-1.09 (m, 12H), 0.92 (t, 3H), 0.84 (t, 3H); MS (ESI) m/z calcd.forC
42H
76N
2O
14832.5; Found (M+H)
+834.1.
4 " O-(allyl group) formamyl clarithromycin (target compound (9)) white solid, yield 55.3%, mp225-227 ℃, TLC R
f=0.412 (chloroform/methanol, 5: 1); IR (KBr): 3459,3340,2973,2941,2885,2831,2781,1735,1742,1692,1641,1537,1505,1457,1404,1377,1336,1278,1266,1247,1164,1109,1082,1053,1032,1012cm
-1,
1HNMR (600MHz, CDCl
3): δ 5.8-5.82 (m, 1H), 5.20-5.13 (m, 2H), (5.08-5.06 dd, J=9.6, J=1.9,1H), (4.98-4.97 d, J=4.9,2H), 4.56-4.55 (m, 1H), 4.28 (m, 1H), 3.97 (s, 1H), 3.85-3.82 (m, 2H), 3.77-3.74 (m, 3H), 3.67-3.66 (d, J=6.6,1H), (3.30 s, 4H), 3.18 (m, 1H), (3.00 s, 3H), 2.99-2.97 (m, 1H), (2.89-2.87 m, 2H), 2.60-2.59 (m, 3H), (2.42-2.39 m, 2H), 1.85-2.01 (m, 3H), (1.80-1.78 m, 2H), 1.67-1.62 (m, 6H), (1.48-1.46 m, 2H), 1.37 (s, 3H), (1.22-1.18 m, 12H), 1.14-1.12 (m, 9H), (1.07-1.05 m, 3H), 0.85-0.83 (t, 3H); MS (ESI) m/z calcd.for C
42H
74N
2O
14830.5; Found (M+H)
+832.1.
4 " O-(normal-butyl) formamyl clarithromycin (target compound (10)) white solid, yield 61.8%, mp229-232 ℃, TLC R
f=0.450 (chloroform/methanol, 5: 1); IR (KBr): 3459,2973,2938,2877,2832,2785,1733,1638,1507,1459,1378,1342,1266,1245,1209,1171,1110,1093,1071,1053,1033,1012cm
-1 1HNMR (600MHz, CDCl
3): δ 5.07-5.04 (d, J=8.7,1H), 4.96 (s, 1H), 4.73-4.72 (m, 1H), 4.54-4.51 (m, 2H), 4.29-4.27 (m, 1H), 3.99-3.98 (d, J=4.4,1H), 3.78-3.76 (m, 2H), (3.67-3.65 m, 2H), 3.42 (m, 1H), (3.32-3.31 m, 3H), 3.26-3.20 (m, 4H), (3.04-3.00 m, 3H), 3.00-2.99 (m, 1H), (2.89-2.80 m, 1H), 2.33 (s, 5H), (1.93-1.83 m, 3H), 1.69-1.67 (m, 2H), 1.66-1.63 (m, 4H), (1.48-1.47 m, 4H), 1.39-1.38 (m, 3H), 1.20-1.17 (m, 15H), (1.13-1.11 m, 12H), 0.93 (t, 3H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
43H
78N
2O
14846.6; Found (M+H)
+848.2.
4 " O-(n-pentyl) formamyl clarithromycin (target compound (11)) white solid, yield 53.8%, mp135-137 ℃, TLC R
f=0.455 (chloroform/methanol, 5: 1); IR (KBr): 3459,2972,2937,2877,2832,2785,1732,1507,1458,1378,1342,1279,1247,1171,1109,1093,1071,1050,1034,1012cm
-1 1HNMR (600MHz, CDCl
3) δ: 5.07-5.06 (d, J=9.9,1H), 4.97-4.96 (d, J=4.8,1H), 4.55-4.53 (d, J=9.8,1H), (3.98 s, 1H), 3.78-3.74 (m, 2H), (3.69-3.66 m, 1H), 3.31 (s, 3H), (3.25-3.16 m, 4H), 3.04 (s, 3H), (3.00-2.97 m, 1H), 2.89-2.87 (m, 1H), (2.17 s, 1H), 1.93-1.91 (m, 2H), (1.67-1.63 dd, J=15.1, J=5.1,2H), (1.57 s, 15H), 1.50-1.48 (m, 3H), (1.38 s, 3H), 1.34-1.27 (m, 5H), (1.21-1.18 m, 12H), 1.13-1.08 (m, 12H), (0.90-0.85 t, 3H), 0.85-0.83 (t, 3H); MS (ESI) m/z calcd.forC
44H
80N
2O
14860.6; Found (M+H)
+862.5.
B): 4 " the preparation of O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (19))
" O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl-2 '-O-ethanoyl clarithromycin (1.50g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 24h, and evaporated under reduced pressure gets white foam shape solid with 4.(eluent is methylene dichloride to silica gel column chromatography: methyl alcohol=40: 1), get white foam shape solid.Yield 75.7%, mp 120-126 ℃, TLC R
f=0.32 (chloroform/methanol, 10: 1); IR (KBr): 3450,2973,2938,1732,1654,1515,1458,1378,1338,1267,1172,1110,1072,1051,1014cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.14 (t, 1H), 5.07 (dd, J=10.8Hz, J=2.4Hz, 1H), 4.98-4.97 (m, 1H), 4.53-4.52 (m, 2H), (4.32-4.30 m, 1H), 3.99 (m, 1H), (3.79-3.77 m, 2H), 3.69-3.67 (m, 2H), (3.32 m, 2H), 3.29-3.25 (m, 2H), (3.24-3.22 m, 2H), 3.21-3.18 (m, 2H), (3.05 m, 3H), 3.03-2.99 (m, 1H), (2.92-2.89 m, 1H), 2.60-2.53 (m, 2H), (2.44-2.41 m, 2H), 2.30-2.29 (m, 5H), (2.23-2.21 m, 2H), 1.95-1.92 (m, 2H), (1.91-1.82 m, 3H), 1.73-1.63 (m, 5H), (1.55-1.48 m, 2H), 1.40 (s, 3H), (1.26-1.15 m, 12H), 1.14-1.11 (m, 10H), (0.93 t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd.for C
46H
83N
3O
15917.6; Found (M+H)
+919.0.
Compound 12～18,20～22 adopts and embodiment 4b) identical method; but replace embodiment 4a with target product among other corresponding embodiment 4) in 4 " O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin replaces embodiment 4b with corresponding amine) middle Tri N-Propyl Amine.
4 " O-(((benzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (12)) white solid, yield 73.2%, mp 133-142 ℃, TLC R
f=0.33 (chloroform/methanol, 10: 1); IR (KBr): 3449,2973,2938,1731,1662,1513,1456,1378,1337,1266,1171,1110,1073,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.27 (m, 5H), 5.79 (m, 1H), 5.63 (m, 1H), 5.14 (m, 1H), 5.08-5.06 (m, 1H), (4.98-4.97 m, 1H), 4.53 (m, 2H), 4.35 (m, 1H), 3.99 (s, 1H), 3.79-3.74 (m, 3H), (3.68-3.67 m, 2H), 3.39-3.36 (m, 1H), (3.34-3.30 m, 3H), 3.28-3.25 (m, 2H), (3.25-2.90 m, 6H), 2.62-2.52 (m, 2H), (2.44-2.41 m, 1H), 2.31 (m, 4H), (2.25-2.23 m, 1H), 2.21-2.19 (m, 2H), (1.99-1.89 m, 4H), 1.88-1.78 (m, 3H), (1.73-1.67 m, 4H), 1.66-1.64 (m, 1H), (1.61 m, 4H), 1.52-1.34 (m, 5H), (1.26-1.20 m, 6H), 1.20-1.15 (m, 4H), (1.14-1.12 m, 8H), 0.85 (m, 2H); MS (ESI) m/z calcd.forC
50H
83N
3O
15965.6; Fpund (M+H)
+967.0.
4 " O-(((4-luorobenzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (13)) white solid, yield 85.7%, mp 127-132 ℃, TLC R
f=0.35 (chloroform/methanol, 10: 1); IR (KBr): 3449,2974,2939,1731,1662,1514,1459,1378,1346,1248,1173,1110,1072,1050,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.01-7.27 (m, 4H), 5.07 (dd, J=11.4Hz, J=1.8Hz, 2H), 4.98 (d, J=5.4Hz, 1H), (4.54-4.51 m, 2H), 4.42-4.41 (m, 2H), (4.30 m, 1H), 3.99 (s, 1H), (3.79-3.77 m, 2H), 3.68-3.66 (m, 1H), (3.32-3.18 m, 6H), 3.05-2.97 (m, 3H), (2.91-2.89 m, 2H), 2.64-2.52 (m, 1H), (2.44-2.41 m, 1H), 2.32-2.26 (m, 9H), (1.94-1.90 m, 2H), 1.90-1.86 (m, 1H), (1.71-1.63 m, 3H), 1.49 (m, 1H), (1.39 s, 2H), 1.23-1.17 (m, 15H), (1.14-1.11 m, 12H), 0.87-0.84 (t, 3H); MS (ESI) m/z calcd.for C
50H
82FN
3O
15983.6; Found (M+H)
+984.8.
4 " O-(((4-methoxy-benzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (14)) white solid, yield 85.7%, mp 127-132 ℃, TLC R
f=0.35 (chloroform/methanol, 10: 1); IR (KBr): 3391,2972,2937,1732,1656,1537,1459,1379,1340,1267,1172,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.20 (d, J=8.4Hz, 2H), 6.88-6.87 (d, J=9.0Hz, 2H), 5.06 (dd, J=10.8Hz, J=1.8Hz, 1H), (4.97 d, J=4.8Hz, 1H), (4.53-4.51 m, 2H), 4.38-4.37 (m, 2H), 4.32-4.28 (m, 1H), (3.80 s, 3H), 3.78-3.77 (m, 2H), 3.69-3.66 (m, 2H), (3.37-3.36 m, 2H), 3.32 (s, 3H), 3.29-3.25 (m, 2H), (3.22-3.18 m, 2H), 3.05 (s, 2H), 3.02-3.00 (m, 1H), (2.93-2.88 m, 1H), 2.61-2.53 (m, 2H), 2.43-2.41 (m, 1H), (2.30 s, 6H), 2.28-2.24 (m, 1H), 1.94-1.90 (m, 2H), (1.73-1.63 m, 3H), 1.51-1.47 (m, 1H), 1.39 (s, 3H), (1.24-1.19 m, 18H), 1.19-1.10 (m, 9H), 0.85 (t, 3H); MS (ESI) m/z calcd.for C
51H
85N
3O
16995.6; Found (M+H)
+997.1.
4 " O-(((4-leptodactyline) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (15)) white solid, yield 69.2%, mp 135-137 ℃, TLC R
f=0.35 (chloroform/methanol, 10: 1); IR (KBr): 3409,2974,2939,1731,1655,1516,1457,1378,1347,1247,1171,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.06 (d, J=9.6Hz, 2H), 6.77 (d, J=9.6Hz, 2H), 5.07 (d, J=8.4Hz, 1H), 4.97 (m, 2H), 4.52 (m, 2H), 4.30 (m, 2H), (4.23 m, 2H), 3.99 (m, 2H), 3.78 (m, 2H), 3.66 (m, 2H), 3.51 (m, 2H), (3.35 m, 3H), 3.16 (m, 2H), 3.00-3.05 (m, 3H), 2.89 (m, 2H), 2.73-2.78 (m, 3H), (2.45 m, 2H), 2.35-2.44 (m, 6H), 2.12 (m, 2H), 1.92 (m, 2H), 1.75-1.85 (m, 4H), (1.69 m, 5H), 1.40-1.60 (m, 4H), (1.25 m, 2H), 1.18 (m, 3H), (1.13 m, 6H), 1.12 (m, 9H); MS (ESI) m/zcalcd.for C
51H
85N
3O
16995.6; Found (M+H)
+997.1.
4 " O-(((2-chlorobenzene ethyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (16)) white solid, yield 73.1%, mp117-122 ℃, TLC R
f=0.32 (chloroform/methanol, 10: 1); IR (KBr): 3442,2974,2938,1731,1660,1515,1457,1378,1338,1266,1172,1110,1072,1052,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.36-7.35 (m, 2H), 7.27-7.09 (m, 2H), 5.08 (d, J=9.6Hz, 1H), 4.99-4.98 (m, 1H), (4.53-4.50 m, 1H), 4.24 (m, 2H), (3.97 m, 1H), 3.78-3.76 (m, 2H), (3.70-3.67 m, 1H), 3.59-3.52 (m, 3H), (3.31-3.30 m, 3H), 3.25-3.18 (m, 3H), (3.04 m, 3H), 3.00-2.96 (m, 2H), (2.92-2.87 m, 2H), 2.64-2.58 (m, 3H), (2.42-2.40 m, 3H), 2.22-2.18 (m, 3H), (1.97-1.90 m, 3H), 1.85-1.79 (m, 3H), (1.67-1.63 m, 4H), 1.51-1.46 (m, 1H), (1.40-1.38 m, 3H), 1.26 (m, 3H), (1.23-1.19 m, 9H), 1.14-1.13 (m, 6H), (1.09-1.08 m, 6H), 0.89-0.84 (m, 3H); MS (ESI) m/z calcd.for C
51H
84ClN
3O
151013.6; Found (M+H)
+1014.6.
4 " O-(((cyclohexyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (17)) white solid, yield 75.3%, mp 122-126 ℃, TLC R
f=0.30 (chloroform/methanol, 10: 1); IR (KBr): 3415,2973,2935,1732,1650,1540,1454,1379,1348,1257,1171,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.18 (m, 1H), 5.06 (d, J=9.6Hz, 1H), (4.97 m, 1H), 4.53-4.50 (m, 2H), 4.45 (d, J=6.0Hz, 1H), 4.28 (m, 2H), (3.97 s, 1H), 3.77-3.72 (m, 3H), (3.69-3.65 m, 2H), 3.38-3.36 (m, 2H), (3.35-3.29 m, 3H), 3.28-3.24 (m, 4H), (3.17 m, 2H), 3.04 (m, 3H), (3.00-2.99 m, 3H), 2.60 (m, 2H), (2.42-2.18 m, 8H), 1.94-1.84 (m, 6H), (1.72 m, 6H), 1.66 (m, 2H), (1.38 m, 4H), 1.25-1.16 (m, 10H), (1.16-1.10 m, 10H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
49H
87N
3O
15957.6; Found (M+H)
+958.8.
4 " O-(((sec.-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (18)) white solid, yield 75.1%, mp 118-121 ℃, TLC R
f=0.30 chloroform/methanol, 10: 1); IR (KBr): 3450,2973,2938,1732,1654,1515,1458,1378,1338,1267,1172,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.14 (m, 1H), 5.07 (dd, J=10.8Hz, J=1.8Hz, 1H), (4.98-4.97 m, 1H), 4.54-4.52 (m, 2H), 4.32-4.30 (m, 1H), (3.99 m, 1H), 3.82-3.78 (m, 2H), 3.70-3.67 (m, 2H), (3.34-3.32 m, 3H), 3.28-3.25 (m, 2H), 3.21-3.18 (m, 2H), (3.05 m, 3H), 3.03-2.99 (m, 1H), 2.92-2.89 (m, 1H), (2.60-2.56 m, 2H), 2.43-2.41 (m, 2H), 2.36-2.27 (m, 5H), (2.21-2.17 m, 2H), 1.95-1.89 (m, 2H), 1.88-1.82 (m, 3H), (1.72-1.63 m, 5H), 1.50-1.47 (m, 2H), 1.42-1.40 (m, 3H), (1.32-1.24 m, 3H), 1.23-1.22 (m, 7H), 1.20-1.15 (m, 7H), 1.14-1.10 (m, 9H), 0.89-0.84 (m, 3H); MS (ESI) m/z calcd.for C
46H
83N
3O
15945.6; Found (M+H)
+947.2.
4 " O-(((allyl group) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (20)) white solid, yield 74.2%, mp 135-140 ℃, TLC R
f=0.34 (chloroform/methanol, 10: 1); IR (KBr): 3436,2974,2938,1731,1660,1529,1458,1382,1339,1266,1247,1171,1110,1072,1051,1013,986,933cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.85-5.83 (m, 1H), 5.22-5.19 (m, 1H), (5.16-1.15 m, 1H), 5.08-5.06 (m, 2H), (4.98-4.97 m, 1H), 4.54-4.52 (m, 2H), (4.31 m, 2H), 3.99 (s, 2H), (3.90-3.89 m, 2H), 3.79-3.77 (m, 2H), (3.68-3.67 m, 2H), 3.3-3.28 (m, 6H), (3.20-3.18 m, 2H), 3.05-3.00 (m, 3H), (2.91 m, 2H), 2.44-2.41 (m, 2H), (2.28-2.24 m, 6H), 1.94-1.85 (m, 6H), (1.73-1.63 m, 7H), 1.40 (m, 4H), (1.27-1.19 m, 9H), 1.17-1.13 (m, 8H), 0.85 (t, 3H); MS (ESI) m/z, calcd.for C
46H
81N
3O
15915.6; Found (M+H)
+917.0.
4 " O-(((normal-butyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (21)) white solid, yield 77.2%, mp 127-130 ℃, TLC R
f=0.33 (chloroform/methanol, 10: 1); IR (KBr): 3435,2972,2936,1730,1648,1525,1459,1378,1349,1261,1170,1126,1080,1047,1012cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.11 (m, 1H), 5.09 (m, 1H), (4.68 m, 1H), 4.55-4.51 (m, 1H), (3.99-3.98 m, 1H), 3.79-3.76 (m, 2H), (3.69-3.67 m, 2H), 3.31 (m, 6H), (3.05 m, 3H), 3.02-2.99 (m, 2H), (2.94-2.91 m, 2H), 2.82-2.57 (m, 8H), (2.43-2.41 m, 1H), 2.25-2.03 (m, 2H), (2.03 m, 1H), 1.94-1.89 (m, 2H), (1.88-1.80 m, 3H), 1.53-1.46 (m, 5H), (1.39-1.35 m, 9H), 1.28-1.18 (m, 12H), (1.16-1.14 m, 6H), 1.09-1.08 (m, 3H), (0.96-0.92 m, 3H), 0.87-0.85 (m, 3H); MS (ESI) m/z calcd.forC
47H
85N
3O
15931.6; Found (M+H)
+932.9.
4 " O-(((n-pentyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin (target compound (22)) white solid, yield 71.3%, mp 132-136 ℃, TLC R
f=0.35 (chloroform/methanol, 10: 1); IR (KBr): 3450,2973,2938,1732,1654,1515,1458,1378,1338,1267,1172,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.06 (d, J=9.6Hz, 1H), 4.97-2.92 (m, 1H), 4.53-4.51 (m, 3H), 3.99 (s, 1H), 3.81-3.76 (m, 2H), 3.69-3.66 (m, 2H), 3.35-3.30 (m, 3H), 3.28-3.18 (m, 6H), 3.10-3.02 (m, 3H), 3.01-2.92 (m, 1H), 2.91-2.87 (m, 1H), 2.59-2.56 (m, 2H), 2.43-2.38 (m, 1H), 2.32-2.24 (m, 6H), 2.22-2.19 (m, 2H), 2.04-1.90 (m, 2H), 1.88-1.81 (m, 2H), 1.75-1.63 (m, 4H), 1.53-1.45 (m, 3H), 1.41-1.39 (m, 3H), 1.35-1.25 (m, 6H), 1.23-1.19 (m, 9H), 1.16 (m, 3H), (1.17-1.11 m, 10H), 0.89 (t, 3H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
48H
87N
3O
15945.6; Found (M+H)
+947.1.
C): 4 " the preparation of O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (30))
" O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl-2 '-O-ethanoyl clarithromycin (1.45g) is dissolved in the methyl alcohol (15mL), and 55 ℃ are stirred 24h, and evaporated under reduced pressure gets white foam shape solid with 4.(eluent is methylene dichloride to silica gel column chromatography: methyl alcohol=20: 1), get white foam shape solid.Yield 76.3%, mp112-115 ℃, TLC R
f=0.36 (chloroform/methanol, 10: 1); IR (KBr): 3452,2972,2937,1731,1655,1537,1459,1378,1337,1266,1171,1110,1072,1050,1012cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.07 (d, J=10.2Hz, 1H), 4.97-4.96 (m, 1H), 4.57-4.50 (m, 2H), 3.99 (s, 1H), 3.82-3.76 (m, 2H), 3.68-3.59 (m, 2H), 3.36-3.31 (m, 2H), 3.23-3.18 (m, 6H), 3.15-3.09 (m, 1H), 3.05-3.00 (m, 2H), 2.89 (m, 2H), 2.59-2.57 (m, 2H), 2.44-2.41 (m, 1H), 2.31-2.29 (m, 6H), 2.16 (t, 2H), (1.94-1.87 m, 1H), 1.73-1.63 (m, 3H), 1.54-1.48 (m, 3H), (1.40-1.34 m, 4H), 1.27-1.24 (m, 2H), 1.24-1.18 (m, 14H), (1.17-1.11 m, 16H), 0.93 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd.for C
48H
87N
3O
15945.6; Found (M+H)
+947.1; Anal.Calcd.for C
48H
87N
3O
15(946.2) (%): C 60.93, and H 9.27, and N 4.44, and Found (%): C 60.85, and H 9.21, N4.39.
Compound 23～29,30～33 adopts and embodiment 4c) identical method; but replace embodiment 4a with target product among other corresponding embodiment 4) in 4 " O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin replaces embodiment 4b with corresponding amine) middle Tri N-Propyl Amine.
4 " O-(((benzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (23)) white solid, yield 81.3%, mp 115-118 ℃, TLC R
f=0.35 (chloroform/methanol, 10: 1); IR (KBr): 3454,2974,2938,1731,1514,1456,1378,1346,1247,1171,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.35-7.26 (m, 5H), 5.06 (d, J=10.8Hz, 1H), 4.58-4.50 (m, 2H), 4.44-4.43 (m, 2H), 4.30-4.27 (m, 2H), 3.98 (m, 1H), 3.81-3.76 (m, 2H), 3.67-3.63 (m, 2H), 3.35-3.27 (m, 3H), 3.21-3.17 (m, 4H), 3.00-2.98 (m, 2H), 2.90-2.89 (m, 2H), 2.58-2.56 (m, 2H), 2.30-2.29 (m, 7H), 2.22 (t, 2H), 1.94-1.84 (m, 1H), 1.72-1.62 (m, 2H), 1.54-1.46 (m, 8H), 1.39-1.35 (m, 11H), 1.25-1.23 (m, 9H), 1.12-1.10 (m, 9H), 0.84 (t, 3H), MS (ESI) m/z, calcd.for C
52H
87N
3O
15993.6; Found (M+H)
+995.1; Anal.Calcd.for C
52H
87N
3O
155C 62.82, and H 8.82, and N 4.23, and Found (%): C 62.71, H 8.78.N 4.25.
4 " O-(((4-luorobenzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (24)) white solid, yield 73.6%, mp 110-112 ℃, TLC R
f=0.36 (chloroform/methanol, 10: 1); IR (KBr): 3381,2974,2938,1730,1658,1605,1511,1459,1378,1345,1266,1171,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.26-7.24 (m, 2H), 7.04-7.01 (m, 2H), (5.07 dd, J=11.4Hz, J=1.8Hz, 1H), (4.98 m, 1H), 4.41-4.40 (m, 2H), (4.30-4.26 m, 2H), 4.10-4.09 (m, 1H), (3.82-3.76 m, 2H), 3.69-3.59 (m, 2H), (3.23-3.17 m, 8H), 3.05-3.03 (m, 1H), (2.94-2.87 m, 2H), 2.65-2.55 (m, 2H), (2.43-2.41 m, 2H), 2.33 (m, 6H), (2.22-2.20 m, 3H), 1.94-1.92 (m, 1H), (1.72-1.63 m, 3H), 1.55-1.48 (m, 8H), (1.38-1.35 m, 9H), 1.26-1.15 (m, 9H), (1.14-1.12 m, 9H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
52H
86FN
3O
151011.6; Found (M+H)
+1012.8; Anal.Calcd.for C
52H
86FN
3O
15: C 61.70, and H 8.56, and F 1.88, and N 4.15, and Found:C 61.46, and H 8.63, and F 1.83, N 4.18.
4 " O-(((4-methoxy-benzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (25)) white solid, yield 70.1%, mp 120-124 ℃, TLC R
f=0.28 (chloroform/methanol, 10: 1); IR (KBr): 3369,2973,2937,1730,1654,1514,1458,1378,1335,1249,1172,1110,1083,1048,1012cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.21 (d, J=8.4Hz, 2H), 6.88 (d, J=8.4Hz, 2H), 5.07 (d, J=8.4Hz, 1H), 4.39-4.38 (m, 2H), 4.31-4.28 (m, 1H), 4.01 (m, 1H), 3.82-3.81 (m, 3H), 3.79-3.77 (m, 2H), 3.69-3.67 (m, 2H), 3.33-3.32 (m, 3H), 3.29-3.30 (m, 3H), 3.06-2.93 (m, 3H), 2.92-2.89 (m, 2H), 2.61-2.58 (m, 2H), 2.44-2.42 (m, 1H), 2.34-2.31 (m, 6H), 2.22-2.21 (m, 2H), 1.95-1.85 (m, 1H), (1.73-1.63 m, 6H), 1.55-1.48 (m, 4H), 1.43-1.35 (m, 5H), (1.29-1.20 m, 15H), 1.19-1.12 (m, 12H), 0.84 (t, 3H); MS (ESI) m/z calcd.for C
53H
89N
3O
161023.6; Found (M+H)
+1025.2.
4 " O-(((4-leptodactyline) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (26)) white solid, yield 71.2%, mp 129-133 ℃, TLC R
f=0.33 (chloroform/methanol, 10: 1); IR (KBr): 3409,2974,2939,1731,1655,1516,1457,1378,1347,1247,1171,1110,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.05 (d, J=8.4Hz, 2H), 6.77 (d, J=8.4Hz, 2H), 5.07 (d, J=11.4Hz, 1H), 4.99 (m, 1H), 4.74 (d, J=6.6Hz, 1H), 4.50 (d, J=9.6Hz, 1H), 4.20-4.17 (m, 1H), (3.96 m, 1H), 3.88-3.87 (m, 1H), (3.76-3.73 m, 2H), 3.66-3.65 (m, 2H), (3.56-3.55 m, 2H), 3.37-3.28 (m, 6H), (3.21-3.19 m, 3H), 3.09-3.03 (m, 3H), (3.00-2.92 m, 2H), 2.90-2.84 (m, 6H), (2.59-2.56 m, 4H), 2.40 (m, 2H), (1.97-1.91 m, 1H), 1.78-1.73 (m, 3H), (1.67-1.56 m, 3H), 1.51-1.42 (m, 2H), (1.41-1.36 m, 3H), 1.18-1.13 (m, 18H), (1.05-1.03 m, 4H), 0.89-0.83 (m, 6H).
4 " O-(((2-chlorobenzene ethyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (27)) white solid, yield 72.1%, mp 127-131 ℃, TLC R
f=0.31 (chloroform/methanol, 10: 1); IR (KBr): 3446,2973,2934,1730,1651,1534,1459,1378,1348,1264,1170,1110,1082,1053,1011cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 7.37 (m, 1H), 7.29-7.19 (m, 3H), 5.09 (d, J=11.4Hz, 1H), 4.99-4.98 (m, 1H), (4.63-4.62 m, 1H), 4.55-4.53 (m, 1H), (4.24-4.22 m, 1H), 3.99 (m, 1H), (3.79-3.76 m, 4H), 3.69-3.68 (m, 2H), (3.35-3.32 m, 2H), 3.24-3.21 (m, 2H), (3.11-3.05 m, 3H), 3.02-2.97 (m, 2H), (2.94-2.87 m, 2H), 2.65-2.54 (m, 2H), (2.43-2.36 m, 2H), 2.21-2.16 (m, 2H), (2.05-1.92 m, 1H), 1.84-1.80 (m, 1H), (1.72-1.64 m, 3H), 1.55-1.48 (m, 4H), (1.42-1.36 m, 4H), 1.36-1.33 (m, 4H), (1.27-1.25 m, 8H), 1.25-1.20 (m, 15H), (1.19-1.14 m, 8H), 0.91-0.86 (m, 3H); MS (ESI) m/zcalcd.for C
53H
88ClN
3O
151041.6; Found (M+H)
+1043.0.
4 " O-(((cyclohexyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (28)) white solid, yield 79.7%, mp 100-103 ℃, TLC R
f=0.34 (chloroform/methanol, 10: 1); IR (KBr): 3435,2972,1730,1648,1525,1459,1378,1349,1261,1170,1126,1080,1047,1012cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.08-5.06 (m, 1H), 4.98-4.96 (m, 1H), (4.74 m, 1H), 4.54-4.51 (m, 2H), (4.31-4.28 m, 2H), 4.10-4.09 (m, 1H), (3.99-3.97 m, 2H), 3.79-3.74 (m, 1H), (3.69-3.64 m, 2H), 3.33-3.31 (m, 2H), (3.26-3.17 m, 6H), 3.05-2.97 (m, 3H), (2.92-2.88 m, 2H), 2.60-2.57 (m, 2H), 2.44-2.41 (m, 1H), (2.31-2.92 m, 6H), 2.17-2.14 (m, 2H), 1.73-1.63 (m, 7H), (1.54-1.47 m, 6H), 1.40-1.26 (m, 10H), 1.24-1.16 (m, 9H), (1.15-1.12 m, 9H), 1.11-0.90 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd.forC
50H
91N
3O
15973.7; Found (M+H)
+975.0.
4 " O-(((sec.-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (29)) white solid, yield 69.2%, mp 123-127 ℃, TLC R
f=0.29 (chloroform/methanol, 10: 1); IR (KBr): 3377,2973,2933,1730,1643,1544,1460,1382,1349,1266,1170,1127,1082,1046,1011cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.10 (d, J=11.4Hz, 1H), 5.01-5.00 (m, 1H), 4.74-4.73 (d, J=7.2Hz, 1H), (4.59-4.53 m, 1H), 4.12-4.06 (m, 1H), (3.84-3.82 m, 1H), 3.79-3.73 (m, 2H), (3.69-3.68 m, 1H), 3.56-3.53 (m, 1H), (3.38-3.28 m, 6H), 3.27-3.19 (m, 3H), (3.05 m, 2H), 3.01-2.98 (m, 2H), (2.92-2.81 m, 2H), 2.63-2.56 (m, 3H), (2.42-2.40 m, 1H), 2.22-2.16 (m, 3H), (1.95-1.89 m, 1H), 1.88-1.75 (m, 3H), (1.75-1.65 m, 5H), 1.50-1.47 (m, 2H), (1.32-1.24 m, 3H), 1.25-1.19 (m, 15H), (1.19-1.15 m, 9H), 1.14-1.10 (m, 6H), 0.90-0.85 (m, 6H); MS (ESI) m/z calcd.for C
48H
87N
3O
15919.2; Found (M+H)
+919.0.
4 " O-(((allyl group) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (31)) white solid, yield 72.3%, mp 119-122 ℃, TLC R
f=0.38 (chloroform/methanol, 10: 1); IR (KBr): 3454,2974,2939,1731,1664,1514,1458,1378,1339,1266,1171,1110,1072,1051,1013,986,934cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.87-5.82 (m, 1H), 5.20-5.13 (m, 2H), 5.08-5.07 (m, 1H), 4.98-4.97 (m, 1H), 4.56-4.52 (m, 2H), (4.27 m, 1H), 3.98 (s, 2H), 3.89 (t, 2H), 3.68-3.67 (m, 2H), 3.32 (m, 3H), 3.23-3.18 (m, 3H), 3.05 (m, 1H), 3.01 (m, 2H), 2.89 (m, 2H), 2.59 (m, 2H), 2.43-2.41 (m, 7H), 2.22-2.19 (m, 2H), 1.96-1.85 (m, 2H), 1.70-1.63 (m, 4H), 1.55-1.49 (m, 6H), 1.39-1.35 (m, 9H), 1.27-1.24 (m, 2H), 1.22-1.14 (m, 9H), 1.13-1.10 (m, 9H), 0.85 (t, 3H); MS (ESI) m/z, calcd.for C
48H
85N
3O
15943.6; Found (M+H)
+945.0; Anal.Calcd.for C
48H
85N
3O
15: C 61.06, and H 9.07, N4.45, and Found:C 61.12, and H 9.11, N 4.40.
4 " O-(((normal-butyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (32)) white solid, yield 72.0%, mp 102-106 ℃, TLC R
f=0.33 (chloroform/methanol, 10: 1); IR (KBr): 3431,2933,1749,1734,1647,1547,1457,1378,1267,1172,1110,1069,1011cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.08-5.07 (m, 1H), 5.00-4.97 (m, 1H), (4.56-4.53 m, 1H), 4.53-4.47 (m, 1H), (3.83-3.77 m, 1H), 3.74-3.66 (m, 2H), 3.35-3.20 (m, 6H), (3.05-2.98 m, 4H), 2.45-2.37 (m, 7H), 2.32-2.17 (m, 1H), (2.16-1.73 m, 3H), 1.72-1.67 (m, 5H), 1.54-1.43 (m, 4H), (1.43-1.34 m, 6H), 1.33-1.26 (m, 8H), 1.23-1.18 (m, 12H), (1.15-1.12 m, 12H), 0.95-0.91 (m, 3H), 0.89-0.85 (m, 6H); MS (ESI) m/zcalcd.for C
49H
89N
3O
15959.6; Found (M+H)
+961.0.
" O-(((n-pentyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin (target compound (33)) white solid, yield 72.5%, mp 104-107 ℃, TLC R
f=0.34 (chloroform/methanol, 10: 1); IR (KBr): 3391,2936,1731,1656,1536,1459,1378,1343,1247,1171,1111,1072,1051,1013cm
-1 1H NMR (600MHz, CDCl
3) δ (ppm) 5.08-5.06 (m, 1H), 4.98-4.96 (m, 1H), (4.74 m, 1H), 4.54-4.51 (m, 2H), (4.31-4.28 m, 2H), 4.10-4.09 (m, 1H), (3.99-3.97 m, 2H), 3.79-3.74 (m, 1H), (3.69-3.64 m, 2H), 3.33-3.31 (m, 2H), (3.26-3.17 m, 6H), 3.05-2.97 (m, 3H), (2.92-2.88 m, 2H), 2.60-2.57 (m, 2H), 2.44-2.41 (m, 1H), (2.31-2.92 m, 6H), 2.17-2.14 (m, 2H), 1.73-1.63 (m, 7H), (1.54-1.47 m, 6H), 1.40-1.26 (m, 10H), 1.24-1.16 (m, 9H), (1.15-1.12 m, 9H), 1.11-0.90 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd, for C
50H
91N
3O
15973.7; Found (M+H)
+975.0; Anal.Calcd.for C
50H
91N
3O
15C61.64, H 9.41, and N 4.31, and Found:C 61.57, and H 9.37, N 4.35.
Embodiment 5.
The preparation of the amino butyryl of 4--Tri N-Propyl Amine hydrochloride
A): the preparation of ((4-tertbutyloxycarbonyl) amino) butyric acid
γ-aminobutyric acid (1.94g, 15.27mmol) is dissolved in the 1mol/L sodium hydroxide solution of 15.3mL, drips (BOC) that be dissolved in 5mL tetrahydrofuran (THF) (THF)
2O (2.7g, 16.97mmol), stirring at normal temperature 24 hours.Stopped reaction, underpressure distillation evaporates THF, and the 1mol/L citric acid is transferred pH 2～3, ethyl acetate extraction, water layer merges organic layer with the washing of 5mL ethyl acetate.The organic layer that the saturated sodium-chloride water solution washing merges, anhydrous sodium sulfate drying filters, and underpressure distillation gets oily liquids, and vacuum-drying gets the 2.98g white solid, yield 76.0%.R
f=0.32 (developping agent: methylene dichloride: methyl alcohol=10: 1).
B): the preparation of ((4-tertbutyloxycarbonyl) amino) butyryl Tri N-Propyl Amine
With ((4-tertbutyloxycarbonyl) amino) butyric acid (1.5g, 7.35mmol) and HOBt (1.13g, 8.09mmol) be dissolved among the anhydrous THF of 10mL, splash into the DCC (1.67g with the THF dissolving, 8.09mmol), ice bath stirred 8 hours, added the 1.5mL Tri N-Propyl Amine, continue to stir 2h, underpressure distillation gets white solid.The white solid that the 20mL acetic acid ethyl dissolution obtains, suction filtration.25mL 1mol/L citric acid wash filtrate, 50 ℃ of stirring in water bath 0.5h, separatory, water layer 5mL ethyl acetate extraction merges organic layer.The anhydrous sodium sulfate drying organic layer filters, and underpressure distillation gets pressed powder.R
f=0.45 (developping agent: methylene dichloride: methyl alcohol=15: 1).
C): the preparation of the amino butyryl of 4--Tri N-Propyl Amine hydrochloride
((4-tertbutyloxycarbonyl) amino) butyric acid (2.0g, 8.20mmol) is dissolved in the saturated hydrogen chloride solution 10mL of anhydrous ethyl acetate, and stirring at room 2h, suction filtration get white powder end 1.09g, yield 81.3%.R
f=0.53 (developping agent: methylene dichloride: methyl alcohol=15: 1).
Other embodiment adopts the method identical with embodiment 5, but with other aliphatic amide, substituted aroma aliphatic amide, replace the virtue aliphatic amide replacement embodiment 5b that mixes), 5c) in Tri N-Propyl Amine.
Embodiment 6.
The preparation of the amino hexanoyl of 6--Tri N-Propyl Amine hydrochloride
A): the preparation of ((6-tertbutyloxycarbonyl) amino) n-caproic acid
6-aminobutyric acid (2g, 15.27mmol) is dissolved in the 1mol/L sodium hydroxide solution of 15.3mL, drips (BOC)
2The THF solution 5mL's of O (2.7g, 16.97mmol), stirring at normal temperature 24 hours.Stopped reaction, underpressure distillation evaporates THF, and the 1mol/L citric acid is transferred pH 2～3, ethyl acetate extraction, water layer merges organic layer with the washing of 5mL ethyl acetate.The organic layer that the saturated sodium-chloride water solution washing merges, anhydrous sodium sulfate drying filters, and underpressure distillation gets oily liquids, and vacuum-drying gets white solid.
B): the preparation of ((6-tertbutyloxycarbonyl) amino) positive hexanoyl Tri N-Propyl Amine
With ((6-tertbutyloxycarbonyl) amino) butyric acid (1.7g, 7.35mmol) and HOBt (1.13g, 8.09mmol) be dissolved among the anhydrous THF of 10mL, splash into the DCC (1.67g with the THF dissolving, 8.09mmol), ice bath stirred 8 hours, added the 1.5mL Tri N-Propyl Amine, continue to stir 2h, underpressure distillation gets white solid.The white solid that the 20mL acetic acid ethyl dissolution obtains, suction filtration.25mL 1mol/L citric acid wash filtrate, 50 ℃ of stirring in water bath 0.5h, separatory, water layer 5mL ethyl acetate extraction merges organic layer.The anhydrous sodium sulfate drying organic layer filters, and underpressure distillation gets pressed powder.
C): the preparation of the amino positive hexanoyl of 6--Tri N-Propyl Amine hydrochloride
((6-tertbutyloxycarbonyl) amino) positive hexanoyl Tri N-Propyl Amine (2.23g, 8.20mmol) is dissolved in the saturated hydrogen chloride solution 10mL of anhydrous ethyl acetate, and stirring at room 2h, suction filtration get the white powder end.
Other embodiment adopts the method identical with embodiment 6, but with other aliphatic amide, substituted aroma aliphatic amide, replace the virtue aliphatic amide replacement embodiment 6b that mixes), 6c) in Tri N-Propyl Amine.
Claims (3)
1.4 " ''-aralkyl carbamic acid ester clarithomycin derivative has following logical formula II:
Wherein, R
1Represent hydrogen, acetyl or benzoyl base, R
2Represent 4-luorobenzyl, 4-methoxy-benzyl, 4-leptodactyline, 2-chlorobenzene ethyl, 3,4-methylenedioxy benzene ethyl, cyclohexyl, sec.-propyl, n-propyl, allyl group, normal-butyl or n-pentyl; N is 3 or 5.
2. 4 of claim 1 " ''-aralkyl carbamic acid ester clarithomycin derivative it is characterized in that one of following:
(13) 4 " O-(((4-luorobenzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(14) 4 " O-(((4-methoxy-benzyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(15) 4 " O-(((4-leptodactyline) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(16) 4 " O-(((2-chlorobenzene ethyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(17) 4 " O-(((cyclohexyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(18) 4 " O-(((sec.-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(19) 4 " O-(((n-propyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(20) 4 " O-(((allyl group) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(21) 4 " O-(((normal-butyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(22) 4 " O-(((n-pentyl) amino)-4-oxo-normal-butyl) formamyl clarithromycin,
(24) 4 " O-(((4-luorobenzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(25) 4 " O-(((4-methoxy-benzyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(26) 4 " O-(((4-leptodactyline) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(27) 4 " O-(((2-chlorobenzene ethyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(28) 4 " O-(((cyclohexyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(29) 4 " O-(((sec.-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(30) 4 " O-(((n-propyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(31) 4 " O-(((allyl group) amino)-6-oxo-n-hexyl) formamyl clarithromycin,
(32) 4 " O-(((normal-butyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin or
(33) 4 " O-(((n-pentyl) amino)-6-oxo-n-hexyl) formamyl clarithromycin.
3. pharmaceutical composition that is used for bacterial-infection resisting comprises compound and one or more pharmaceutically acceptable carriers or the vehicle of claim 1 or 2.
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| Zhaohai J. Zhu等.Structure-activity relationships of macrolides against Mycobacterium tuberculosis.《Tuberculosis》.2008,第88卷(第suppl.1期),第S49-S63页. * |
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