CN108610388A - A kind of preparation method of macrolide - Google Patents
A kind of preparation method of macrolide Download PDFInfo
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- CN108610388A CN108610388A CN201611135959.1A CN201611135959A CN108610388A CN 108610388 A CN108610388 A CN 108610388A CN 201611135959 A CN201611135959 A CN 201611135959A CN 108610388 A CN108610388 A CN 108610388A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- 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
Then the invention discloses a kind of preparation methods of macrolide directly to dock cyclization with side chain compound again by desugar hydroxyl protection base first, that is, obtain the macrolide.The reaction avoids final step desugar hydroxyl protection base in the prior art and is easy to happen side reaction, generates the defect for the impurity for being difficult to remove and purify.Therefore, macrolide (especially rope Citropten) the product purity higher obtained according to the method for the present invention, side reaction is less, convenient post-treatment, safe operation, is suitble to large-scale production.
Description
Technical field
The invention belongs to medical synthesis fields, are related to a kind of preparation method of macrolide.
Background technology
It is well known that macrolide can be used for treating various infectious diseases, can effectively treat and prevent thin by wide spectrum
Infection caused by bacterium and protozoal pathogens, they apply also for treatment respiratory tract infection and soft tissue infection.Macrolide
Compound is characterized in that there are big lactonic ring, is usually 14 yuan, 15 yuan or 16 membered macrolides, one or more sugar can
It is attached to, including desoxysugar, such as cladinose and desosamine.Erythromycin is the first such chemical combination for introducing clinical practice
Object, molecular structure include 14 membered macrolides of two saccharide parts, and intramolecular includes ketone lactone loop section.Therefore, in ketone
Ester represents a kind of macrolide antibiotics compared with new category, because its absolute acid stability and it is excellent with pharmacological property due to cause many passes
Note.
Rope Citropten (Solithromycin, also known as CEM-101, OPT-1068, CAS No.：760981-83-7) it is
The third generation macrolide antibiotics of Cempra drugmakers exploitation, for treating Community-acquired bacterium pneumonia
(CABP), it is currently in crucial III clinical trial phases.Rope Citropten is to contain fluorine-substituted big ring into clinical first
Lactone drug, and another orally available and intravenous injection administration the macrolide antibiotics after azithromycin, structure
As shown in following formula I A：
It is reported in the prior art about the synthetic route of rope Citropten relatively more.WO 2009055557A1 disclose one
The synthetic route that rope Citropten IA is prepared using clarithromycin as starting material, referring to following routes 1, wherein clarithromycin is logical first
The sugared hydroxyl of acyl group (such as benzoyl Bz) protection is crossed, then anti-with the hydroxy activating reagent carbonyl dimidazoles (CDI) with steric hindrance
Intermediate CL-1 should be generated；Then the oxazole ring intermediates of containing nitrine CL-2 is generated with nitrine butylamine；Later in acid condition
One of glycosyl is removed, intermediate CL-3 is formed；Then it uses oxidant to be aoxidized the hydroxyl formed after glycosyl is removed, is formed
Intermediate CL-4；Then F substitutions are carried out at ortho position by fluorination reaction, forms intermediate CL-5；Finally three are formed with aromatic alkyne
Nitrogen azoles, and sugared hydroxyl protection base is sloughed, form target rope Citropten IA.WO 2010048599A1 have carried out one to the route
It sets the tone whole, i.e., during preparing CL-2 from CL-1, uses 4- amino butanols for raw material, hydroxyl is then converted to azido
Group, then by former route reaction.However the process route still takes off since reaction step is longer, and to containing azide intermediate
The reactions such as sugar, oxidation are all risky operation (azido compound is all to be easy explosion and toxic compound)；Simultaneously among nitrine
Side reaction is more in the step of body generates five-membered ring triazole with acetylenic by cyclization, thus it is extensive raw to be not suitable for industrialization
Production.
WO 2014145210A1 are optimized above-mentioned route to reduce reaction step, as shown in Scheme 2, adopt
With the raw material mode for being introduced directly into included side chain five-membered ring triazole.Specifically synthesis step includes：It is prepared by clarithromycin
Then intermediate CL-1 is docked with five-membered ring triazole side chain, Xing Cheng oxazole rings intermediate (wherein CP is amino, protects amino,
Or nitro), then pass through desugar, oxidation, fluorination successively, finally take corresponding method to form it into according to CP groups
Amino obtains rope Citropten IA.Although the route without introduce azido, again with alkynes carry out cyclization step, reduce reaction step
Suddenly, but with the increasing of reaction raw materials and moiety intermediate molecular weight, reaction raw materials and moiety intermediate are reduced organic
Solubility in reaction, affects post-reaction treatment, and side chain five-membered ring triazole needs to be subjected to desugar, oxidation,
More side reaction is easy tod produce, thus is difficult large-scale production.
The preparation method that CN 104650166A disclose another rope Citropten is used and is first taken off shown in following route 3
Intermediate II is prepared after glycoxidative, then uses 2 identical mode of above-mentioned route, shape is docked with five-membered ring triazole side chain
At oxazole ring, most afterwards after fluoro, desugar hydroxyl protection base, rope Citropten IA is formed.This method avoid side chain five-membered rings three
Nitrogen azoles is subjected to desugar, oxidation step, reduces the generation of side reaction.But due to the compound intermediate II after desugar, oxidation
Than intermediate CL-1 poor solubilities, cause reaction difficult, conversion ratio is low；Moreover, exposed amino when Deprotection, can produce
Formula 1,2 impurity of formula are given birth to, the two impurity are that with methyl benzoate (or methyl acetate) acylated pair occurs for amino triazole side chain
It is generated when reaction, not only lead to cost increase due to consuming amino side chain, and the more difficult purifying of the by-product influences most more
The final product quality of finished product rope Citropten IA.
Invention content
In order to reduce danger and/or murder by poisoning in existing macrolides compound (especially rope Citropten) synthetic route
Operating procedure reduces the generation of side reaction, improves the quality and reaction efficiency of target product, reduces production cost, realizes industry
Change large-scale production, the present invention provides the synthesis route of a new macrolide, to make up the deficiencies in the prior art.
The present invention realizes above-mentioned purpose using following technical scheme.
Specifically, the present invention provides a kind of preparation method of improved macrolide, and synthetic route is as follows, wherein
Make formula III compound desugar hydroxyl protection first, obtain formula IV compound, then docks ring closure reaction through side chain again, that is, obtain
Macrolide shown in formula I.The reaction avoids desugar hydroxyl protection generation side reaction again after docking cyclization in the prior art,
Generate the defect for the impurity for being difficult to remove and purify.Therefore, the Macrocyclic lactone compounds obtained according to the method for the present invention are (especially
Rope Citropten IA) product purity higher, side reaction is less, convenient post-treatment, safe operation, is suitble to large-scale production.
Wherein R is sugared hydroxyl protection base, such as acyl protecting groups, such as substituted or unsubstituted alkyl acyl, aryl-acyl,
Heteroaroyl, aralkyl acyl group or heteroarylalkyl acyl group, the substituent group are C1-C4Alkyl or halogen, R are preferably benzoyl
Base or acetyl group.
X is H；Y is OR1, wherein R1It is H, monosaccharide, disaccharides, polysaccharide or alkyl, such as includes protection or unprotected 2 '-hydroxyl
The monosaccharide of base, protecting group therein are steric hindrance acyl group, such as substituted or unsubstituted alkyl acyl, aryl-acyl, heteroaryl
Base acyl group, aralkyl acyl group or heteroarylalkyl acyl group, the substituent group are C1-C4Alkyl or halogen；Or X, Y with connect
Carbon forms carbonyl-C=O together.
W is H, halogen or OH, preferably halogen, such as F, Cl, Br, I, more preferably F or Cl.
A, B forms-(CH together2)n, wherein n be 1~10 integer, preferably 1~4 integer, more preferably 1,2,3 or
4；Or A, B form the unsaturated alkyl comprising 2~10 carbon, preferably 2~5 carbon together.
C is substituted or unsubstituted aminoaryl, azyl aryl alkyl or alkylaminoaryl, and the substituent group is C1-C4
Alkyl or halogen, C are preferably aminophenyl, aminobenzyl, Methylaminophenyl.
The desugar hydroxyl protection refers to removing the hydroxyl protection base in sugar unit segment, can taking in carbohydrate chemistry
The mode of some conventional desugar protecting groups carries out, such as formula III compound is sloughed sugar under alcoholic solvent, room temperature to counterflow condition
Hydroxyl protection base obtains formula IV compound.The alcoholic solvent is selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol.
Side chain dock ring closure reaction in, formula IV compound can by with Formula V A compounds through side chain dock ring closure reaction come
Preparation of compounds of formula I.
Wherein CP be amino, amino protecting group or nitro, the amino protecting group be selected from Boc, BsMoc, Trityl or
MeOTrityl, A, B are as defined above.
When CP is amino, formula IV compound and Formula V A compounds progress side chain dock ring closure reaction, and to directly obtain Formulas I big
Cyclic lactone.
When CP is amino protecting group, formula IV compound with Formula V A compounds after side chain docks ring closure reaction, then deamination
Base protecting group is to get Formulas I macrolide.Amino protecting group is generally wherein removed using acidolysis reaction, wherein reaction temperature is 20
DEG C~50 DEG C, the reaction time is about 0.5h~10h.The acid of the acidolysis reaction is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrogen bromine
Acid；The method for realizing the deamination protecting group of the application can also be its other party that those skilled in the art can be readily accomplished the present invention
Method, it is not limited to this.
When Cp be nitro when, formula IV compound with Formula V A compounds after side chain docks ring closure reaction, catalytic hydrogenating reduction
Nitro is amino to get Formulas I macrolide.The molar ratio of its compound of formula IV and Formula V A compounds is 1:1~3.It is preferred that 1:1
~2.The catalyst of the catalytic hydrogenation is selected from palladium carbon or Raney's nickel, preferably palladium carbon, and dosage is the 10wt% of formula IV compound, is added
Hydrogen pressure is normal pressure to 10Mpa, preferably normal pressure；Reaction dissolvent is selected from alcohols, esters or ethers, and preferably alcohols, wherein alcohols is molten
Agent is selected from methanol, ethyl alcohol or the preferred methanol of isopropanol, and esters solvent is selected from ethyl acetate or isopropyl acetate ethyl acetate,
Ether solvent is selected from ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran or the preferred tetrahydrofuran of 2- methyltetrahydrofurans.Reaction temperature is
20 DEG C~80 DEG C, reaction time 1h~10h.Realize that the nitro reduction of the application can also be those skilled in the art and can be readily accomplished
Other reduction nitro methods of the present invention, it is not limited to this.
Alternatively, formula IV compound can react Xian Xing Cheng oxazole ring intermediates with Formula V B compounds, then again with alkine compounds
(such as 3- amino phenylacetylene) carries out ring closure reaction, obtains Formulas I macrolide.
Wherein R2For azido, A, B are as defined above.
The docking ring closure reaction can carry out in organic solvent, and the organic solvent is selected from tetrahydrofuran, acetonitrile, N, N-
Dimethylamino formamide, dimethyl sulfoxide (DMSO), dichloromethane, toluene, preferably acetonitrile.
The docking ring closure reaction can also react in mixed system of the above-mentioned organic solvent with water, the organic solvent with
The volume ratio of water is 1~10:1, preferably 2:1；It is preferred that the mixed system is the mixed system of acetonitrile/water, the volume ratio of the two
It is 1~10:1, preferably 2:1.
The docking ring closure reaction time is 0.5h~16h, preferably 2~8h；, 50 DEG C of reaction temperature~100 DEG C, preferably 50
DEG C~80 DEG C.
The docking ring closure reaction can carry out under the promotion of organic base, and the organic base is selected from 1,8- diazabicylos ten
One carbon -7- alkene (DBU), dicyclohexylcarbodiimide (DCC), N, N- lutidines amine (DMAP), triethylenediamine
(DABCO) or 1, one or more, the preferably DBU in 5- diazabicyclos [4.3.0] -5- nonenes (DBN).
Formula III compound can the root prior art obtain, such as include but not limited to：Formula II compound is generated through halogenating reaction
Formula III compound, reaction equation are as follows：
Wherein R, X, Y, W are as defined above.
The halogenating reaction includes but not limited to fluoro-reaction, and the fluoro reagent used can be selected from：The double benzene sulfonyls of N- fluoro
The fluoro- benzene disulfonic acid amide of amine, N- or the double tetraphydro-borates of the fluoro- 4- hydroxyls of 1--Isosorbide-5-Nitrae-diaza-bicyclo [2,2,2] octane, preferably N- fluorine
Generation double benzsulfamides.The molar ratio of fluoro reagent and Formula II compound is 1:1~2, preferably 1:1.2~1.5.The fluoro-reaction
It is carried out at a temperature of -78 DEG C~30 DEG C, preferably -20~0 DEG C；Reaction time 0.5h~4h, preferably 2~3h.
The organic solvent that the fluoro-reaction uses is selected from tetrahydrofuran, 2- methyltetrahydrofurans, toluene, 1,4- dioxies six
It is one or more in ring, n,N-Dimethylformamide, ethyl acetate or isopropyl acetate, preferably n,N-Dimethylformamide with
The mixed system of tetrahydrofuran.
The fluoro-reaction preferably carries out under alkaline condition, such as selected from potassium carbonate, saleratus, sodium carbonate, carbon
Sour hydrogen sodium, cesium carbonate, potassium tert-butoxide, tert-butyl alcohol lithium, sodium methoxide, sodium ethoxide, sodium hydrogen or two (trimethyl silicon substrate) Sodamides
(NaHMDS), it is carried out in the presence of one or more alkaline matters in 1,8- diazabicylos, 11 carbon -7- alkene (DBU), it is excellent
Select potassium tert-butoxide.
The Formula II compound of above-mentioned reaction can the root prior art obtain, such as include but not limited to：It is with clarithromycin
Beginning material, after sugared hydroxyl protection, shape compound of formula II under the action of carbonyl dimidazoles (CDI).The following institute of synthetic route
Show：
Wherein R, X, Y are as hereinbefore defined.As W=H, Formula II compound is formula III compound, however, for side
Just it for the sake of, is still indicated in the present invention with Formula II compound.
In one embodiment of the invention, what the synthesis of the compound of formula I was optional further includes desugar, aoxidizes instead
It answers.The desugar, oxidation reaction refer to the sugar unit sloughed in acid condition in intermediate molecule, then use chloro-chromic acid
Pyridiniujm (PCC) or polite oxidation carry out oxidation reaction, and the hydroxyl on macrolide is oxidized to carbonyl.The desugar, oxidation
Reaction can be in the reaction incipient stage, such as will be carried out after clarithromycin sugar hydroxyl protection, after desugar, oxidation, in two miaow of carbonyl
Shape compound of formula II under the action of azoles (CDI).Alternatively, the desugar, oxidation reaction can also in the reaction phase or later stage carry out,
Such as after closing compound of formula II, either closes compound of Formula III and carry out or close later the laggard of compound of formula IV
Row, such as including but not limited to following reaction route：
Above compound is further through desugar, oxidation, production IA rope Citroptens after fluoro-reaction.
In addition, halogenated (fluoro) reaction is not limited to carry out before desugar hydroxyl protection reacts, optional, may be used also
It before the reaction of desugar hydroxyl protection or side chain docking ring closure reaction, carries out later or between them, as long as this hair can be realized
Bright technical solution obtains target compound of formula I (especially Formulas I A ropes Citropten).
The present invention by first dehydroxylation protecting group, then dock cyclization mode synthesize Formulas I macrolide (especially Suo Li it is mould
Plain IA), the impurity for being difficult to purify and remove is generated when avoiding final step dehydroxylation protecting group in the prior art.According to this hair
Target product macrolide I (especially rope Citropten IA) purity higher that bright method obtains, yield is more preferable, and side reaction is few,
Convenient post-treatment, safe operation are suitble to large-scale production.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are only used for illustrating mesh
, rather than limiting the invention.In addition, it should also be understood that, after the design for having read the present invention, those skilled in the art couple
Its various changes made or adjustment, should all fall within the scope of protection of the present invention, such equivalent forms also belong to the application
The appended claims limited range.
In addition to dated actual conditions, each test method in embodiment can be carried out conventionally.
Additive amount, content and the concentration of many kinds of substance is referred to herein, shown in percentage composition, except illustrate
Outside, all refer to mass percentage.
It in embodiment hereof, is illustrated if do not made for reaction temperature or operation temperature, the temperature is usual
Refer to room temperature (20~25 DEG C).
Herein, for the sake of brevity, Formula II compound is referred to as " compound II ", " chemical combination shown in Formula II sometimes
Object ", " intermediate shown in Formula II ", or " intermediate II ", they all refer to the compound that number is II, and wherein II refers to compound
Number/code, such as I, II, III, IV, V, VI, A, B, C, D etc..Similarly, macrolide is become into macrolide sometimes herein
I or Formulas I macrolide, they indicate identical meaning.
Unless otherwise indicated, refer to optionally replacing or not taking when term " aryl " is independent or is used in conjunction with other groups
The aromatic ring systems in generation.Term aryl includes monocyclic aromatic rings and more aromatic rings.The example of aryl includes but not limited to phenyl, biphenyl
Base, naphthalene and anthryl loop system.
Unless otherwise indicated, when term " heteroaryl " is independent or is used in conjunction with other groups, it includes one or more to refer to
The aromatic ring system of a hetero atom such as oxygen, nitrogen, sulphur, selenium and phosphorus.Term heteroaryl may include 5- or 6- circle heterocyclic rings, polycyclic hetero-aromatic ring
System and more heterocyclic ring systems.
As described herein, term " aralkyl " is equal to term aryl alkyl, and indicates one that is connected to moieties
Or multiple substituted or unsubstituted monocycles or polycyclic aromatic ring；Illustrative example includes but not limited to benzyl, diphenyl methyl, three
Benzyl, 2- phenylethyls, 1- phenylethyls, 2- pyridylmethyls, 4,4 '-dimethoxytrityls etc..
Unless otherwise indicated, term " sugar " includes the monosaccharide, disaccharides and polysaccharide being optionally substituted or unsubstituted, such as including
The sugar and desoxysugar optionally replaced by amino, amide groups, ureyl, halogen, nitrile or azido.Illustrative example includes glucose
Amine, N- acetyl glucosamines, desosamine, forosamine, sialic acid etc..
Unless otherwise indicated, term " alkyl " refers to the straight of 1-20 (such as 1~10, preferably 1~4) a carbon atom
The alkyl of chain, branch and/or ring-type (" naphthenic base "), wherein the moieties with 1~4 carbon are referred to as " low alkyl group ".
Burn base example include but is not limited to, methyl, ethyl, propyl, isopropyl, normal-butyl, tertiary butyl, isobutyl group, defend base, oneself
Base, isohesyl, heptyl, 4,4- pendimethalin bases, octyl, 2,2,4- trimethylphenyls, nonyl, decyl, undecyl and dodecane
Base.Cycloalkyl moiety may be monocyclic or polycyclic, and include but not limited to, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene
Base and adamantyl.Other examples of moieties include the alkyl for having branch, branch and/or annulus, such as 1- second
Base -4- methyl-cyclohexyl bases.In addition, term " alkyl " includes saturated hydrocarbyl and alkenyl and alkynyl moiety.
The preparation (R=-AcO) of -1 compound of 1 formula III of embodiment
- 1 compound of Formula II (2.90mmol) that 2.05g acetyl group is protected is dissolved in the mixed solution of 20ml DMF/THF
In (9:1), under the conditions of -20 DEG C, 0.39g potassium tert-butoxides (3.48mmol) are added portionwise, after, by the mixture at -20 DEG C
Then lower stirring 0.5 hour is added 1.01g NFSI (the double benzsulfamides of N- fluoro) (3.19mmol), finishes, continue -20 DEG C instead
Answer two hours.It samples HPLC detections after completion of the reaction, a small amount of water quenching is added and goes out reaction, with 50ml ethyl acetate diluting reactions
Then liquid uses saturated common salt water washing repeatedly (50ml/ time), anhydrous sodium sulfate drying, filtering to be spin-dried for obtaining crude product (can directly use
In in next step).Crude product purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) by column chromatography, and 4L ethyl acetate is eluant, eluent, is obtained
1.57g foamy white solids III-1 (yield 74.7%).
ESI (M+1)=724
The preparation of -1 compound of 2 formula IV of embodiment
7.23g compounds III-1 (0.01mol) is dissolved in 100ml methanol, is stirred overnight at room temperature.Sample detection is reacted
After completely, the solvent of reaction solution is evaporated off, obtains white solid 7g, crude product can be directly used in next step.Crude product is purified through column chromatography
(silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% triethylamine be eluant, eluent, obtain 5.78g bubble
Foam shape white solid IV-1 (yield 85%).
ESI (M+1)=682.
Preparation (the Cp=-NH of 3 Formulas I A rope Citroptens of embodiment2)
- 1 compound of 6.82g formula IVs (0.01mol) and 6.93g Formula V A-1 compounds (0.03mol) are mixed in 100ml second
Nitrile:Water=9:In 1, above-mentioned mixed liquor heated overnight at reflux.Sample detection stops heating after the reaction was complete, waits for that reaction solution cools down
To room temperature, organic solvent is evaporated off, 50ml water is added to dilute, dichloromethane 20ml*3 extractions merge organic phase, and anhydrous sodium sulfate is dry
It is dry, it filters, is spin-dried for, column chromatography purifying, (silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% 3
Ethamine is eluant, eluent, obtains 6.34g foamy white solids, i.e. rope Citropten IA (yield 75%).
ESI (M+1)/2=423.
The preparation (R=-BzO) of -2 compound of 4 formula III of embodiment
- 2 compound of Formula II (3.84g, 0.005mol) being dissolved in DMF (20ml), nitrogen displacement, reaction solution is cooled to-
25℃.Potassium tert-butoxide (0.84g, 0.0075mol, 1.5eq) is added, after, react 1h in -20~-25 DEG C.It is added portionwise
NFSI (2.5g, 0.0075mol, 1.5eq), after, react 1h in -20~-25 DEG C.Sample detection raw material is after the reaction was complete,
Ice water 60ml is added dropwise, temperature control is no more than 10 DEG C, there is solid precipitation.After being added dropwise, 15min is stirred, is filtered, ice water elution.Filter
Cake is dissolved in 50ml ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, is spin-dried for, column chromatography purifying obtains
3.14g white solids III-2 (yield 80%).
MS=786.
The preparation of -1 compound of 5 formula IV of embodiment
- 2 compound of 7.86g formula IIIs (0.01mol) is dissolved in 100ml methanol, is stirred overnight at room temperature.Sample detection is anti-
After answering completely, the solvent of reaction solution is evaporated off, obtains white solid 7g, crude product can be directly used in next step.Crude product is pure through column chromatography
Change (silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% triethylamine be eluant, eluent, obtain 5.44
Gram foamy white solid IV-1 (yield 80%).
ESI (M+1)=682.
The preparation (Cp=amino protecting groups-NHBoc) of 6 Formulas I A rope Citroptens of embodiment
By compound IV-1 (3.4g, 0.005mol), Boc protection amino side chain VA-2 (4.96g, 0.015mol, 3eq),
Acetonitrile (20ml), water (2ml) mixing, under nitrogen protection, the heating reaction 6h at 55-60 DEG C.The reaction was complete for sample detection, rotation
Dry reaction liquid, column chromatography purifying.(silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% triethylamine
For eluant, eluent, 3.3g foamy white solids, i.e. VI-1 compounds, yield 70% are obtained.
The VI-1 compound solids of above-mentioned 3.3g are dissolved in the dichloromethane DCM of 50ml, addition trifluoracetic acid (1.14g,
0.01mol, 3eq), 4h is stirred to react at 20~25 DEG C.It is spin-dried for reaction solution, is diluted with water, pH=8~9, DCM (30ml* are adjusted
3) it extracts, merges organic phase, anhydrous sodium sulfate drying is filtered, is spin-dried for, and column chromatography purifying obtains IA rope Citropten white solids
1.97g, yield 70%.
MS=423 [(M+2)/2].
Preparation (the Cp=-NH of 7 Formulas I A rope Citroptens of embodiment2)
In reaction bulb be added compound IV-1 (6.81g, 0.01mol), nitrine butylamine (2.28g, 0.02mol, 2eq),
Acetonitrile:Water=1:1 (40ml) reacts overnight at 55~65 DEG C.Sample detection compound IV-1 is removed under reduced pressure molten after the reaction was complete
Agent, residue add water (50ml) to dilute, and ethyl acetate (50ml*2) extraction merges organic phase, washed with saturated salt solution (30ml)
It washs, anhydrous sodium sulfate drying is filtered, is spin-dried for, and column chromatography purifying obtains white solid 5.46g, i.e. -2 compound of Formula IV, yield
75%, MS (M+1)=728.
Intermediate VI-2 (6.4g, 0.0088mol) is added in reaction bulb, is dissolved in 30ml ethyl acetate, ammonia between addition
Base phenylacetylene (1.24g, 0.0106mol, 1.2eq), water 30ml, sodium ascorbate (0.87g, 0.0044mol, 0.5eq), stirring
The aqueous solution (cupric sulfate pentahydrate, 0.44g, 0.00176mol, 0.2eq, 25ml water) of copper sulphate is added dropwise in dissolved clarification.Drop finishes, and room temperature is stirred
It mixes overnight.Sample detection intermediate compound IV -2 filters reaction solution through diatomite, filtrate liquid separation, water phase acetic acid second after the reaction was complete
Ester (30ml*2) extracts, and merges organic phase, and anhydrous sodium sulfate drying is filtered, is spin-dried for, column chromatography purifying (silica gel 200-300 mesh,
The Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% triethylamine be eluant, eluent, obtain 5.2 grams of foamy white solids, i.e.,
Rope Citropten IA (yield 70%).
ESI (M+1)/2=423.
Preparation (the Cp=-NO of 8 Formulas I A rope Citroptens of embodiment2)
By compound IV-1 (3.4g, 0.005mol), nitro side chain VA-3 (4.96g, 0.015mol, 3eq), acetonitrile
(20ml), water (2ml) mixing, under nitrogen protection, the heating reaction 6h at 55-60 DEG C.The reaction was complete for sample detection, is spin-dried for anti-
Liquid is answered, purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) through column chromatography, 4L dichloromethane:Methanol=30:1 and 1% triethylamine be
Eluant, eluent obtains 2.62g foamy white solids, i.e. -3 compound of Formula IV, yield 60%.
- 3 compound 2.62g solids of above-mentioned Formula IV are dissolved in 100ml THF, 10% palladium carbon (200mg) are added, hydrogen is set
It changes, 6h is stirred to react in 20~25 DEG C.The reaction was complete for sample detection, filters out palladium carbon, is spin-dried for reaction solution, and crude product is tied again with methanol
Crystalline substance obtains IA rope Citropten white solids 1.26g.
MS=423 [(M+1)/2].
The preparation of -2 compound of 9 formula IV of embodiment
7g compounds II-1 (0.01mol) is dissolved in 50ml methanol, is stirred overnight at room temperature.The reaction was complete for sample detection
Afterwards, the solvent of reaction solution is evaporated off, crude product purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) through column chromatography, 4L dichloromethane:Methanol
=30:1 and 1% triethylamine be eluant, eluent, obtain 4.77g foamy white solids, i.e. formula IV -2 (yield 72%).
ESI (M+1)=664.
The preparation of -1 compound of 10 formula IV of embodiment
- 2 compound of 6.6g formula IVs (0.01mmol) is dissolved in (9 in the mixed solution of 20ml DMF/THF:1), -20 DEG C
Under the conditions of, 1.34g potassium tert-butoxides (0.012mmol) are added portionwise, after, which is stirred into 0.5h at -20 DEG C.So
The mixed liquor that 3.47g NFSI (0.011mmol) are dissolved in 20ml DMF is added dropwise afterwards, finishes, continues -20 DEG C of two hours of reaction.It takes
Sample HPLC detection reaction finishes, and a small amount of water quenching reaction of going out is added and then uses saturated common salt with 50ml ethyl acetate dilute reaction solutions
Repeatedly (50ml/ times), anhydrous sodium sulfate drying, filtering is spin-dried for obtaining crude product (can be directly used in next step) water washing.Crude product passes through
Cross column chromatography purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane：Methanol=30：1 is eluant, eluent, obtains 4.56g
Foamy white solid IV-1 (yield 67%).
LC-MS M+1=664.
The preparation of 11 Formulas I A rope Citroptens of embodiment
- 2 compound of 6.63g formula IVs (0.01mol) and 6.93g Formula V A-1 compounds (0.03mol) are mixed in 100ml second
Nitrile:Water=9:In 1, above-mentioned mixed liquor heated overnight at reflux.Sample detection stops heating after the reaction was complete, waits for that reaction solution cools down
To room temperature, organic solvent is evaporated off, 50ml water is added to dilute, dichloromethane 20ml*3 extractions merge organic phase, and anhydrous sodium sulfate is dry
It is dry, it filters, is spin-dried for, column chromatography purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L dichloromethane:Methanol=30:1 and 1% 3
Ethamine is eluant, eluent, obtains 5.78 grams of foamy white solids (yield 70%).LC-MS (M+1)/2=414.
The 5.78g foamy white solids (0.007mmol) of above-mentioned acquisition are dissolved in 20ml DMF solutions, -20 DEG C
Under the conditions of, 0.94g potassium tert-butoxides (0.0084mmol) are added, after, which is stirred 1 hour at -20 DEG C.Then
The mixed liquor that 2.65g NFSI (0.0084mmol) are dissolved in 20ml DMF is added dropwise, temperature control is less than -20 DEG C.It finishes, continues -20 DEG C instead
Answer two hours.Sampling HPLC detection reactions finish, and a small amount of water quenching is added and goes out reaction, with 50ml ethyl acetate dilute reaction solutions,
Then saturated common salt water washing is used repeatedly (50ml/ time), anhydrous sodium sulfate drying is filtered to be spin-dried for obtaining crude product and (be can be directly used for
In next step).Crude product purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) by column chromatography, 4L dichloromethane:Methanol=30:1 is to wash
De- agent, obtains 4.26g foamy white solids, i.e. rope Citropten IA (yield 72%).
ESI (M+1)/2=423.
Claims (14)
1. a kind of preparation method of macrolide, which is characterized in that include the following steps：Make formula III compound desugar hydroxyl first
Base protecting group obtains formula IV compound, then docks ring closure reaction through side chain again, that is, obtains macrolide shown in formula I；Its
Reaction equation is as follows：
Wherein R is sugared hydroxyl protection base, preferably acyl protecting groups；
X is H；Y is OR1, wherein R1It is monosaccharide, disaccharides, polysaccharide or the alkyl of H, protection or unprotected 2 '-hydroxyl；Or X, Y
With carbonyl-C=O is formed together with the carbon connected；
W is H, halogen or OH, preferably halogen；
A, B forms-(CH together2)n, integer or A, B that wherein n is 1~10 form the unsaturation for including 2~10 carbon together
Alkyl；
C is substituted or unsubstituted aminoaryl, azyl aryl alkyl or alkylaminoaryl, and the substituent group is C1-C4Alkyl
Or halogen.
2. according to the method described in claim 1, it is characterized in that, preferably, R is benzoyl or acetyl group；X is H；Y is
OR1, R1Monosaccharide or X, Y for protection or unprotected 2 '-hydroxyl form carbonyl together with the carbon connected；W is F or Cl；
A, B forms-(CH together2)n, wherein n be 1~4 integer；C is aminophenyl, aminobenzyl, Methylaminophenyl.
3. according to the method described in claim 1, it is characterized in that, formula III compound is under alcoholic solvent, room temperature to counterflow condition
Sugared hydroxyl protection base is sloughed, formula IV compound is obtained；The alcoholic solvent is selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol.
4. according to the method described in claim 1, it is characterized in that, formula IV compound docks pass with Formula V A compounds through side chain
Ring obtains Formulas I macrolide,
Wherein CP is amino, amino protecting group or nitro, and A, B are as described in claim 1；
When CP is amino, formula IV compound is directly reacted with Formula V A compounds obtains Formulas I macrolide；
When CP is amino protecting group, formula IV compound with Formula V A compounds after side chain docks cyclization, then deamination protecting group,
Obtain Formulas I macrolide；Or
When Cp is nitro, for formula IV compound with Formula V A compounds after side chain docks cyclization, catalytic hydrogenating reduction nitro is ammonia
Base obtains Formulas I macrolide.
5. according to the method described in claim 1, it is characterized in that, formula IV compound first with Formula V B compounds are counter answers Sheng Cheng Evil
Then azoles ring intermediate obtains Formulas I macrolide with alkynes ring closure reaction again,
Wherein R2For azido, A, B are as described in claim 1.
6. according to Claims 1 to 5 any one of them method, which is characterized in that the side chain docks cyclization step organic
It is carried out in the mixed system of solvent or organic solvent and water, the organic solvent is selected from tetrahydrofuran, acetonitrile, N, N- diformazan ammonia
Base formamide, dimethyl sulfoxide (DMSO), dichloromethane, toluene；The volume ratio of the organic solvent and water is 1~10:1.
7. according to Claims 1 to 5 any one of them method, which is characterized in that the side chain docking ring closure reaction time is
0.5h~16h, 50 DEG C~100 DEG C of reaction temperature.
8. according to the method described in claim 1, it is characterized in that, optional, further include halogenating reaction, it is anti-to preferably include fluoro
Answer, the fluoro-reaction desugar hydroxyl protection react or side chain docking ring closure reaction before, carry out later or between them.
9. according to the method described in claim 8, it is characterized in that, the fluoro reagent that the fluoro-reaction uses is selected from N- fluoro
The fluoro- benzene disulfonic acid amide of double benzsulfamides, N- or the double tetraphydro-borates of fluoro- 4- hydroxyls -1,4- diaza-bicyclos [2,2,2] octanes of 1-.
10. according to the method described in claim 8, it is characterized in that, the organic solvent that the fluoro-reaction uses is selected from tetrahydrochysene
In furans, 2- methyltetrahydrofurans, toluene, 1,4- dioxane, N,N-dimethylformamide, ethyl acetate or isopropyl acetate
One or more, the preferred mixed system of n,N-Dimethylformamide and tetrahydrofuran.
11. according to the method described in claim 8, it is characterized in that, the fluoro-reaction preferably carries out under alkaline condition, example
Such as selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, tert-butyl alcohol lithium, sodium methoxide, ethyl alcohol
It is carried out in the presence of one or more alkaline matters in sodium, sodium hydrogen, NaHMDS or DBU.
12. according to the method described in claim 8, it is characterized in that, the fluoro-reaction at a temperature of -78 DEG C~30 DEG C into
Row, reaction time are 0.5h~4h.
Further include desugar, oxidation reaction 13. according to the method described in claim 1, it is characterized in that, optional, it is described de-
Sugar, oxidation reaction desugar hydroxyl protection react or side chain docking ring closure reaction before, carry out later or between them.
14. according to the method for claim 13, which is characterized in that the desugar, oxidation reaction refer in acid condition
The sugar unit in intermediate molecule is sloughed, then uses pyridinium chloro-chromate or polite oxidation to carry out oxidation reaction, by big ring
Hydroxyl on lactone is oxidized to carbonyl.
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| CN113773355B (en) * | 2021-08-23 | 2023-03-10 | 湖南省微生物研究院 | Polyene macrolide compound and preparation method and application thereof |
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