CN106554381A - Ketolide antibiotics intermediate and its preparation method and application - Google Patents
Ketolide antibiotics intermediate and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to ketone lactone antibiotic intermediates and preparation method thereof, and the application in preparing in terms of Solithromycin.The compound structure formula of the ketone lactone antibiotic intermediates that the present invention is provided is as follows, such ketone lactone antibiotic intermediates can be obtained with the simple a few step reactions of existing raw material Jing, and operation is easy, Macrolide parent nucleus raw material and side chain raw material availability height, yield are higher.When such ketone lactone antibiotic intermediates is used for the synthesis of Solithromycin, purity and yield Integrated comparative prior art are greatly improved, and have good practical value.
Description
Technical field
The invention belongs to organic drug synthesis field, and in particular in the middle of the ketone lactone antibiotic of Macrolide
Body, and preparation method thereof, and the application in Solithromycin is prepared.
Background technology
Research to macrolide antibiotics at present has proceeded to the third generation, including ketolide antibiosis
Element, acyl lactone class antibiotic etc..These antibiotic are because with the binding site of antibacterial ribosome subunit
Change, therefore can partly overcome the drug resistance of antibacterial, not only to former macrolide antibiotics sensitive organism effectively,
But also it is active to partial multi fastbacteria, become study hotspot at present.
Ketek (Telithromycin, HMR3647) is the C-11 of first listing, 12 modifications
Ketone lactone.Solithromycin (CEM-101) is the ketolide researched and developed on the basis of Ketek
Compound, the product are developed by Cempra companies, are that the fluorine of first entrance clinical research replaces ketone lactone medicine
Thing, which is different from the connection of the end of Ketek except the heteroaromatic of end connection, is also connected with one at 2
Fluorine atom, can suppress peptidyl transferase, affect shifting process, increase its antibacterial activity, with wide
General antimicrobial spectrum, it is also active to the antibacterial of resistance to Macrolide and ketolide antibiotics.Its has a broad antifungal spectrum
Property, toleration it is good, after oral administration its experimenter's blood plasma, tissue and it is intracellular be in higher concentration.
Solithromycin is proved there is good safety and toleration in serious patients with chronic liver.
Its pharmacokinetics also shows that the patient that liver function declines need not adjust dosage.This product treats Community-acquired
The curative effect of bacterial pneumonia (CABP) is close with standard treatment, and safety is higher.
In prior art, the preparation method of Solithromycin mainly has following several：
Patent US8343936 reports Solithromycin first generation synthetic methods, and its route is with red mould
Plain A is initiation material, and the preparation of side chain carried out on precursor structure, and raw material utilization rate is low.Synthetic route
It is as follows：
Patent WO2009055557 reports a kind of with clarithromycin as initiation material preparation
The method of Solithromycin, the route are similar with patent US8343936, and the preparation of its side chain is equally
Carry out on precursor structure, reduce the instream factor of raw material, and be easily caused sending out for some side reactions
Raw, ultimately result in final products isolates and purifies difficulty.
Patent WO2014145210 reports a kind of route of employing convergent type, and side chain has been directly synthesized it
React with precursor structure again afterwards, be enhanced compared with aforementioned schemes.But obtain with side chain reaction
Intermediate need the reaction of 5 steps just to obtain final products, and need to protect the amino above side chain,
Step is more, and total recovery is not high, is easily caused side chain and unnecessary loss is produced in Jing multistep synthetic procedures,
Atom economy is poor, relatively costly.
The present inventor in view of the foregoing, considers the factors such as product yield, purity, raw material availability,
With reference to existing document method, creative discovery is simultaneously obtained the new ketone lactone antibiotic intermediates of a class.
The content of the invention
One of the object of the invention is to provide a class ketone lactone antibiotic intermediates compound.
The two of the object of the invention are to provide the preparation method of above-mentioned ketone lactone antibiotic intermediates.
Another object of the present invention is to provide above-mentioned ketone lactone antibiotic intermediates on Solithromycin is prepared
Application.
To reach above-mentioned purpose, the technical solution used in the present invention includes：
The ketone lactone antibiotic intermediates of below formula I structure and its salt, solvate, polymorph：
Wherein,
R include H,Or-COOH, R1Including phenyl, the aromatic radical for replacing or C2～C6 alkyl.
Compounds of formula I of the present invention, can occur elimination reaction by Ia and obtain, and Ia structural formulas are as follows：
Wherein, R1Including phenyl, the aromatic radical for replacing or C2～C6 alkyl.
The preparation method of above-mentioned general formula compound I, when R is H, i.e., above-mentioned general formula compound I is formula
During compound I7, the reaction of general formula compound I4 Jing 3- positions hydroxyl oxidize, the fluorine substitution reaction of 2- positions, 11- positions,
12- positions deprotection reaction is prepared into general formula compound I7,
Oxidising agent used by the oxidation reaction is Dai Si-Martin's oxidant, Sha Ruite reagents or Corey-Kim
Oxidising agent, fluorination reagent used by the fluorine substitution reaction are N- fluoro double benzsulfamide, SelectFluor
Or TBAF, the deprotection reaction hydrolyzes Deprotection in the basic conditions.The alkalescence condition includes various
Inorganic base or various organic bases, the inorganic base such as similar alkali such as potassium carbonate, sodium carbonate, sodium bicarbonate, organic base
The such as similar alkali such as triethylamine, DBU, lutidines, diisopropylethylamine.
The preparation method of above-mentioned general formula compound I7, it is preferable that comprise the steps：
Step one, general formula compound I4 react under room temperature or low temperature, oxidant existence condition prepare it is generalized
Compound I5, wherein, oxidant is 1.5 with the molar ratio range of general formula compound I4:1～3:1, the oxygen
Agent is preferably Sha Ruite reagents；Step 2, general formula compound I5 at 50～-50 DEG C, DBU, NaH, KH,
One or more alkaline environment in tBuONa, tBuOK, NaHMDS or KHMDS, SelectFluor, NFSI
Or reaction prepares general formula compound I6 under the conditions of TBAF fluorine reagents, wherein, fluorine reagent and general formula compound I5
Molar ratio range be 1:1～3:1；Step 3, general formula compound I6 in organic solvent, in DBU, NaH
Alkalescence condition reaction is prepared into general formula compound I7.Organic solvent described in step 3 is preferably acetonitrile or acetone.
General formula compound I7 is prepared by general formula compound I4 Jing general formula compound I5, general formula compound I6,
Wherein R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl.Closer, R1Preferably methyl or
Phenyl, as shown in following routes, respectively with R1As a example by phenyl and methyl：
That is R1For phenyl when, the synthesis of compound 4 obtains compound 5, the further synthesisization of compound 5
Compound 6, finally prepares compound 7 by compound 6.
And for example：
That is R1For methyl when, compound 4 ' synthesis obtain compound 5 ', compound 5 ' is further closed
Into compound 6 ' is obtained, compound 7 ' is finally prepared by compound 6 '.
The preparation method of above-mentioned general formula compound I7, another preferred version comprise the steps：
Step one, general formula compound I4 in organic solvent, are prepared into compound 10 in alkalescence condition reaction,
It is preferred that DBU alkalescence conditions；Step 2, it is logical that general formula compound I10 reacts preparation under room temperature, oxidizing condition
Formula compound I11, wherein, oxidant is 1 with the molar ratio range of general formula compound I10:1～3:1, institute
State the preferred Dai Si of oxidant-Martin's oxidant；Step 3, general formula compound I11 at 50～-50 DEG C, DBU,
One or more alkaline environment in NaH, KH, tBuONa, tBuOK, NaHMDS or KHMDS, SelectFluor,
Reaction under the conditions of the fluorine reagents such as NFSI or TBAF prepares general formula compound I7, fluorine reagent and general formula compound I 11
Molar ratio range be 1:1～3:1.Organic solvent described in step one is preferably acetone or acetonitrile.
General formula compound is prepared by general formula compound I4 Jing general formula compound I10, general formula compound I 11
I7, wherein R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl., closer, R1Preferably
Methyl or phenyl, as shown in following routes, with R1As a example by phenyl：
That is R1For phenyl when, the synthesis of compound 4 obtains compound 10, and compound 10 further synthesizes and obtains
Compound 11, finally prepares compound 7 by compound 11.
The preparation method of above-mentioned general formula compound I7, also it may be preferred that comprising the steps：
Step one, reaction prepares general formula compound I5 to general formula compound I4 under oxidative conditions, wherein, Sha Rui
The molar ratio range 2 of special reagent and general formula compound I4:1～5:1, the preferred room temperature of reaction condition and Sha Ruite examination
Agent oxidizing condition；Step 2, general formula compound I5 are in organic solvent, anti-in DBU, NaH alkalescence condition
General formula compound I11 should be prepared into；Step 3, general formula compound I11 at 50～-50 DEG C, DBU, NaH,
One or more alkaline environment in KH, tBuONa, tBuOK, NaHMDS or KHMDS, SelectFluor,
Reaction under the conditions of NFSI or TBAF fluorine reagents prepares general formula compound I7, fluorine reagent and general formula compound I 11
Molar ratio range be 1:1～3:1.Organic solvent described in step 2 is preferably acetonitrile or acetone.
General formula compound is prepared by general formula compound I4 Jing general formula compound I5, general formula compound I 11
I7, wherein R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl., closer, R1Preferably
Methyl or phenyl, as shown in following routes, with R1As a example by phenyl：
That is R1For phenyl when, the synthesis of compound 4 obtains compound 5, the further synthesisization of compound 5
Compound 11, finally prepares compound 7 by compound 11.
It should be noted that the preparation method of general formula compound I of the present invention, as R in general formula compound I
For H when, including general formula compound I6 Jing 12- positions elimination reaction is the step of be prepared into general formula compound I7,
Wherein, in organic solvent, the reaction of DBU, NaH alkalescence condition is prepared into compound 7 to compound 6,
It is described
R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl, closer, R1Preferably methyl or
Phenyl.It should be noted that the preparation method of general formula compound I of the present invention, when in general formula compound I, R
For H when, including general formula compound I11 Jing 2- position fluorine substitution reactions are the step of be prepared into general formula compound I7,
General formula compound I11 at 50～-50 DEG C, DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or
One or more alkaline environment in KHMDS, reacts under the conditions of SelectFluor, NFSI or TBAF fluorine reagent
General formula compound I7 is prepared, fluorine reagent is 1 with the molar ratio range of general formula compound I11:1～3:1, it is described
R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl., closer, R1Preferably methyl or
Phenyl.
The preparation method of general formula compound I of the present invention, the R of general formula compound I isWhen it is logical
Formula compound I8, is prepared by general formula compound I7：
Wherein, general formula compound I7 reactions under room temperature and DBU alkalescence conditions prepare general formula compound 8, institute
State R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl.Closer, R1Preferably methyl or benzene
Base.
The above-mentioned general formula compound I8 of the present invention, can be used for Solithromycin as a kind of medicine intermediate
Preparation.The invention provides one kind is prepared by raw material of compound formula compound I8
The method of Solithromycin, reaction scheme are as follows：
General formula compound I9, formula chemical combination are prepared after general formula compound I8 and 12 replacement annulation of compound
Thing I9 hydrolysis is prepared into compound Solithromycin, described
R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl, closer, R1Preferably methyl or
Phenyl.
Preferably, the general formula compound I8 and the molar ratio range of compound 12 are 1:1～1:3.It is described
General formula compound I8 and compound 12 prepare general formula compound in organic solvent, under DBU catalytic conditions
I9, the organic solvent may include acetonitrile, NMP, DMF, DMAC, DMSO, DMI etc. or above-mentioned suitable mixed
Compound, the organic solvent are preferably acetonitrile.
In the above-mentioned method for preparing Solithromycin by general formula compound I8, it is preferable that formula chemical combination
Thing I9 is in NH3Hydrolysis under the conditions of MeOH prepares Solithromycin.
The present invention provides class ketone lactone antibiotic intermediates and preparation method thereof and is preparing
Application on Solithromycin.Such ketone lactone antibiotic intermediates can be simple with existing raw material Jing
The reaction of several steps be obtained, operation is easy, and Macrolide parent nucleus raw material and side chain raw material availability are high,
Yield is higher.It is comprehensive that class ketone lactone antibiotic intermediates are used for purity and yield during the synthesis of Solithromycin
Composition and division in a proportion is greatly improved compared with prior art, has good practical value.
Specific embodiment
The present invention is further illustrated with embodiment below, but the embodiment does not constitute the limit to the scope of the invention
System.
Embodiment 1, the preparation of compound 2.
During Weigh Compound 1 (270g) adds reaction bulb, EtOH (1.32L) and H is measured2O (3.24L) adds anti-
In answering bottle, 20min is stirred at room temperature.1NHCl (0.65L) is added dropwise to afterwards.After HCl completion of dropping, room
Temperature reaction.Treat raw material reaction completely, be initially added into 2NNaOH solution and adjust pH to 10-11, separate out a large amount of solid
Body.Then start reaction timing 2h is stirred at room temperature.Reactant liquor sucking filtration, filter cake are washed with 800mL cooling waters.
Filter cake obtains white solid in 50 DEG C of convection oven baking materials.Yield 82%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 5.18 (dd, J=11.1,2.5Hz, 1H), 4.39 (d,
J=7.3Hz, 1H), 3.92 (s, 1H), 3.86 (d, J=1.5Hz, 2H), 3.69 (d, J=
1.5Hz,1H),3.59–3.48(m,3H),3.31–3.19(m,2H),3.07–2.91
(m,4H)。
Embodiment 2, the preparation of compound 3.
During Weigh Compound 2 (150g) adds reaction bulb, measure DCM (525mL) and add reaction bulb, room temperature
Stirring makes which complete molten.Benzoyl oxide (86.3g) is weighed, triethylamine (38.6g) adds reaction bulb, N2Protection.Room
Warm stirring reaction.Question response is complete.Add saturation NaHCO3Solution, stirs 30min, reaction is quenched.Reaction
DCM and water, point liquid is added to collect organic faciess in liquid.Water is extracted with DCM, merges organic faciess.It is organic
Mutually wash with water, collect organic faciess, organic faciess anhydrous Na2SO4It is dried.Organic faciess decompression is spin-dried for, and obtains thick
Product.Crude product EA and normal hexane recrystallization, obtain product compound 3, yield 97%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3)δ8.10–8.03(m,2H),7.61–7.53(m,1H),
7.44 (dd, J=10.6,4.7Hz, 2H), 5.12 (dd, J=11.1,2.4Hz, 1H), 5.04
(dd, J=10.5,7.6Hz, 1H), 4.75 (d, J=7.6Hz, 1H), 3.91 (s, 1H), 3.78
–3.72(m,2H),3.56(s,1H),3.49–3.41(m,1H),3.22(s,1H)。
Embodiment 3, the preparation of compound 4.
During Weigh Compound 3 (78g) adds reaction bulb, measure DCM (624mL) and add reaction bulb, room temperature
Stirring makes which complete molten.Ice salt bath is lowered the temperature, and adds pyridine (71.2g), continues cooling stirring reaction.Deca BTC
(50g) DCM (156mL) solution, completion of dropping go to, and TLC detection reactions are to raw material
Reaction is complete.System is lowered the temperature, and adds saturated aqueous common salt that reaction is quenched.Divide liquid, water to be extracted with DCM, close
And organic faciess.Organic faciess are washed with Brine, are collected organic faciess, are used anhydrous Na2SO4It is dried, decompression is spin-dried for
To 4 crude product of compound.To crude product isopropyl acetate and normal hexane purification, product compound 4, yield are obtained
77%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3) δ 8.10-8.03 (m, 2H), 7.56 (dd, J=10.5,
4.3Hz, 1H), 7.44 (t, J=7.7Hz, 2H), 5.10-4.99 (m, 2H), 4.75 (d,
J=7.6Hz, 1H), 4.69 (s, 1H), 3.73 (d, J=2.6Hz, 1H), 3.62-3.51
(m, 1H), 3.45 (dd, J=10.5,5.9Hz, 1H).
Embodiment 4, the preparation of compound 10.
During Weigh Compound 4 (1g) adds reaction bulb, acetone (15mL), stirring and dissolving is added to add
DBU (0.53g), heating reflux reaction.Reaction terminates, and cools, and is spin-dried for post, obtains product, yield
60%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3)δ8.14–8.06(m,2H),7.57–7.49(m,1H),
7.44 (dd, J=10.4,4.6Hz, 2H), 6.34 (d, J=1.2Hz, 1H), 5.05-4.96
(m, 1H), 4.94-4.84 (m, 2H), 3.89 (d, J=3.0Hz, 1H), 3.60 (d, J=
10.2Hz,2H),3.12(s,4H)。
Embodiment 5, the preparation of compound 11.
Scheme 1：
During Weigh Compound 5 (6.24g) adds reaction bulb, MeCN (62mL) stirring and dissolving is added.Add
DBU (4g), stirs to reaction under room temperature and terminates.Post was spin-dried for, product, yield 41% was obtained.
Scheme 2：
During Weigh Compound 10 (0.505g) adds reaction bulb, DCM (10mL) stirring and dissolving is added.Add
Dess-Martin oxidants (0.8g), Dess-Martin oxidants are existed with the molar ratio range of compound 10
1:1～3:1.Stir to reaction under room temperature and terminate.Add K2CO3Aqueous solution and Brine are quenched reaction, point liquid,
Water is extracted with DCM, merges organic faciess, and anhydrous magnesium sulfate is dried, and filtration was spin-dried for post, obtained product, receives
Rate 95%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3)δ8.05–7.98(m,2H),7.60–7.49(m,1H),
7.43 (t, J=7.7Hz, 2H), 6.54 (d, J=1.1Hz, 1H), 5.01 (dd, J=10.4,
7.6Hz, 1H), 4.94 (dd, J=9.8,2.9Hz, 1H), 4.51 (d, J=7.6Hz, 1H),
4.15 (d, J=8.4Hz, 1H), 3.61 (d, J=6.9Hz, 2H), 3.15 (d, J=6.6Hz,
1H),3.02–2.90(m,1H)。
Embodiment 6, the preparation of compound 5.
During Weigh Compound 4 (51g) adds reaction bulb, measure DCM (765mL) and add reaction bulb, room temperature to stir
Mixing makes which complete molten.Add PCC (Sha Ruite reagents) (45.8g), the mol ratio model of the PCC and compound 4
It is trapped among 1.5:1～5:1.Displacement inert gas shielding, is stirred at room temperature reaction.Reaction terminates, and adds saturation NaHCO3
Solution, point liquid, water are extracted with DCM, merge organic faciess.Organic faciess saturation NaHCO3Solution, water,
Brine is washed, and uses anhydrous Na2SO4It is dried.Organic faciess are filtered, and decompression is spin-dried for, and obtains 5 crude product of compound.Purification
Obtain product, yield 88%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 8.06-7.99 (m, 2H), 7.57 (t, J=7.4Hz,
1H), 7.44 (t, J=7.7Hz, 2H), 7.27 (s, 1H), 5.00 (ddd, J=12.8,10.3,
5.2Hz, 2H), 4.60 (s, 1H), 4.54 (d, J=7.6Hz, 1H), 4.19 (d, J=7.8
Hz,1H),3.73–3.54(m,2H)。
Embodiment 7, the preparation of compound 6.
During Weigh Compound 5 (1g) adds reaction bulb, measure DMF (8mL) and add reaction bulb, replace inertia
Gas shield, being stirred at room temperature makes which complete molten.Lower the temperature in going to -30 DEG C of cold baths, add DBU (0.23mL),
Stirring 10min.Start DMF (4mL) solution of Deca NFSI (0.527g), Deca during -20 DEG C or so of interior temperature
Finish, under low temperature, continue reaction.The molar ratio range of NFSI and compound 5 is 1:1～3:Can between 1
Starting compound 5 is made preferably to convert.Reaction terminates, and adds water and DCM point of liquid, water to be extracted with DCM,
Merge organic faciess, organic phases washed with water.Anhydrous magnesium sulfate is dried, and filters, was spin-dried for post and obtains product, yield
73%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 8.10-7.99 (m, 2H), 7.57 (dd, J=10.4,
4.4Hz, 1H), 7.46 (q, J=7.3Hz, 2H), 5.02 (dd, J=10.5,7.6Hz, 1H),
4.96-4.87 (m, 1H), 4.53 (d, J=7.5Hz, 1H), 4.46 (s, 1H), 4.05 (d,
J=9.0Hz, 1H), 3.59 (dd, J=9.1,6.0Hz, 1H), 3.35 (ddd, J=10.6,
7.3,3.5Hz,1H)。
Embodiment 8, the preparation of compound 7.
During Weigh Compound 6 (1.01g) adds reaction bulb, measure DMF (10mL) and add reaction bulb, displacement
Inert gas shielding, being stirred at room temperature makes which complete molten.Lower the temperature in going to -30 DEG C of cold baths, add DBU
(0.42mL), stir 10min.Interior temperature starts the DMF solution of Deca NFSI (0.95g) when being down to -20 DEG C,
Completion of dropping, continues reaction to raw material and converts completely under low temperature, NFSI is existed with the molar ratio range of compound 5
1:1～3:The preferably conversion stirring reaction of compound 5 can be made between 1.Reaction terminates, and adds water and DCM
Divide liquid, water to be extracted with DCM, merge organic faciess, organic phases washed with water.Anhydrous magnesium sulfate is dried, and filters,
It was spin-dried for post and obtained product, yield 52%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 8.08-8.00 (m, 2H), 7.56 (t, J=7.4Hz,
1H), 7.44 (t, J=7.7Hz, 2H), 6.44 (d, J=1.3Hz, 1H), 5.07-4.94
(m, 2H), 4.54 (d, J=7.5Hz, 1H), 4.02 (d, J=9.8Hz, 1H), 3.59 (dd,
J=10.1,5.2Hz, 1H), 3.43-3.29 (m, 1H), 3.00 (d, J=12.4Hz, 1H).
Embodiment 9, the preparation of compound 8.
Scheme 1：
During Weigh Compound 6 (3.24g) adds reaction bulb, measure MeCN (32.4mL) and add reaction bulb, put
Inert gas shielding is changed, being stirred at room temperature makes which complete molten.DBU (1.86mL) is added, reaction is stirred at room temperature, must be changed
Compound 7 (compound 7 crosses post purification test NMR).CDI (2.14g) is added, under room temperature, continues reaction.Rotation
Column purification was done, product, two step yields 67% were obtained.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 8.05 (dd, J=11.8,4.7Hz, 3H), 7.60-
7.53 (m, 1H), 7.45 (t, J=7.6Hz, 2H), 7.36 (t, J=1.4Hz, 1H), 7.07
(dd, J=1.6,0.8Hz, 1H), 6.67 (s, 1H), 5.60-5.42 (m, 1H), 5.02 (dd,
J=10.6,7.5Hz, 1H), 4.54 (d, J=7.5Hz, 1H), 4.02 (d, J=8.7Hz,
1H), 3.57 (dd, J=9.3,6.2Hz, 1H), 3.36 (s, 1H), 3.03 (s, 1H).
Scheme 2：
During Weigh Compound 7 (236mg) adds reaction bulb, THF (2.5mL) stirring and dissolving is added, added
DBU (53uL), stirring reaction 10min.CDI (243mg) is added, continues stirring reaction.Reaction terminates, plus
Enter EA and moisture liquid, water is extracted with EA, merges organic faciess, and organic faciess are washed with Brine, anhydrous slufuric acid
Magnesium dry filter was spin-dried for post and obtained product, yield 82%.
Embodiment 10, the preparation of compound 9.
During Weigh Compound 8 (1.51g) adds reaction bulb, measure MeCN (22.7ml) and add reaction bulb, put
Change inert gas shielding, stirring and dissolving.Side chain compound 12 (0.53g) is added, adds DBU to be stirred at room temperature instead
Should, compound 8 is 1 with the molar ratio range of compound 12:1～1:3.Reaction terminates, and is spin-dried for column purification,
Obtain product, yield 68%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3)δ8.10–7.98(m,2H),7.79(s,1H),7.57
(d, J=7.4Hz, 1H), 7.45 (t, J=7.7Hz, 2H), 7.27 (s, 1H), 7.19-7.14
(m, 2H), 6.64 (d, J=6.7Hz, 1H), 5.02 (dd, J=10.5,7.6Hz, 1H), 4.84
(dd, J=10.3,2.1Hz, 1H), 4.53 (d, J=7.5Hz, 1H), 4.40 (t, J=7.2
Hz, 2H), 4.09 (d, J=9.4Hz, 1H), 3.87-3.70 (m, 3H), 3.61 (dt, J=
12.6,6.5Hz, 2H), 3.41 (s, 1H), 3.30 (ddd, J=10.5,7.1,3.3Hz, 1H),
3.07 (q, J=7.0Hz, 1H).
Embodiment 11, the preparation of Solithromycin.
During Weigh Compound 9 (0.7g) adds reaction bulb, inert gas shielding is replaced, MeOH (3.5mL) is measured
Add reaction bulb, stirring and dissolving.NH3MeOH (3.5mL) solution is added, reaction is stirred at room temperature.Reaction knot
Beam, was spin-dried for column purification, obtained product, yield 75%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 7.80 (s, 1H), 7.27 (s, 1H), 7.18 (d, J=
6.6Hz, 2H), 6.64 (dt, J=6.7,2.4Hz, 1H), 4.93-4.82 (m, 1H), 4.42
(t, J=7.3Hz, 2H), 4.30 (d, J=7.3Hz, 1H), 4.07 (d, J=10.4Hz, 1H),
3.82–3.70(m,2H),3.68–3.58(m,1H),3.58–3.46(m,3H),3.44
(s, 1H), 3.15 (ddd, J=20.8,12.0,7.1Hz, 2H).
Embodiment 12, the preparation of compound 3 '.
During Weigh Compound 2 (10g) adds reaction bulb, inert gas shielding is replaced, adds DCM (100mL),
Acetic anhydride (3.6mL), stirring reaction under room temperature.Question response completely, adds saturation NaHCO3Reaction is quenched,
Liquid, extraction is divided to be spin-dried for column purification, and obtained product compound 3 ', yield 70%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 5.17 (dd, J=11.1,2.4Hz, 1H), 4.75 (dd,
J=10.5,7.6Hz, 1H), 4.61 (d, J=7.6Hz, 1H), 3.94 (s, 1H), 3.83 (d,
J=1.5Hz, 1H), 3.72 (d, J=2.7Hz, 1H), 3.54-3.42 (m, 2H), 3.26
(s,1H),3.06–2.96(m,1H)。
Embodiment 13, the preparation of compound 4 '.
Weigh Compound 3 ' (1g) is added into dry reaction bulb, replaces inert gas shielding, is added
DCM (8mL), is down to less than 0 DEG C by inside and outside, adds pyridine (1.02mL), stirs 20min.Deca BTC (0.7g)
DCM (2mL) solution, not higher than 0 DEG C of Deca process control interior temperature, completion of dropping goes to room temperature reaction.Instead
Should terminate, add water quenching to go out reaction, point liquid, extraction were spin-dried for column purification, and obtained product compound 4 ', receipts
Rate 70%.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 5.13 (dd, J=10.7,2.5Hz, 1H), 4.81-
4.67 (m, 2H), 4.59 (d, J=7.6Hz, 1H), 3.70 (d, J=2.6Hz, 1H), 3.48
(dt, J=12.0,3.7Hz, 2H), 3.01-2.93 (m, 1H), 2.92 (s, 3H).
Embodiment 14, the preparation of compound 5 '.
Weigh Compound 4 ' (3.2g) is added into dry reaction bulb, replaces inert gas shielding, is added
DCM (32mL), adds PCC oxidants (2.62g), reaction is stirred at room temperature.Reaction terminates, and filters, and adds
Water mutually washs organic faciess, point liquid, and extraction was spin-dried for column purification, and obtained product compound 5 ', yield 71%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3) δ 5.01 (dd, J=10.1,2.8Hz, 1H), 4.73 (dd,
J=10.6,7.6Hz, 1H), 4.64 (d, J=1.0Hz, 1H), 4.38 (d, J=7.6Hz,
1H), 4.17 (d, J=7.8Hz, 1H), 3.80 (q, J=6.8Hz, 1H), 3.60-3.47
(m,1H),3.07–2.90(m,2H)。
Embodiment 15, the preparation of compound 6 '.
Weigh Compound 5 ' (1.5g) is added into dry reaction bulb, replaces inert gas shielding, is added
DMF (12mL), system cooling, adds DBU (0.42mL), stirs 20min.It is inside and outside when being down to less than -15 DEG C,
DMF (6mL) solution of Deca NFSI (0.94g).Completion of dropping, low temperature reaction.Reaction terminates,
Water and DCM point of liquid, extraction are added, post was spin-dried for, and was obtained product compound 6 ', yield 67%.
Nuclear magnetic data is as follows：
1H NMR(400MHz,CDCl3) δ 4.95 (dd, J=9.6,3.0Hz, 1H), 4.74 (dd,
J=10.6,7.6Hz, 1H), 4.48 (s, 1H), 4.38 (d, J=7.6Hz, 1H), 4.02 (dd,
J=10.5,1.5Hz, 1H), 3.58-3.41 (m, 2H), 3.04-2.92 (m, 1H).
Embodiment 16, the preparation of compound 8 '.
During Weigh Compound 6 ' (0.6g) adds reaction bulb, measure MeCN (6mL) and add reaction bulb, displacement
Inert gas shielding, being stirred at room temperature makes which complete molten.DBU (0.38mL) is added, reaction is stirred at room temperature to original
Material consumes complete, obtains compound 7 '.CDI (0.43g) is added, continues to react to obtain compound 8 ' under room temperature.
Column purification was spin-dried for, product compound 8 ', two step yields 67% were obtained.
Nuclear magnetic data is as follows：
1H NMR (400MHz, CDCl3) δ 8.15-8.01 (m, 1H), 7.37 (t, J=1.4Hz,
1H), 7.07 (dd, J=1.6,0.8Hz, 1H), 6.70 (s, 1H), 5.55 (dd, J=9.3,
3.3Hz, 1H), 4.74 (dd, J=10.5,7.6Hz, 1H), 4.39 (d, J=7.6Hz, 1H),
3.99 (dd, J=9.9,1.2Hz, 1H), 3.48 (m, 2H), 3.14-2.92 (br, 1H).
To sum up, the reaction scheme for preparing of Solithromycin of the present invention is preferably following three routes：
Route one：
Route two：
Route three：
Concrete reactions steps in the reaction scheme of above-mentioned three Solithromycin, in the aforementioned embodiment
Make an explanation, therefore here is not repeated.
Above the present invention is described in detail, its object is to allow the personage for being familiar with this art can
Understand present disclosure and be carried out, can not be limited the scope of the invention with this, it is all according to this
Equivalence changes or modification that the spirit of invention is made, should all cover within the scope of the present invention.
Claims (11)
1. there are the ketone lactone antibiotic intermediates and its salt, solvate, polymorphic of below formula I structure
Thing：
Wherein,
R include H,Or-COOH,
R1Including phenyl, the aromatic radical for replacing or C2～C6 alkyl.
2. ketone lactone antibiotic intermediates I as claimed in claim 1, it is characterised in that can occur by Ia
Elimination reaction is obtained, and Ia structural formulas are as follows：
Wherein,
R1Including phenyl, the aromatic radical for replacing or C2～C6 alkyl.
3. the preparation method of ketone lactone antibiotic intermediates described in a kind of claim 1, it is characterised in that include
Following step：The hydroxyl oxidize reaction of general formula compound I4 Jing 3- positions, the fluorine substitution reaction of 2- positions, 11- positions, 12-
Position elimination reaction is prepared into general formula compound I7,
4. preparation method as claimed in claim 3, it is characterised in that comprise the steps：
Step one, general formula compound I4 react under room temperature or low temperature, oxidant existence condition prepare it is generalized
Compound I5, wherein, oxidant is 1 with the molar ratio range of general formula compound I4:1～3:1；
Step 2, general formula compound I5 at 50～-50 DEG C, DBU, NaH, KH, tBuONa, tBuOK,
One or more alkaline environment in NaHMDS or KHMDS, SelectFluor, NFSI or TBAF fluorine reagent bar
Reaction under part prepares general formula compound I6, wherein, fluorine reagent with the molar ratio range of general formula compound I5 is
1:1～3:1；
Step 3, general formula compound I6 in organic solvent, are prepared in the reaction of DBU, NaH alkalescence condition
General formula compound I7.
5. preparation method as claimed in claim 3, it is characterised in that comprise the steps：
Step one, general formula compound I4 in organic solvent, are prepared into compound 10 in alkalescence condition reaction；
Step 2, general formula compound I10 reactions under room temperature, oxidizing condition prepare general formula compound I11,
Wherein, oxidant and the molar ratio range of general formula compound I10 are 1:1～3:1；
Step 3, general formula compound I11 at 50～-50 DEG C, DBU, NaH, KH, tBuONa, tBuOK,
One or more alkaline environment in NaHMDS or KHMDS, SelectFluor, NFSI or TBAF fluorine reagent bar
Reaction under part prepares general formula compound I7, and fluorine reagent is 1 with the molar ratio range of general formula compound I11:1～
3:1。
6. preparation method as claimed in claim 3, it is characterised in that comprise the steps：
Step one, reaction prepares general formula compound I5 to general formula compound I4 under oxidative conditions, wherein, it is husky
The molar ratio range 2 of auspicious special reagent and general formula compound I4:1～5:1；
Step 2, general formula compound I5 in organic solvent, are prepared in the reaction of DBU, NaH alkalescence condition
General formula compound I11；
Step 3, general formula compound I11 at 50～-50 DEG C, DBU, NaH, KH, tBuONa, tBuOK,
One or more alkaline environment in NaHMDS or KHMDS, SelectFluor, NFSI or TBAF fluorine reagent bar
Reaction under part prepares general formula compound I7, and fluorine reagent is 1 with the molar ratio range of general formula compound I11:1～
3:1。
7. arbitrary preparation method as described in claim 3 to 6, it is characterised in that:The R1Including phenyl,
Substituted aromatic radical or C1～C6 alkyl.
8. the preparation method of ketone lactone antibiotic intermediates described in a kind of claim 1, it is characterised in that include
Following step：General formula compound I6 Jing 12- positions elimination reaction is prepared into general formula compound I7,
Wherein, in organic solvent, the reaction of DBU, NaH alkalescence condition is prepared into compound 7 to compound 6,
The R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl.
9. the preparation method of a ketone lactone antibiotic intermediates as claimed in claim 1, it is characterised in that
Comprise the steps：General formula compound I11 Jing 2- position fluorine substitution reactions are prepared into general formula compound I7,
General formula compound I11 at 50～-50 DEG C, DBU, NaH, KH, tBuONa, tBuOK, NaHMDS or
One or more alkaline environment in KHMDS, reacts under the conditions of SelectFluor, NFSI or TBAF fluorine reagent
General formula compound I7 is prepared, fluorine reagent is 1 with the molar ratio range of general formula compound I11:1～3:1, it is described
R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl.
10. a kind of preparation method of ketone lactone antibiotic intermediates described in claim 1, it is characterised in that bag
Include following step：R isGeneral formula compound I8, be prepared by general formula compound I7：
Wherein, general formula compound I7 reactions under room temperature and DBU alkalescence conditions prepare general formula compound 8, institute
State R1Including phenyl, the aromatic radical for replacing or C1～C6 alkyl.
A kind of 11. preparation methoies of compound Solithromycin, comprise the steps：
General formula compound I9, formula chemical combination are prepared after general formula compound I8 and 12 replacement annulation of compound
Thing I9 hydrolysis is prepared into compound Solithromycin, the R1 include phenyl, the aromatic radical for replacing or
C1～C6 alkyl.General formula compound I8 is 1 with the molar ratio range of general formula compound 12:1～1:3, formula
Compound I8 and general formula compound I12 prepare formula chemical combination in organic solvent, under DBU catalytic conditions
Thing I9.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1235162A (en) * | 1998-04-08 | 1999-11-17 | 赫斯特·马里恩·鲁索公司 | New derivatives for erythromycin |
| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN106518939A (en) * | 2015-09-14 | 2017-03-22 | 江苏奥赛康药业股份有限公司 | Method for preparing Solithromycin compound |
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| CN1373767A (en) * | 1999-04-16 | 2002-10-09 | 奥索-麦克尼尔药品公司 | Ketolide antibacterials |
| US7601695B2 (en) * | 2003-03-10 | 2009-10-13 | Optimer Pharmaceuticals, Inc. | Antibacterial agents |
| CN105732745A (en) * | 2007-10-25 | 2016-07-06 | 森普拉制药公司 | Process for the preparation of macrolide antibacterial agents |
| EP2571506B1 (en) * | 2010-05-20 | 2017-05-10 | Cempra Pharmaceuticals, Inc. | Processes for preparing macrolides and ketolides and intermediates therefor |
| WO2014145210A1 (en) * | 2013-03-15 | 2014-09-18 | Cempra Pharmaceuticals, Inc. | Convergent processes for preparing macrolide antibacterial agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1235162A (en) * | 1998-04-08 | 1999-11-17 | 赫斯特·马里恩·鲁索公司 | New derivatives for erythromycin |
| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN106518939A (en) * | 2015-09-14 | 2017-03-22 | 江苏奥赛康药业股份有限公司 | Method for preparing Solithromycin compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106432383A (en) * | 2016-09-14 | 2017-02-22 | 重庆两江药物研发中心有限公司 | Solithromycin and preparation method of intermediate thereof |
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