CN107216360A - A kind of method for preparing rope Citropten - Google Patents
A kind of method for preparing rope Citropten Download PDFInfo
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- CN107216360A CN107216360A CN201610164404.3A CN201610164404A CN107216360A CN 107216360 A CN107216360 A CN 107216360A CN 201610164404 A CN201610164404 A CN 201610164404A CN 107216360 A CN107216360 A CN 107216360A
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- rope citropten
- amino
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- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@@](CC1)OC(*)C1=C Chemical compound C[C@@](CC1)OC(*)C1=C 0.000 description 1
Classifications
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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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- 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
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides a kind of method for preparing rope Citropten, and this method comprises the following steps：Compound II carries out fluoro-reaction; generate compound III, compound III and compound IV five-membered rings triazole (1 (4 aminobutyl) 4 (3 protection aminophenyl) 1H 1,2; 3 triazoles) the docking of side chain ammonia, shape is into oxazole cycle compound V；Compound V be deprotected accordingly or is formed amino after reducing, and obtains rope Citropten I.The method of what the present invention was provided prepare rope Citropten has got rid of azide intermediate oxidation explosive and dangerous in the prior art, fluoro-reaction, and operation is safer；When especially pleasantly surprised is Bei oxazole rings and five-membered ring triazole, because reactant solubility is higher, make the high conversion rate of reactant, side reaction is few, reduce production cost, be conducive to environmental protection, suitable industrialized production has larger application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to process for preparing medicine, more particularly to one kind prepare macrolides medicine
The novel preparation method of thing rope Citropten.
Background technology
Rope Citropten (English name Solithromycin) is the macrolides of new generation of Cempra drugmakers exploitation
Antibiotic medicine, for treating Community-acquired bacterial pneumonia (CABP), can also be applied to COPD
(COPD), bacterial pneumonia and some treatment of infection, the medicine are now in III clinical trial phases.Rope Citropten is to enter at present
Enter first fluorine-containing substituted macrolides of clinic.U.S. chemical abstract CAS：760981-83-7, with following formula
Chemical constitution shown in I：
WO2009055557 discloses the method that rope Citropten I is prepared by initiation material of CLA, such as the institute of reaction equation 1
Show, CLA passes sequentially through the sugared hydroxyl of acyl group (such as benzoyl Bz) protection；With the hydroxy activating reagent carbonyl with steric hindrance
Base diimidazole (CDI) reaction generation intermediate CL-1；With the nitrine butylamine generation oxazole ring intermediates of containing nitrine CL-2；In acid
Property under the conditions of remove one of glycosyl, form intermediate CL-3；The hydroxyl oxidation formed after glycosyl will be removed using oxidant,
Form intermediate CL-4；Perfluorinated reaction carries out F substitutions at ortho position, forms intermediate CL-5；Finally with aromatic alkyne three nitrogen of formation
Azoles, and sugared hydroxyl protection is sloughed, form rope Citropten.International patent application WO2010048599 has been carried out necessarily to above-mentioned
Adjustment, during CL-2 is prepared from CL-1, uses 4- amino butanols for raw material, hydroxyl then is converted into azido group, then press
Former method reaction.This method reactions steps are long, to carrying out the danger of the operations such as desugar, oxidation containing azide intermediate, because folded
Nitrogen compound is all easy blast and poisonous compound；Meanwhile, azide intermediate produces five-membered ring with acetylenic by cyclization
Side reaction is more in the step of triazole.
Reaction equation 1：
WO2014145210 is improved, as shown in reaction equation 2 to reduce reactions steps to the above method.This method is straight
The raw material for introducing and carrying side chain five-membered ring triazole is connect, specific reactions steps include preparing intermediate CL-1 by CLA,
Docked with five-membered ring triazole side chain, Xing Cheng oxazole rings intermediate (wherein CP is amino, protection amino or nitro), then according to
The steps such as secondary process desugar, oxidation, fluorination, take corresponding method to form it into amino, obtain Suo Li finally according to CP groups
Mycin I.Although the step of this method need not introduce azido and carry out cyclization with alkynes, reduces reactions steps, with
The increasing of reaction raw materials and moiety intermediate molecular weight, reduces reaction raw materials and moiety intermediate molten in organic reaction
Xie Du, have impact on post-reaction treatment, and side chain five-membered ring triazole needs to be subjected to the steps such as desugar, oxidation, easily produce compared with
Many side reactions.
Reaction equation 2：
The patent CN104650166 of Guangdong Dongyang Guang Pharmaceutical Co., Ltd discloses another preparation method, such as the institute of reaction equation 3
Show：The intermediate II prepared after being aoxidized using first desugar, then meets Xing Cheng Evil using previous five-membered ring triazole side chain Dui
Azoles ring, last fluoro formation target compound rope Citropten.Desugar, oxidation are subjected to this method avoid side chain five-membered ring triazole
Step, reduces the generation of side reaction.But be due to desugar, oxidation after compound intermediate II than intermediate CL-1 solubility
Difference, causes reaction difficult, and conversion ratio is low；Moreover, exposed amino can produce acyl migration impurity when deprotection, it is difficult to
Implement industrialized production.
Reaction equation 3：
Therefore, the above method has many defects, unsuitable industrialized production, it would be highly desirable to improve.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned weak point, research and design get rid of toxic operation,
Side reaction is reduced, reaction yield is improved, reduces cost, rope Citropten method is prepared beneficial to environmental protection, and suitable for industrialized production.
To achieve the above object, the invention provides the method that one kind prepares rope Citropten (Formulas I), comprise the following steps：
(1) prepare compound III,
Method one：Compound II carries out fluoro-reaction, generates compound III,
Or
Method two：Compound VII first carries out fluoro-reaction, then generates compound III with carbonyl dimidazoles (CDI) reaction；
R is H or hydroxy-protecting agent in formula, and described hydroxyl protecting group is acyl protecting groups, preferably benzoyl (Bz) base or
Acetyl group (Ac).
The fluoro reagent that the fluoro-reaction is used is selected from N- fluoro double benzsulfamide (NFSI), the fluoro- benzene disulfonic acid amides of N-
Or double tetraphydro-borate (NFTh) the electrophilic fluorination agent of 1- fluoro- 4- hydroxyls -1,4- diaza-bicyclos [2,2,2] octanes (NFOBS).It is preferred that
The double benzsulfamides (NFSI) of N- fluoro
Fluoro reagent and compound II consumptions mol ratio 1~2 preferably 1:1.2~1.5
Fluoro reagent and compound VII consumptions mol ratio 1~2 preferably 1:1.2~1.5
The fluoro-reaction of the step (1) 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 step (1) fluoro-reaction is used is selected from tetrahydrofuran, 2- methyltetrahydrofurans, toluene, 1,
One or two kinds of thing mixed above in 4- dioxane, N,N-dimethylformamide, ethyl acetate or isopropyl acetate.It is excellent
Select N,N-dimethylformamide and tetrahydrofuran mixed system.Specific organic solvent can also be that those skilled in the art can be easily
Complete other organic solvents of the present invention, it is not limited to this.
The fluoro-reaction of the step (1) can be carried out under alkali promotion, and described alkali is inorganic base, selected from potassium carbonate,
Saleratus, sodium carbonate, sodium acid carbonate, cesium carbonate, potassium tert-butoxide, tert-butyl alcohol lithium, sodium methoxide, caustic alcohol, sodium hydrogen or NaHMDS
In one or two kinds of thing mixed above, preferred potassium tert-butoxide.The alkali for realizing this programme can also be that those skilled in the art can
It is readily accomplished other alkali of the present invention, it is not limited to this.
(2) compound III and compound IV (1- (4- aminobutyls) -4- (3- protects aminophenyl) -1H-1,2,3- tri-
Nitrogen azoles) five-membered ring triazole the docking of side chain ammonia, shape sees below formula into oxazole cycle compound V：
Wherein CP is amino, protection amino or nitro, and when CP is amino, compound V is rope Citropten I；Work as CP
During for protection amino, the protection amino is selected from Boc-NH, BsMoc-NH, Trityl-NH or MeOTrityl-NH, realizes we
The amino protecting group of case can also be that those skilled in the art can be readily accomplished other amino protecting groups of the present invention, it is not limited to
This.
The step (2) is carried out in organic solvent, and the organic solvent is selected from tetrahydrofuran, acetonitrile, N, N- diformazan ammonia
One or two kinds of thing mixed above in base formamide, dimethyl sulfoxide (DMSO), dichloromethane, toluene, preferably acetonitrile.The reaction
Solvent load is：Solvent (mL):Compound III weight (g)=5~30:1, preferably 5~7:1.
The step (2) can also be in above-mentioned organic solvent and water (such as acetonitrile：Water=1~10：1) preferably 2:1 (mL's)
Reacted under mixed system, (time 0.5h~16h, temperature 50 C~100 DEG C)：Compound III weight (g):Compound V=5~
30:1, preferably 7:1.Compound V sugar unit hydroxyl protecting groups R can be removed voluntarily in the reaction, without further taking remove-insurance
Maintaining method.
And the product that organic solvent obtains, which is used alone, can take the scheme of conventional desugar hydroxyl protection；After reacting
Product is placed in proton solvent, and acyl group protection can be sloughed under room temperature to counterflow condition and obtains compound V, described proton is molten
Agent is selected from alcohol or water or two or more mixtures；The alcohol is selected from methanol, ethanol, isopropanol；It is preferred that methanol；Alcohol:Water volume ratio
For 1~10:1, preferably 2:1.(time 0.5h~16h, 20 DEG C~100 DEG C of temperature, solvent (mL):Compound III weight (g)=5
~30:1, preferably 7:1).
The reaction of the step (2) is carried out under organic base promotion, and described organic base is selected from 1,8- diazabicylos ten
One carbon -7- alkene (DBU), dicyclohexylcarbodiimide (DCC), N, N- lutidines amine (DMAP), triethylenediamine
(DABCO) the one or two kinds of thing mixed above or in 1,5- diazabicyclos [4.3.0] -5- nonenes (DBN).It is preferred that DBU.
The compound III and compound IV mol ratio is 1:1~3.It is preferred that 1:1~2
The reaction temperature of step (2) is 0 DEG C~100 DEG C, preferably 50 DEG C~60 DEG C.
The reaction product V of step (2)：When the CP of the compound V is amino, compound V is rope Citropten I.
When the CP of the compound V is protection amino or is nitro, compound V carries out corresponding deprotection amino or gone back
Amino is formed after former nitro, rope Citropten I is obtained.See below formula：
The step (2), when Cp is protection amino, the protection amino is selected from Boc-NY, BsMoc-NH, Trityl-
During NH or MeOTrityl-NH, amino, (20 DEG C~50 DEG C of temperature, time 0.5h~10h) are deprotected using acidolysis reaction.It is described
The acid of acidolysis reaction is one or more of in hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid；Realize the deaminizating protection of this programme
Method can also be those skilled in the art can be readily accomplished the present invention other method, it is not limited to this.
The step (2), when Cp is nitro, uses catalytic hydrogenating reduction nitro for amino, rope Citropten is made, described
Catalytic hydrogenation catalyst be palladium carbon or Raney's nickel, preferably palladium carbon；Hydrogenation catalyst consumption and compound V mass ratio are 5%
~20%, preferably 5%, the pressure of hydrogenation is normal pressure to 10MPa.It is preferred that normal pressure.Reaction dissolvent is selected from alcohols, esters or ethers；
It is preferred that alcohols, described alcohols solvent is selected from methanol, ethanol or the preferred methanol of isopropanol；Esters solvent is selected from ethyl acetate or second
Isopropyl propionate ethyl acetate, it is excellent that ether solvent is selected from ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran or 2- methyltetrahydrofurans
Select tetrahydrofuran.(20 DEG C~80 DEG C of other conditions temperature, time 1h~10h).Realizing the nitro reduction of this programme can also be
Those skilled in the art can be readily accomplished other reduction nitro methods of the present invention, it is not limited to this.
The compound II is prepared by following method：
R is sugared hydroxyl protecting group
Using CLA as starting material, acyl group protection is carried out to sugared hydroxyl；Then it is single that a sugar is sloughed in acid condition
Member；Under triphosgene or phosgene effect, the double hydroxyls of protection form carbonic ester；Then oxidation hydroxyl forms carbonyl, oxidation reaction
It can be realized using pyridinium chloro-chromate (PCC) or polite oxidation；Finally formed in the presence of carbonyl dimidazoles (CDI)
Compound II, synthetic route is as follows：
Specifically, such as when sugared hydroxyl protecting group R is benzoyl prepare compound II：
(1) prepare compound A
CLA (50g, 0.067mol), triethylamine are added in 500mL reaction bulbs, and (18.75mL, 0.135mol, 2 work as
Amount), ethyl acetate (350mL) stirring mixing.Benzoyl oxide (22.5g, 0.1mol, 1.5 equivalent) is added portionwise.Finish, in room
(20-25 DEG C) stirring 24h under temperature.Detect after CLA reaction completely, remove solvent (45 DEG C of temperature ＜) under reduced pressure.Residue
(0-5 DEG C) stirring 0.5h, suction filtration under middle addition 500mL ice methanol, ice bath.Filter cake is eluted with ice methanol (100mL × 2), 50 DEG C
Vacuum drying, obtains compound A white solids 56g.
(2) prepare compound B
Step reaction gained compound A (56g, 0.0657mol), ethanol (300mL), water on being added in 1000mL reaction bulbs
(300mL) is mixed.Concentrated hydrochloric acid (56mL, 0.672mol, 10 equivalent) is slowly added dropwise, about 0.5h drops finish.After stirring reaction 1h,
Sample detection compound A reactions complete.Reaction solution is put into (0 DEG C -5 DEG C) coolings of ice bath, pH to 9 is adjusted with ammoniacal liquor in less than 10 DEG C
~10, there is white solid precipitation.Continue to stir 0.5h, suction filtration.Filter cake is eluted with water (500mL × 2), 50 DEG C of vacuum drying, is obtained
To compound B white solids 42g.
Gained solid ethyl acetate：Petroleum ether=1：4 77 DEG C of mixed solvents are recrystallized, and obtain white solid 37g.
(3) prepare compound C
In 500mL three-necked flasks add on step reaction product compound B (19.3g, 0.0268mol), pyridine (17.7g,
0.2265mol, 8 equivalents), dichloromethane (150mL), nitrogen displacement, the lower stirring dissolved clarifications of (- 20~-5 DEG C) of ice salt bath cooling.Together
When triphosgene (9.6g, 0.0322mol, 1.2 equivalent) is dissolved in 50mL dichloromethane, question response liquid is cooled to after -10 DEG C,
The dichloromethane solution of above-mentioned triphosgene is added dropwise, temperature control is no more than 5 DEG C.About 1h drops finish, and drop, which finishes, to be warmed naturally to (20-25 DEG C) and stir
Reaction 1h is mixed, after sampling detection intermediate B reaction completely, reaction solution is poured into 300mL brine ices, point liquid, aqueous phase dichloro
Methane (100mL × 3) is extracted, and merges organic phase, with anhydrous sodium sulfate drying, suction filtration is spin-dried for, and obtains compound C crude product 22.9g, nothing
It need to purify and can be directly used for next step reaction.
(4-1) PCC oxidizing process prepare compounds D
Compound C (8g, 0.0111mol), dichloromethane (100mL) obtained by step reaction on being added in 250mL reaction bulbs
Stirring and dissolving, is added portionwise pyridinium chloro-chromate (PCC, 7.16g, 0.0333mol, 3 equivalent).Finish, reaction is stirred at room temperature
24h.Sample after detection compound C reactions completely, reaction solution is filtered through diatomite, and filtrate uses saturated sodium bicarbonate aqueous solution successively
(50mL), saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying, suction filtration, 40 DEG C are spin-dried for, and obtain compound D crude product 7.8g,
Next step reaction is can be directly used for without purifying.
(4-2) polite oxidizing process prepare compound D
DMSO (dimethyl sulfoxide) (2.7g, 0.03459mol, 3 equivalent), dichloromethane are added in tri- mouthfuls of reaction bulbs of 250ml
(50ml), nitrogen displacement is placed in dry ice-propanone bath cooling.Question response liquid is cooled to after -70 DEG C, dropwise addition oxalyl chloride (2.92g,
0.023mol, 2 equivalents), temperature control is no more than -65 DEG C.About 30min drops finish, and are incubated -65~-70 DEG C of stirring reaction 1h.Chemical combination is added dropwise
Thing C (8.3g, 0.01153mol) dichloromethane (30ml) solution, temperature control is no more than -65 DEG C.About 45min drops finish, insulation reaction
1.5h.Add triethylamine (11.64g, 0.1153mol, 10 equivalent).Finish, withdraw from the dry ice bath, warm naturally to room temperature.Add
Dchloromethane reaction solution, uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively.Anhydrous sodium sulfate
Dry, suction filtration, 40 DEG C are spin-dried for obtaining compound D crude product 8.7g, next step reaction is can be directly used for without purifying.
(5) prepare compound should be VII
Step product Compound D (9.7g, 0.0135mol), acetone (60mL) stirring are molten on being added in 250mL reaction bulbs
Solution.Add DBU (carbon -7- alkene of 1,8- diazabicylo 11) (5.27g, 0.03377mol, 2.5 equivalent).Finish, be stirred at room temperature
24h.Sample after detection compound D reactions completely, remove solvent under reduced pressure, residue dichloromethane (60mL) dissolves, and uses 0.5N
Potassium dihydrogen phosphate adjust to pH=7~9, point liquid.Aqueous phase is extracted with dichloromethane (50mL × 2), merges organic phase, is used
Saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying, suction filtration, and 40 DEG C are spin-dried for, and the crude product 6.88g of compound VII are obtained, without pure
Change and can be directly used for next step reaction.
(6) prepare compound II
In 250mL three-necked flasks, step reaction gained intermediate VII (6.88g, 0.0102mol), DMF in addition
(40mL), nitrogen displacement stirs dissolved clarification.Reaction solution is cooled to -25 DEG C, be added portionwise sodium hydride (0.814g, 0.0204mol,
2 equivalents).Finish, in -20 DEG C~-25 DEG C insulated and stirred 1h.Carbonyl dimidazoles CDI is added dropwise, and (5.02g, 0.0306mol, 3 work as
Amount) DMF (dimethylformamide) (20mL) solution, temperature control be no more than -10 DEG C.Drop finishes, in -10~-15 DEG C of insulated and stirred 1h.
After sampling detection reaction completely, frozen water (120mL) is added dropwise into reaction solution, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes,
15min is stirred, suction filtration, filter cake is eluted with water (50mL × 2).Filter cake ethyl acetate (50mL) dissolves, saturated aqueous common salt
(30mL) is washed, and anhydrous sodium sulfate drying, suction filtration is spin-dried for.Column chromatography purifies (200-300 mesh silica gel, column type number：25 × 500m,
Eluent is methanol：Dichloromethane=1:10) compound II white solids 3.6g, is obtained.
The method that what the present invention was provided prepare rope Citropten has got rid of azide intermediate explosive and dangerous in the prior art
Oxidation, fluoro-reaction, operation are safer；When especially pleasantly surprised is Bei oxazole rings and five-membered ring triazole, due to anti-
Answer thing solubility higher, make the high conversion rate of reactant, side reaction is few, reduce production cost, be conducive to environmental protection, suitable industrialization
Production, there is larger application value.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.It should be understood that these embodiments are merely to illustrate this
Invention rather than limitation the scope of the present invention.
Addition, content and the concentration of many kinds of substance is referred to herein, wherein described percentage composition, except special instruction
Outside, weight/mass percentage composition is all referred to.
In the embodiments herein, illustrated if do not made for reaction temperature or operation temperature, the temperature is led to
Often refer to room temperature (20-25 DEG C).
In the structural formula of compound of the present invention, hydroxyl protecting group BzO- is benzoyloxy, and this is people in the art
Known to member.
First, reagent
Reagent：The reactant and catalyst used in the embodiment of the present invention is that chemistry is pure, be can be used directly or according to need
To pass through simple purification；Organic solvent etc. is that analysis is pure, is directly used.Reagent is purchased from Chinese Medicine (group) Shanghai chemistry
Reagent Company.
2nd, detection method
1HNMR NMRs use BRUKER-400MHz.
Mass spectrograph is LC-MS instrument (LCMS), model：Agilent 6120B, detector：DAD, mobile phase A is water, stream
Dynamic phase B is 1% aqueous formic acid.Testing conditions：
| Time (min) | A | B | Flow velocity (ml/min) | Pressure (bar) |
| 0 | 80 | 20 | 1.0 | 400 |
| 30 | 20 | 80 | 1.0 | 400 |
| 31 | 10 | 90 | 1.0 | 400 |
| 40 | 10 | 90 | 1.0 | 400 |
Embodiment 1
The preparation of intermediate II：
1. prepare compound A
CLA (50g, 0.067mol), triethylamine are added in 500mL reaction bulbs, and (18.75mL, 0.135mol, 2 work as
Amount), ethyl acetate (350mL) stirring mixing.Benzoyl oxide (22.5g, 0.1mol, 1.5 equivalent) is added portionwise.Finish, in room
(20-25 DEG C) stirring 24h under temperature.Detect after CLA reaction completely, remove solvent (45 DEG C of temperature ＜) under reduced pressure.In residue
Add (0-5 DEG C) stirring 0.5h, suction filtration under 500mL ice methanol, ice bath.Filter cake is eluted with ice methanol (100mL × 2), and 50 DEG C true
Sky is dried, and obtains compound A white solids 56g.
ESI[M+1]:852
2. prepare compound B
Step reaction gained compound A (56g, 0.0657mol), ethanol (300mL), water on being added in 1000mL reaction bulbs
(300mL) is mixed.Concentrated hydrochloric acid (56mL, 0.672mol, 10 equivalent) is slowly added dropwise, about 0.5h drops finish.After stirring reaction 1h,
Sampling detection intermediate A reaction is complete.Reaction solution is put into the cooling of (0-5 DEG C) of ice bath, in less than 10 DEG C with ammoniacal liquor regulation pH to 9~
10, there is white solid precipitation.Continue to stir 0.5h, suction filtration.Filter cake is eluted with water (500mL × 2), 50 DEG C of vacuum drying, is obtained
White solid 42g.
Gained solid ethyl acetate：Petroleum ether=1：4 mixed solvents are recrystallized, and obtain compound B white solids 37g.
ESI[M+1]:694。
1H NMR(400MHz,CDCl3):δ 8.06 (d, J=7.1Hz, 2H), 7.57 (d, J=7.4Hz, 1H), 7.45 (d, J
=7.8Hz, 2H), 5.12 (dd, J=11.1,2.3Hz, 1H), 5.04 (m, 1H), 4.75 (d, J=7.6Hz, 1H), 3.94 (s,
1H), 3.73~3.75 (m, 2H), 3.53~3.58 (m, 1H), 3.43~3.57 (m, 1H), 2.93 (s, 3H), 2.86~2.90
(m, 1H), 2.48~2.68 (m, 2H), 2.28 (s, 6H), 1.97~1.99 (m, 1H), 1.87~1.92 (m, 1H), 1.60~
1.65 (m, 1H), 1.37~1.47 (m, 3H), 1.19~1.33 (m, 9H), 1.04~1.08 (m, 9H), 0.81 (t, J=
7.4Hz,3H)。
3. prepare compound C
In 500mL three-necked flasks add on step reaction product compound B (19.3g, 0.0268mol), pyridine (17.7g,
0.2265mol, 8 equivalents), dichloromethane (150mL), nitrogen displacement, the lower stirring dissolved clarifications of (- 20~-5 DEG C) of ice salt bath cooling.Together
When triphosgene (9.6g, 0.0322mol, 1.2 equivalent) is dissolved in 50mL dichloromethane, question response liquid is cooled to after -10 DEG C, drop
Plus the dichloromethane solution for stating triphosgene, temperature control is no more than 5 DEG C.About 1h drops finish, and drop, which finishes, warms naturally to (20-25 DEG C) stirring
1h is reacted, after sampling detection intermediate B reaction completely, reaction solution is poured into 300mL brine ices, point liquid, aqueous phase dichloromethane
Alkane (100mL × 3) is extracted, and merges organic phase, with anhydrous sodium sulfate drying, suction filtration, 40 DEG C are spin-dried for, and obtain compound C crude products
22.9g, next step reaction is can be directly used for without purifying.
ESI[M+1]:720。
1H NMR(400MHz,CDCl3):δ 8.06 (d, J=7.8Hz, 2H), 7.56 (t, J=7.4Hz, 1H), 7.45 (t,
J=7.8Hz, 2H), 5.02~5.09 (m, 2H), 4.73 (d, J=7.6Hz, 1H), 4.68 (s, 1H), 3.72 (d, J=2.5Hz,
1H), 3.54~3.60 (m, 1H), 3.43~3.48 (m, 2H), 2.91 (s, 3H), 2.80~2.87 (m, 1H), 2.54~2.64
(m, 2H), 2.28 (s, 6H), 1.76~1.89 (m, 3H), 1.43~51.51 (m, 3H), 1.39~1.41 (m, 1H), 1.38 (s,
3H), 1.20~1.32 (m, 9H), 1.10~1.17 (m, 3H), 1.05 (d, J=7.1Hz, 3H), 0.82 (t, J=7.4Hz,
3H), 0.70 (d, J=7.5Hz, 3H).
4. -1PCC (pyridinium chloro-chromate) oxidizing process prepare compound D
Compound C (8g, 0.0111mol), dichloromethane (100mL) obtained by step reaction on being added in 250mL reaction bulbs
Stirring and dissolving, is added portionwise pyridinium chloro-chromate (PCC, 7.16g, 0.0333mol, 3 equivalent).Finish, reaction is stirred at room temperature
24h.After sampling detection intermediate C reactions completely, reaction solution is filtered through diatomite, and filtrate uses saturated sodium bicarbonate aqueous solution successively
(50mL), saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying, suction filtration is spin-dried for, and obtains compound D crude product 7.8g, without
Purifying can be directly used for next step reaction.
ESI[M+1]:718。
1H NMR(400MHz,CDCl3):δ 8.03 (d, J=7.8Hz, 2H), 7.57 (t, J=7.4Hz, 1H), 7.44 (t,
J=7.8Hz, 2H), 4.95~5.05 (m, 2H), 4.60 (s, 1H), 4.54 (d, J=7.6Hz, 1H), 4.19 (d, J=
7.8Hz, 1H), 3.59~3.71 (m, 2H), 2.80~2.93 (m, 3H), 2.64 (s, 3H), 2.26 (s, 6H), 1.78~1.85
(m, 2H), 1.65 (dd, J=14.5,2.7Hz, 1H), 1.51~1.56 (m, 1H), 1.48 (s, 3H), 1.25~1.34 (m,
9H), 1.17 (d, J=6.8Hz, 3H), 1.13 (d, J=7.0Hz, 3H), 0.96 (d, J=7.5Hz, 3H), 0.86 (t, J=
7.4Hz,3H).
4. -2 polite oxidizing process prepare compound D
DMSO (2.7g, 0.03459mol, 3 equivalent), dichloromethane (50ml), nitrogen are added in tri- mouthfuls of reaction bulbs of 250ml
Gas is replaced, and is placed in dry ice-propanone bath cooling.Question response liquid is cooled to after -70 DEG C, and oxalyl chloride (2.92g, 0.023mol, 2 is added dropwise
Equivalent), temperature control is no more than -65 DEG C.30min drops finish, and are incubated -65~-70 DEG C of stirring reaction 1h.Dropwise addition intermediate C (8.3g,
Dichloromethane (30ml) solution 0.01153mol), temperature control is no more than -65 DEG C.45min drops finish, insulation reaction 1.5h.Add three
Ethamine (11.64g, 0.1153mol, 10 equivalent).Finish, withdraw from the dry ice bath, warm naturally to room temperature.Add dchloromethane
Reaction solution, uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively.Anhydrous sodium sulfate drying, suction filtration, rotation
It is dry to obtain crude Compound D8.7g, it can be directly used for next step reaction without purifying.
ESI[M+1]:718。
5. prepare compound VII
Step product Compound D (9.7g, 0.0135mol), acetone (60mL) stirring are molten on being added in 250mL reaction bulbs
Solution.Add DBU (5.27g, 0.03377mol, 2.5 equivalent).Finish, 24h is stirred at room temperature.Sample detection compound D reactions complete
Afterwards, solvent is removed under reduced pressure, residue dichloromethane (60mL) dissolves, adjusted with 0.5N potassium dihydrogen phosphate to pH=7
~9, point liquid.Aqueous phase is extracted with dichloromethane (50mL × 2), is merged organic phase, is washed with saturated aqueous common salt (50mL), anhydrous sulphur
Sour sodium is dried, and suction filtration is spin-dried for, and obtains the crude product 6.88g of compound VII, and next step reaction is can be directly used for without purifying.
ESI[M+1]:674。
1H NMR(400MHz,CDCl3):δ 8.01 (d, J=8.1Hz, 2H), 7.55 (t, J=7.6Hz, 1H), 7.43 (t,
J=7.6Hz, 2H), 6.55 (s, 1H), 4.99~5.04 (m, 1H), 4.54 (dd, J=9.6,2.7Hz, 1H), 4.51 (d, J=
7.6Hz, 1H), 4.15 (d, J=8.3Hz, 1H), 3.59~3.64 (m, 2H), 3.13~3.16 (m, 1H), 2.92~2.96 (m,
1H), 2.85 (s, 3H), 2.33~2.36 (m, 1H), 2.26 (s, 6H), 1.99 (s, 3H), 1.86~1.95 (m, 2H), 1.77~
1.82 (m, 2H), 1.50~1.56 (m, 1H), 1.40~1.48 (m, 3H), 1.36 (s, 3H), 1.26~1.30 (m, 9H), 1.15
(d, J=6.8Hz, 3H), 0.95 (d, J=7.4Hz, 3H), 0.89 (t, J=7.3Hz, 3H).
6. prepare compound II
In 250mL three-necked flasks, step reaction gained compound VII (6.88g, 0.0102mol), DMF in addition
(40mL), nitrogen displacement stirs dissolved clarification.Reaction solution is cooled to -25 DEG C, be added portionwise sodium hydride (0.814g, 0.0204mol,
2 equivalents).Finish, in -20~-25 DEG C of insulated and stirred 1h.It is added dropwise carbonyl dimidazoles CDI's (5.02g, 0.0306mol, 3 equivalent)
DMF (20mL) solution, temperature control is no more than -10 DEG C.Drop finishes, in -10~-15 DEG C of insulated and stirred 1h.Sampling HPLC detections have been reacted
Quan Hou, frozen water (120mL) is added dropwise into reaction solution, and temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, stirring 15min, suction filtration,
Filter cake is eluted with water (50mL × 2).Filter cake ethyl acetate (50mL) dissolves, saturated aqueous common salt (30mL) washing, anhydrous slufuric acid
Sodium is dried, and suction filtration is spin-dried for.Column chromatography purifies (200-300 mesh silica gel, column type number：25 × 500m, eluent is methanol：Dichloromethane
Alkane=1:10) white solid 3.6g, as compound II, are obtained.
ESI[M+1]:768。
1H NMR(400MHz,CDCl3):δ 8.08 (s, 1H), 8.03 (d, J=7.1Hz, 2H), 7.56 (t, J=7.4Hz,
1H), 7.44 (t, J=7.8Hz, 2H), 7.35~7.36 (m, 1H), 7.06~7.07 (m, 1H), 6.76 (s, 1H), 5.66 (dd,
J=9.8,3.2Hz, 1H), 4.99~5.04 (m, 1H), 4.51 (d, J=7.6Hz, 1H), 4.15 (d, J=8.8Hz, 1H),
3.55~3.66 (m, 3H), 3.08~3.23 (m, 3H), 2.90 (s, 1H), 2.80~2.97 (m, 2H), 2.78 (m, 3H), 2.28
~2.34 (m, 4H), 2.25 (s, 6H), 2.17 (d, J=3.1Hz, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 1.59~1.68
(m, 4H), 1.40~1.48 (m, 3H), 1.36 (s, 3H), 1.22~1.35 (m, 15H), 1.15 (d, J=6.7Hz, 3H), 0.95
(t, J=7.3Hz, 3H).
Embodiment 2
Fluoro-reaction prepare compound III
Wherein sugared hydroxyl protecting group is acetyl group
The compound II (2.90mmol) of 2.05 grams of acetyl group protections is dissolved in 20 milliliters of DMF/THF mixed solution
(9:1), under the conditions of -20 DEG C, 0.39 gram of potassium tert-butoxide (3.48mmol) is added portionwise, finishes, -20 DEG C of mixture stirs 0.5
Hour, 1.01 grams of NFSI (the double benzsulfamides of N- fluoro) (3.19mmol) are then added, finishes, continues -20 DEG C of reactions two small
When.Sampling HPLC detection reactions are finished, and are added a small amount of water quenching and are gone out reaction, with 50 milliliters of ethyl acetate dilute reaction solutions, Ran Houyong
Saturated aqueous common salt is repeatedly washed (6*50 milliliters), anhydrous sodium sulfate drying, and filtering is spin-dried for obtaining crude product (can be directly used for next
Step).Crude product is eluant, eluent by column chromatography purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea), 4L ethyl acetate, obtains 1.57 grams
Foamy white solid IIIB, should be III！(yield 74.7%).ESI (M+1)=724
Embodiment 3
Docking reaction prepare compound V
1.33 g of compound III (1.84mmol) and 2.44 grams of I (7.36mmol) are dissolved in into 20 milliliters of acetonitrile/waters to mix
(10 in liquid:1), heated overnight at reflux.Second day, reaction solution is cooled to room temperature, is directly spin-dried for, residue passes through column chromatography
(silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane：Methanol=30:1) V crude products (being directly used in next step) are obtained.
Embodiment 4
Deprotection reaction prepares rope Citropten I
V dissolving crude products prepared by upper step are in 20 milliliters of dichloromethane, and 10 milliliters of trifluoroacetic acids, room temperature are added dropwise in zero degree
Stir 3 hours.Reaction solution is spin-dried for, and residue purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane by column chromatography：
Methanol=20:1) 1.26 grams of rope Citropten I are obtained.
MS=423 [(M+2)/2]
Embodiment 5
Compound III CP is that amino directly prepares rope Citropten
By compound III (0.94g, 0.0012mol), 1- (4- aminobutyls) -4- (3- aminophenyls) -1H-1,2,3-
Triazole (0.83g, 0.0036mol, 3eq), acetonitrile (10ml), water (1ml) mixing.Under nitrogen protection, at 55-60 DEG C plus
Thermal response 12h.It is spin-dried for reaction solution, column chromatography purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane：Methanol=20:1),
Obtain rope Citropten white solid, 0.5g, MS=423 [(M+2)/2].
Embodiment 6
Compound III CP is that nitro directly prepares rope Citropten
By compound III (0.94g, 0.0012mol), 1- (4- aminobutyls) -4- (3- nitrobenzophenones) -1H-1,2,3-
Triazole (0.94g, 0.0036mol, 3eq), acetonitrile (10ml), water (1ml) mixing.Under nitrogen protection, at 55 DEG C -60 DEG C
Heating response 6h.40 DEG C are spin-dried for reaction solution, obtain crude product.Column chromatography purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane
Alkane：Methanol=20:1) nitro compound V is obtained, white solid 0.5g adds above-mentioned nitro compound V in reaction bulb
(0.4g, 0.00046mol), methanol 20ml, acetic acid 2 drips, 5% palladium carbon (0.04g, 10%wt), hydrogen displacement, is stirred at room temperature anti-
Answer 16h.After sampling detection intermediate compound I reaction completely, palladium carbon is filtered out, filter cake is eluted with methanol (20ml), and filtrate is spin-dried for, obtain thick
Product.Column chromatography purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane：Methanol=20:1) rope Citropten white, is obtained solid
Body 0.1g.MS=423 ((M+2)/2).
Embodiment 8
Prepare compound III
Compound VII (6.74g, 0.01mol) is dissolved in DMF:THF=9:In 1 mixed solvent (40ml), nitrogen displacement.Will
Reaction solution is cooled to -25 DEG C.Add sodium hydrogen (1g, 0.025mol, 2.5eq).Finish, 1h is reacted in -20 DEG C~-25 DEG C.In batches
Add NFSI (5g, 0.015mol, 1.5eq).Finish, 1h is reacted in -20 DEG C~-25 DEG C.After sampling detection raw material reaction completely,
Frozen water 90ml is added dropwise, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, and stirs 15min, suction filtration, frozen water elution.Filter cake is dissolved in
In 50ml ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Suction filtration, is spin-dried for, and obtains light yellow solid crude product
6.67g, MS=692.The not purified direct next step reaction of crude product.Above-mentioned crude product (6.67g, 0.0096mol) is dissolved in 40mlDMF
In, nitrogen displacement.Reaction solution is cooled to -25 DEG C.Add sodium hydrogen (0.77g, 0.0193mol, 2eq).Finish, in -20 DEG C
~-25 DEG C of reaction 1h.CDI DMF solution (4.84g, 0.0288mol, 3eq) 30ml is added dropwise.Drop finishes, anti-in -20 DEG C~-25 DEG C
Answer 1h.After sampling detection raw material reaction completely, frozen water 90ml is added dropwise, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, stirring
15min, suction filtration, frozen water elution.Filter cake is dissolved in 50ml ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Take out
Filter, 40 DEG C are spin-dried for, and obtain crude product light yellow solid 6.6g, MS=786.Column chromatography purifies (silica gel 200-300 mesh, the Qingdao Huanghai Sea)
(petroleum ether：Acetone=6：1+1% triethylamines) obtain compound as white solid VII6g.
Claims (10)
1. a kind of method for preparing rope Citropten, it is characterised in that this method comprises the following steps：
(1) prepare compound III,
1. compound II carries out fluoro-reaction, generates compound III,
2. compound VII first carries out fluoro-reaction, then generates compound III with carbonyl dimidazoles reaction；
R is H or hydroxy-protecting agent in formula, and described hydroxyl protecting group is acyl protecting groups, preferably benzoyl or acetyl group；
(2) compound III and compound IV (1- (4- aminobutyls) -4- (3- protects aminophenyl) -1H-1,2,3- triazoles)
The side chain ammonia docking of five-membered ring triazole, shape sees below formula into oxazole cycle compound V：
Wherein CP is amino, protection amino or nitro, and the compound V when CP is amino is rope Citropten I；Or
When CP is protection amino, compound V carries out Deprotection after amino, to obtain rope Citropten I；Or
When Cp is nitro, after using catalytic hydrogenating reduction nitro for amino, rope Citropten I is obtained,
See below formula：
2. the method for rope Citropten is prepared according to claim 1, it is characterised in that step (1) fluoro-reaction is used
Fluoro reagent be selected from the double benzsulfamides of N- fluoro, the fluoro- benzene disulfonic acid amides of N- or the fluoro- 4- hydroxyls -1,4- diaza-bicyclos of 1- [2,2,
2] the double tetraphydro-borates of octane；It is preferred that the double benzsulfamides of N- fluoro；
Fluoro reagent and compound II consumptions mol ratio 1~2 preferably 1:1.2~1.5；Fluoro reagent is rubbed with compound VII consumptions
That ratio 1~2 preferably 1:1.2~1.5；The fluoro-reaction 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.
3. the method for rope Citropten is prepared according to claim 1, it is characterised in that step (1) fluoro-reaction is used
Organic solvent be selected from tetrahydrofuran, 2- methyltetrahydrofurans, toluene, 1,4- dioxane, N,N-dimethylformamide, acetic acid
One or two kinds of thing mixed above in ethyl ester or isopropyl acetate, preferably DMF is mixed with tetrahydrofuran
System.
4. the method for rope Citropten is prepared according to claim 1, it is characterised in that the fluoro-reaction of the step (1) exists
Alkali promotes lower progress, and described alkali is selected from potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, cesium carbonate, potassium tert-butoxide, tertiary fourth
One or two kinds of thing mixed above in lithium alkoxide, sodium methoxide, caustic alcohol, sodium hydrogen or NaHMDS, preferably potassium tert-butoxide.
5. the method for rope Citropten is prepared according to claim 1, it is characterised in that the step (2) is in organic solvent
Or organic solvent, with being carried out in water, the organic solvent is selected from tetrahydrofuran, acetonitrile, N, N- dimethylaminos formamide, dimethyl
One or two kinds of thing mixed above in sulfoxide, dichloromethane, toluene；It is preferred that acetonitrile；The organic solvent and water volume ratio
For 1~10：1, preferably 2：1；The reaction dissolvent consumption is：Solvent and compound III ratio are 5~30:1V/W, preferably 5
~7：1V/W；The reaction time is 0.5h~16h；Temperature is 50 DEG C~100 DEG C.
6. the method for rope Citropten is prepared according to claim 5, it is characterised in that the step (2) is used alone organic
During solvent reaction, obtained product is placed in proton solvent, and acyl protecting groups can be sloughed under room temperature to counterflow condition and are obtained
Compound V, described proton solvent is selected from one or both of methanol, ethanol, isopropanol or water thing mixed above；It is preferred that first
Alcohol, the volume ratio of the alcohol and water is 1~10：1, preferably 2：1；Time 0.5h~16h；20 DEG C~100 DEG C of temperature.
7. the method for rope Citropten is prepared according to claim 1, it is characterised in that the reaction of the step (2) is organic
Alkali promotes lower progress, and described organic base is selected from the carbon -7- alkene of 1,8- diazabicylos 11, dicyclohexylcarbodiimide, N, N-
More than the one or two kinds of in lutidines amine, triethylenediamine or 1,5- diazabicyclos [4.3.0] -5- nonenes mix
Compound, preferably DBU；The compound III and compound IV mol ratio is 1:1~3, preferably 1:1~2；Reaction temperature is 0 DEG C
~100 DEG C, preferably 20 DEG C~60 DEG C.
8. preparing the method for rope Citropten according to claim 1, it is characterised in that the step (2), Cp is protection amino
When, reaction product uses acidolysis reaction Deprotection, and rope Citropten is made；The acid of the acidolysis reaction is selected from hydrochloric acid, sulfuric acid, three
It is one or more of in fluoroacetic acid or hydrobromic acid, the protection amino be selected from Boc-NH, BsMoc-NH, Trityl-NH or
MeOTrityl-NH；20 DEG C~50 DEG C of temperature, time 0.5h~10h.
9. the method for rope Citropten is prepared according to claim 1, it is characterised in that the step (2), when Cp is nitro
When, use catalytic hydrogenating reduction nitro for amino, rope Citropten is made；Described catalytic hydrogenation catalyst is palladium carbon or thunder Buddhist nun
Nickel, preferably palladium carbon；The mass ratio of compound V and catalyst amount is 5%~20%, preferably 5%, the pressure of hydrogenation for normal pressure extremely
10MPa, preferably normal pressure；Reaction dissolvent is selected from alcohols, esters or ethers；It is preferred that alcohols；Described alcohols solvent is selected from methanol, second
Alcohol or isopropanol, preferably methanol；Esters solvent is selected from ethyl acetate or isopropyl acetate, ethyl acetate, ether solvent choosing
From ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran or 2- methyltetrahydrofurans, preferably tetrahydrofuran；Reaction temperature is 20 DEG C~80
DEG C, time 1h~10h.
10. the method for rope Citropten is prepared according to claim 1, it is characterised in that the compound II passes through following side
It is prepared by method：
Wherein R is sugared hydroxyl protecting group；
Using CLA as starting material, acyl group protection is carried out to sugared hydroxyl；Then a sugar unit is sloughed in acid condition；
Under triphosgene or phosgene effect, the double hydroxyls of protection form carbonic ester；Then oxidation hydroxyl formation carbonyl, oxidation reaction can be with
Realized using pyridinium chloro-chromate or polite oxidation；Compound II is finally formed in the presence of carbonyl dimidazoles.
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| WO2012117357A3 (en) * | 2011-03-01 | 2012-12-20 | Wockhardt Limited | Process for preparation of ketolide intermediates |
| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN105348341A (en) * | 2015-12-04 | 2016-02-24 | 浙江京新药业股份有限公司 | Method for preparing solithromycin |
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| CN104650166A (en) * | 2014-11-17 | 2015-05-27 | 广东东阳光药业有限公司 | New preparation method of macrolide |
| CN105348341A (en) * | 2015-12-04 | 2016-02-24 | 浙江京新药业股份有限公司 | Method for preparing solithromycin |
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