CN107216360B - A method of preparing rope Citropten - Google Patents
A method of preparing rope Citropten Download PDFInfo
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- CN107216360B CN107216360B CN201610164404.3A CN201610164404A CN107216360B CN 107216360 B CN107216360 B CN 107216360B CN 201610164404 A CN201610164404 A CN 201610164404A CN 107216360 B CN107216360 B CN 107216360B
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Abstract
The present invention provides a kind of method for preparing rope Citropten; method includes the following steps: compound II carries out fluoro-reaction; generate compound III; compound III and compound IV five-membered ring triazole (1- (4- aminobutyl) -4- (3- protects aminophenyl) -1H-1; 2; 3- triazole) side chain ammonia docking, formed oxazole cycle compound V；Compound V forms amino after being deprotected or restored accordingly, obtains rope Citropten I.The method provided by the invention for preparing rope Citropten has got rid of azide intermediate oxidation explosive and dangerous in the prior art, fluoro-reaction, and operation is safer；Especially pleasantly surprised is, since reactant solubility is higher, to make the high conversion rate of reactant when preparing oxazole ring and five-membered ring triazole, and side reaction is few, reduces production cost, is good for the environment, and is suitable for industrialized production, there is biggish application value.
Description
Technical field
The present invention relates to pharmaceutical chemistry, and in particular to process for preparing medicine more particularly to a kind of prepares macrolides medicine
The novel preparation method of object rope Citropten.
Background technique
Rope Citropten (English name Solithromycin) is the macrolides of new generation of Cempra drugmaker exploitation
Antibiotic medicine can also be applied to Chronic Obstructive Pulmonary Disease for treating Community-acquired bacterial pneumonia (CABP)
(COPD), bacterial pneumonia and some treatment of infection, the drug are now in III clinical trial phase.Rope Citropten be at present into
Enter clinical first containing fluorine-substituted macrolides.U.S. chemical abstract CAS:760981-83-7 has following formula
Chemical structure shown in I:
WO2009055557 discloses the method for preparing rope Citropten I as starting material using clarithromycin, such as 1 institute of reaction equation
Show, clarithromycin passes sequentially through acyl group (such as benzoyl Bz) and protects sugared hydroxyl；With the hydroxy activating reagent carbonyl with steric hindrance
Base diimidazole (CDI) reaction generates intermediate CL-1；The oxazole ring intermediate CL-2 containing nitrine is generated with nitrine butylamine；In acidity
Under the conditions of remove one of glycosyl, form intermediate CL-3；It is aoxidized using oxidant by the hydroxyl formed after glycosyl is removed, shape
At intermediate CL-4；Perfluorinated reaction carries out F substitution at ortho position, forms intermediate CL-5；Triazole finally is formed with aromatic alkyne,
And sugared hydroxyl protection is sloughed, rope Citropten is formed.International patent application WO2010048599 has carried out certain tune to above-mentioned
It is whole, it during preparing CL-2 from CL-1, uses 4- amino butanol for raw material, hydroxyl is then converted into azido group, then by original
Method reaction.Reactions steps of this method is long, the danger of the operations such as desugar, oxidation is carried out to containing azide intermediate, because of nitrine
Compound is all to be easy explosion and toxic compound；Meanwhile azide intermediate and acetylenic generate five-membered ring three by cyclization
Side reaction is more in the step of nitrogen azoles.
Reaction equation 1:
WO2014145210 is to reduce reaction step, is improved to the above method, as shown in reaction equation 2.This method is straight
The raw material for introducing included side chain five-membered ring triazole is connect, specific reaction step includes that intermediate CL-1 is prepared by clarithromycin,
It docks, is formed oxazole ring intermediate (wherein CP is amino, protection amino or nitro) with five-membered ring triazole side chain, then according to
It is secondary by desugar, oxidation, fluorination, finally take corresponding method to form it into amino according to CP group, obtain Suo Li
Mycin I.Although the step of this method is without introducing azido and carrying out cyclization with alkynes, reduces reaction step, with
The increasing of reaction raw materials and moiety intermediate molecular weight reduces the dissolution of reaction raw materials and moiety intermediate in organic reaction
Degree, affects post-reaction treatment, and side chain five-membered ring triazole needs to be subjected to desugar, oxidation, is easy to produce more
Side reaction.
Reaction equation 2:
The patent CN104650166 of Guangdong Dongyang Guang Pharmaceutical Co., Ltd discloses another preparation method, such as 3 institute of reaction equation
Show: using the intermediate II being prepared after first desugar oxidation, then docking to form evil using previous five-membered ring triazole side chain
Azoles ring, last fluoro form target compound rope Citropten.This method avoid side chain five-membered ring triazoles to be subjected to desugar, oxidation
Step reduces the generation of side reaction.But since the compound intermediate II after desugar, oxidation is than intermediate CL-1 solubility
Difference causes reaction difficult, and conversion ratio is low；Moreover, exposed amino can generate acyl migration impurity when deprotection, it is difficult to
Implement industrialized production.
Reaction equation 3:
Therefore, there is many defects, unsuitable industrialized productions, it would be highly desirable to improve for the above method.
Summary of the invention
Technical problem to be solved by the present invention lies in overcoming above-mentioned shortcoming, researching and designing get rid of toxic operation,
Side reaction is reduced, reaction yield is improved, reduces cost, is conducive to environmental protection, and prepare rope Citropten method suitable for industrialized production.
To achieve the above object, rope Citropten (Formulas I is prepared the present invention provides a kind of
) method, comprising the following steps:
(1) prepare compound III,
Method one: compound II carries out fluoro-reaction, generates compound III,
Method two: compound VII first carries out fluoro-reaction, then reacts with carbonyl dimidazoles (CDI) and generate compound III；
In formula R be H or hydroxy-protecting agent, the hydroxyl protection base be acyl protecting groups, preferably benzoyl (Bz) base or
Acetyl group (Ac).
The fluoro reagent that the fluoro-reaction uses is selected from N- fluoro bis benzene sulfonamide (NFSI), the fluoro- benzene disulfonic acid amide of N-
(NFOBS) or double tetraphydro-borate (NFTh) the electrophilic fluorination agent of 1- fluoro- 4- hydroxyl -1,4- diaza-bicyclo [2,2,2] octane.It is preferred that
N- fluoro bis benzene sulfonamide (NFSI)
Fluoro reagent and preferred 1:1.2~1.5 of compound II dosage molar ratio 1~2
Fluoro reagent and preferred 1:1.2~1.5 of compound VII dosage molar ratio 1~2
The fluoro-reaction of the step (1) carries out at a temperature of -78 DEG C~30 DEG C, and preferably -20~0 DEG C
Reaction time 0.5h~4h, preferably 2~3h.
The organic solvent that step (1) fluoro-reaction uses is selected from tetrahydrofuran, 2- methyltetrahydrofuran, toluene, 1,
One of 4- dioxane, N,N-dimethylformamide, ethyl acetate or isopropyl acetate or two or more mixtures.It is excellent
Select N,N-dimethylformamide and tetrahydrofuran mixed system.Specific organic solvent is also possible to those skilled in the art can be easily
Complete other organic solvents of the invention, it is not limited to this.
The fluoro-reaction of the step (1) can alkali promotion under carry out, the alkali be inorganic base, selected from potassium carbonate,
Saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, tert-butyl alcohol lithium, sodium methoxide, sodium ethoxide, sodium hydrogen or NaHMDS
One of or two or more mixtures, preferred potassium tert-butoxide.The alkali of realization this programme is also possible to those skilled in the art can
It is readily accomplished other alkali of the invention, it is not limited to this.
(2) compound III and compound IV (1- (4- aminobutyl) -4- (3- protects aminophenyl) -1H-1,2,3- tri-
Nitrogen azoles) five-membered ring triazole side chain ammonia docking, formed oxazole cycle compound V, see below formula:
Wherein CP is amino, protection amino or nitro, and when CP is amino, compound V is rope Citropten I；Work as CP
When to protect amino, the protection amino is selected from Boc-NH, BsMoc-NH, Trityl-NH or MeOTrityl-NH, realizes we
The amino protecting group of case, which is also possible to those skilled in the art, can be readily accomplished other amino protecting groups of the invention, it is not limited to
This.
The step (2) carries out in organic solvent, and the organic solvent is selected from tetrahydrofuran, acetonitrile, N, N- diformazan ammonia
One of base formamide, dimethyl sulfoxide, methylene chloride, toluene or two or more mixtures, preferably acetonitrile.The reaction
Solvent usage are as follows: solvent (mL): compound III weight (g)=5~30:1, preferably 5~7:1.
The step (2) can also be above-mentioned organic solvent and water (such as acetonitrile: water=1~10:1) preferably 2:1 (mL)
It is 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 protection base 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 can be sloughed under room temperature to counterflow condition and protects to obtain compound V, the proton is molten
Agent is selected from alcohol or water or two or more mixtures；The alcohol is selected from methanol, ethyl alcohol, 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) carries out under organic base promotion, and the organic base is selected from 1,8- diazabicylo ten
One carbon -7- alkene (DBU), dicyclohexylcarbodiimide (DCC), N, N- lutidines amine (DMAP), triethylenediamine
(DABCO) or one of 1,5- diazabicyclo [4.3.0] -5- nonene (DBN) or two or more mixtures.It is preferred that DBU.
The molar ratio of the compound III and compound IV 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 goes back
Amino is formed after former nitro, obtains rope Citropten I.See below formula:
The step (2), when Cp is protection amino, the protection amino is selected from Boc-NY, BsMoc-NH, Trityl-
When 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 deamination protection of this programme
Method be also possible to those skilled in the art and can be readily accomplished other methods of the invention, it is not limited to this.
The step (2) uses catalytic hydrogenating reduction nitro for amino, rope Citropten is made when Cp is nitro, described
Catalytic hydrogenation catalyst be palladium carbon or Raney's nickel, preferably palladium carbon；The mass ratio of hydrogenation catalyst dosage and compound V are 5%
~20%, preferably 5%, add the pressure of hydrogen for normal pressure to 10MPa.It is preferred that normal pressure.Reaction dissolvent is selected from alcohols, esters or ethers；
It is preferred that alcohols, the alcohols solvent is selected from methanol, ethyl alcohol 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- methyltetrahydrofuran
Select tetrahydrofuran.(20 DEG C~80 DEG C of other conditions temperature, time 1h~10h).Realize that the nitro reduction of this programme is also possible to
Those skilled in the art can be readily accomplished other reduction nitro methods of the invention, it is not limited to this.
The compound II is prepared by following method:
Using clarithromycin 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, double hydroxyls are protected, carbonic ester is formed；Then oxidation hydroxyl forms carbonyl, oxidation reaction
It can be realized using pyridinium chloro-chromate (PCC) or polite oxidation；Finally formed under the action of carbonyl dimidazoles (CDI)
Compound II, synthetic route are as follows:
Specifically, such as prepare compound II when sugared hydroxyl protection base R is benzoyl:
(1) prepare compound A
In 500mL reaction flask be added clarithromycin (50g, 0.067mol), (18.75mL, 0.135mol, 2 work as triethylamine
Amount), ethyl acetate (350mL) is stirred.Benzoyl oxide (22.5g, 0.1mol, 1.5 equivalent) is added portionwise.It finishes, in room
It is stirred for 24 hours for (20-25 DEG C) under temperature.After detecting clarithromycin fully reacting, evaporating solvent under reduced pressure (45 DEG C of temperature <).In residue
500mL ice methanol is added, (0-5 DEG C) stirring 0.5h under ice bath is filtered.Filter cake is eluted with ice methanol (100mL × 2), and 50 DEG C true
Sky is dry, obtains compound A white solid 56g.
(2) prepare compound B
Step reaction gained compound A (56g, 0.0657mol), ethyl alcohol (300mL), water on being added in 1000mL reaction flask
(300mL) is mixed.It is slowly added dropwise concentrated hydrochloric acid (56mL, 0.672mol, 10 equivalent), about 0.5h drop finishes.After being stirred to react 1h,
Sample detection compound A fully reacting.Reaction solution is set into (0 DEG C -5 DEG C) coolings of ice bath, adjusts pH to 9 with ammonium hydroxide in 10 DEG C or less
~10, there is white solid precipitation.Continue to stir 0.5h, filter.Filter cake is eluted with water (500mL × 2), and 50 DEG C of vacuum drying obtain
To compound B white solid 42g.
Obtained solid ethyl acetate: petroleum ether=77 DEG C of 1:4 mixed solvent recrystallization obtains white solid 37g.
(3) prepare compound C
In 500mL three-necked flask be added on walk reaction product compound B (19.3g, 0.0268mol), pyridine (17.7g,
0.2265mol, 8 equivalents), methylene chloride (150mL), nitrogen displacement, the lower stirring dissolved clarification of (- 20~-5 DEG C) cooling of ice salt bath.Together
When triphosgene (9.6g, 0.0322mol, 1.2 equivalent) is dissolved in 50mL methylene chloride, after reaction solution is cooled to -10 DEG C, drop
In addition stating the dichloromethane solution of triphosgene, temperature control is no more than 5 DEG C.About 1h drop finishes, and drop, which finishes, warms naturally to (20-25 DEG C) stirring
Reaction 1h pours into reaction solution in 300mL brine ice, liquid separation after sample detection intermediate B fully reacting, water phase dichloromethane
Alkane (100mL × 3) extraction, merges organic phase, dry with anhydrous sodium sulfate, and suction filtration is spin-dried for, obtains compound C crude product 22.9g, be not necessarily to
Purifying can be directly used for reacting in next step.
(4-1) PCC oxidizing process prepare compound D
Compound C (8g, 0.0111mol), methylene chloride (100mL) obtained by step reaction on being added in 250mL reaction flask
Pyridinium chloro-chromate (PCC, 7.16g, 0.0333mol, 3 equivalent) is added portionwise in stirring and dissolving.It finishes, reaction is stirred at room temperature
24h.After sample detection compound C fully reacting, reaction solution is filtered through diatomite, and filtrate successively uses saturated sodium bicarbonate aqueous solution
(50mL), saturated salt solution (50mL) washing, anhydrous sodium sulfate is dry, filters, and 40 DEG C are spin-dried for, and obtains compound D crude product 7.8g,
It can be directly used for reacting in next step without purifying.
(4-2) polite oxidizing process prepare compound D
DMSO (dimethyl sulfoxide) (2.7g, 0.03459mol, 3 equivalent), methylene chloride are added in tri- mouthfuls of reaction flasks of 250ml
(50ml), nitrogen displacement are placed in dry ice-propanone bath cooling.After reaction solution is cooled to -70 DEG C, dropwise addition oxalyl chloride (2.92g,
0.023mol, 2 equivalents), temperature control is no more than -65 DEG C.About 30min drop finishes, and -65~-70 DEG C of heat preservation is stirred to react 1h.Chemical combination is added dropwise
Methylene chloride (30ml) solution of object C (8.3g, 0.01153mol), temperature control are no more than -65 DEG C.About 45min drop finishes, insulation reaction
1.5h.It is added triethylamine (11.64g, 0.1153mol, 10 equivalent).It finishes, withdraws from the dry ice bath, warm naturally to room temperature.It is added
Methylene chloride dilute reaction solution successively uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Anhydrous sodium sulfate
It is dry, it filters, 40 DEG C are spin-dried for obtaining compound D crude product 8.7g, can be directly used for reacting in next step 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 flask
Solution.It is added DBU (1,8- diazabicylo, 11 carbon -7- alkene) (5.27g, 0.03377mol, 2.5 equivalent).It finishes, is stirred at room temperature
24h.After sample detection compound D fully reacting, evaporating solvent under reduced pressure, residue is dissolved with methylene chloride (60mL), uses 0.5N
Potassium dihydrogen phosphate be adjusted to pH=7~9, liquid separation.Water phase is extracted with methylene chloride (50mL × 2), merges organic phase, is used
Saturated salt solution (50mL) washing, anhydrous sodium sulfate is dry, filters, and 40 DEG C are spin-dried for, and obtains VII crude product 6.88g of compound, without pure
Changing can be directly used for reacts in next step.
(6) prepare compound II
In 250mL three-necked flask, 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).It finishes, in -20 DEG C~-25 DEG C insulated and stirred 1h.It is added dropwise carbonyl dimidazoles CDI (5.02g, 0.0306mol, 3 equivalent)
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.It takes
After sample detects fully reacting, ice water (120mL) is added dropwise into reaction solution, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, and stirs
15min is mixed, is filtered, filter cake is eluted with water (50mL × 2).Filter cake is dissolved with ethyl acetate (50mL), saturated salt solution (30mL)
Washing, anhydrous sodium sulfate is dry, filters, is spin-dried for.Column chromatographic purifying (200-300 mesh silica gel, column type number: 25 × 500m, eluent
For methanol: methylene chloride=1:10), obtain compound II white solid 3.6g.
The method provided by the invention for preparing rope Citropten has got rid of azide intermediate explosive and dangerous in the prior art
Oxidation, fluoro-reaction, operation are safer；Especially pleasantly surprised is when preparing oxazole ring and five-membered ring triazole, due to anti-
It answers object solubility higher, makes the high conversion rate of reactant, side reaction is few, reduces production cost, is good for the environment, and is suitable for industrialization
Production, there is biggish application value.
Specific 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
It invents rather than limits the scope of the invention.
Additive amount, content and the concentration of many kinds of substance is referred to herein, wherein the percentage composition, except special instruction
Outside, all refer to mass percentage.
It in the embodiments herein, is illustrated if do not made for reaction temperature or operation temperature, the temperature is logical
Often refer to room temperature (20-25 DEG C).
In the compound of the present invention structural formula, hydroxyl protection base BzO- is benzoyloxy, this is those skilled in the art
Known to member.
One, reagent
Reagent: reactant and catalyst used in the embodiment of the present invention are 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.
Two, detection method
1HNMR Nuclear Magnetic Resonance uses BRUKER-400MHz.
Mass spectrograph is LC-MS instrument (LCMS), and model: Agilent 6120B, detector: DAD, mobile phase A are 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
In 500mL reaction flask be added clarithromycin (50g, 0.067mol), (18.75mL, 0.135mol, 2 work as triethylamine
Amount), ethyl acetate (350mL) is stirred.Benzoyl oxide (22.5g, 0.1mol, 1.5 equivalent) is added portionwise.It finishes, in room
It is stirred for 24 hours for (20-25 DEG C) under temperature.After detecting clarithromycin fully reacting, evaporating solvent under reduced pressure (45 DEG C of temperature <).In residue
500mL ice methanol is added, (0-5 DEG C) stirring 0.5h under ice bath is filtered.Filter cake is eluted with ice methanol (100mL × 2), and 50 DEG C true
Sky is dry, obtains compound A white solid 56g.
ESI[M+1]:852
2. prepare compound B
Step reaction gained compound A (56g, 0.0657mol), ethyl alcohol (300mL), water on being added in 1000mL reaction flask
(300mL) is mixed.It is slowly added dropwise concentrated hydrochloric acid (56mL, 0.672mol, 10 equivalent), about 0.5h drop finishes.After being stirred to react 1h,
Sample detection intermediate A fully reacting.Reaction solution is set into (0-5 DEG C) cooling of ice bath, in 10 DEG C or less with ammonium hydroxide adjust pH to 9~
10, there is white solid precipitation.Continue to stir 0.5h, filter.Filter cake is eluted with water (500mL × 2), and 50 DEG C of vacuum drying obtain
White solid 42g.
Obtained solid ethyl acetate: petroleum ether=1:4 mixed solvent recrystallization obtains compound B white solid 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 flask be added on walk reaction product compound B (19.3g, 0.0268mol), pyridine (17.7g,
0.2265mol, 8 equivalents), methylene chloride (150mL), nitrogen displacement, the lower stirring dissolved clarification of (- 20~-5 DEG C) cooling of ice salt bath.Together
When triphosgene (9.6g, 0.0322mol, 1.2 equivalent) is dissolved in 50mL methylene chloride, after reaction solution is cooled to -10 DEG C, drop
In addition stating the dichloromethane solution of triphosgene, temperature control is no more than 5 DEG C.About 1h drop finishes, and drop, which finishes, warms naturally to (20-25 DEG C) stirring
Reaction 1h pours into reaction solution in 300mL brine ice, liquid separation after sample detection intermediate B fully reacting, water phase dichloromethane
Alkane (100mL × 3) extraction, merges organic phase, dry with anhydrous sodium sulfate, filters, 40 DEG C are spin-dried for, and obtain compound C crude product
22.9g can be directly used for reacting in next step 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).
- 1PCC 4. (pyridinium chloro-chromate) oxidizing process prepare compound D
Compound C (8g, 0.0111mol), methylene chloride (100mL) obtained by step reaction on being added in 250mL reaction flask
Pyridinium chloro-chromate (PCC, 7.16g, 0.0333mol, 3 equivalent) is added portionwise in stirring and dissolving.It finishes, reaction is stirred at room temperature
24h.After sample detection intermediate C fully reacting, reaction solution is filtered through diatomite, and filtrate successively uses saturated sodium bicarbonate aqueous solution
(50mL), saturated salt solution (50mL) washing, anhydrous sodium sulfate is dry, filters, is spin-dried for, obtains compound D crude product 7.8g, be not necessarily to
Purifying can be directly used for reacting in next step.
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), methylene chloride (50ml), nitrogen are added in tri- mouthfuls of reaction flasks of 250ml
Gas displacement is placed in dry ice-propanone bath cooling.After reaction solution is cooled to -70 DEG C, oxalyl chloride (2.92g, 0.023mol, 2 is added dropwise
Equivalent), temperature control is no more than -65 DEG C.30min drop finishes, and -65~-70 DEG C of heat preservation is stirred to react 1h.Dropwise addition intermediate C (8.3g,
Methylene chloride (30ml) solution 0.01153mol), temperature control are no more than -65 DEG C.45min drop finishes, insulation reaction 1.5h.It is added three
Ethamine (11.64g, 0.1153mol, 10 equivalent).It finishes, withdraws from the dry ice bath, warm naturally to room temperature.Methylene chloride dilution is added
Reaction solution successively uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Anhydrous sodium sulfate is dry, filters, rotation
It is dry to obtain crude Compound D8.7g, it can be directly used for reacting in next step 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 flask
Solution.It is added DBU (5.27g, 0.03377mol, 2.5 equivalent).It finishes, is stirred at room temperature for 24 hours.Sample detection compound D fully reacting
Afterwards, evaporating solvent under reduced pressure, residue are dissolved with methylene chloride (60mL), are adjusted to pH=7 with the potassium dihydrogen phosphate of 0.5N
~9, liquid separation.Water phase is extracted with methylene chloride (50mL × 2), is merged organic phase, is washed with saturated salt solution (50mL), anhydrous sulphur
Sour sodium is dry, filters, is spin-dried for, obtains VII crude product 6.88g of compound, can be directly used for reacting in next step 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 flask, 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).It finishes, in -20~-25 DEG C of insulated and stirred 1h.Carbonyl dimidazoles CDI (5.02g, 0.0306mol, 3 equivalent) is added dropwise
DMF (20mL) solution, temperature control are no more than -10 DEG C.Drop finishes, in -10~-15 DEG C of insulated and stirred 1h.Sampling HPLC detection has been reacted
Ice water (120mL) is added dropwise into reaction solution in Quan Hou, and temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, and stirs 15min, filters,
Filter cake is eluted with water (50mL × 2).Filter cake is dissolved with ethyl acetate (50mL), saturated salt solution (30mL) washing, anhydrous slufuric acid
Sodium is dry, filters, is spin-dried for.(200-300 mesh silica gel, column type number: 25 × 500m, eluent are methanol to column chromatographic purifying: dichloromethane
Alkane=1:10), obtain white solid 3.6g, as compound II.
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 protection base is acetyl group
The compound II (2.90mmol) that 2.05 grams of acetyl group are protected is dissolved in the mixed solution of 20 milliliters of DMF/THF
(9:1) under the conditions of -20 DEG C, is added portionwise 0.39 gram of potassium tert-butoxide (3.48mmol), finishes, and -20 DEG C of mixture are stirred 0.5
Hour, 1.01 grams of NFSI (N- fluoro bis benzene sulfonamide) (3.19mmol) are then added, finish, it is two small to continue -20 DEG C of reactions
When.It samples HPLC and detects end of reaction, a small amount of water quenching reaction is added, with 50 milliliters of ethyl acetate dilute reaction solutions, then uses
Saturated salt solution repeatedly washs (6*50 milliliters), and anhydrous sodium sulfate, which dries, filters, to be spin-dried for obtaining crude product and (can be directly used for next
Step).Crude product passes through column chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea), and 4L ethyl acetate is eluant, eluent, obtains 1.57 grams
Foamy white solid 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 20 milliliters of acetonitrile/waters to mix
(10:1), heated overnight at reflux in liquid.Second day, reaction solution is cooled to room temperature, is directly spin-dried for, residue is chromatographed by column
(silica gel 200-300 mesh, the Qingdao Huanghai Sea) (methylene chloride: methanol=30:1) obtains V crude product (being directly used in next step).
Embodiment 4
Deprotection reaction prepares rope Citropten I
V crude product prepared by upper step is dissolved in 20 milliliters of methylene chloride, 10 milliliters of trifluoroacetic acids, room temperature is added dropwise in zero degree
Stir 3 hours.Reaction solution is spin-dried for, residue by column chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (methylene chloride:
Methanol=20:1) obtain 1.26 grams of rope Citropten I.
MS=423 [(M+2)/2]
Embodiment 5
The CP of compound III is that amino directly prepares rope Citropten
By compound III (0.94g, 0.0012mol), 1- (4- aminobutyl) -4- (3- aminophenyl) -1H-1,2,3-
Triazole (0.83g, 0.0036mol, 3eq), acetonitrile (10ml), water (1ml) mixing.Under nitrogen protection, add at 55-60 DEG C
Thermal response 12h.It is spin-dried for reaction solution, column chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (methylene chloride: methanol=20:1),
Obtain rope Citropten white solid, 0.5g, MS=423 [(M+2)/2].
Embodiment 6
The CP of compound III is that nitro directly prepares rope Citropten
By compound III (0.94g, 0.0012mol), 1- (4- aminobutyl) -4- (3- nitrobenzophenone) -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 reaction 6h.40 DEG C are spin-dried for reaction solution, obtain crude product.Column chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (dichloromethane
Alkane: methanol=20:1) obtain nitro compound V, white solid 0.5g be added in reaction flask above-mentioned nitro compound V (0.4g,
0.00046mol), methanol 20ml, acetic acid 2 drip, 5% palladium carbon (0.04g, 10%wt), and reaction 16h is stirred at room temperature in hydrogen displacement.
After sample detection intermediate compound I fully reacting, palladium carbon is filtered out, filter cake is eluted with methanol (20ml), and filtrate is spin-dried for, and obtains crude product.Column
Chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea) (methylene chloride: methanol=20:1), obtains rope Citropten white solid
0.1g.MS=423 ((M+2)/2).
Embodiment 8
Prepare compound III
Compound VII (6.74g, 0.01mol) is dissolved in DMF:THF=9:1 mixed solvent (40ml), nitrogen displacement.It will
Reaction solution is cooled to -25 DEG C.It is added sodium hydrogen (1g, 0.025mol, 2.5eq).It finishes, in -20 DEG C~-25 DEG C reaction 1h.In batches
It is added NFSI (5g, 0.015mol, 1.5eq).It finishes, in -20 DEG C~-25 DEG C reaction 1h.After sample detection raw material fully reacting,
Ice water 90ml is added dropwise, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, and stirs 15min, filters, ice water elution.Filter cake is dissolved in
In 50ml ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, is spin-dried for, obtains light yellow solid crude product
6.67g MS=692.Crude product directly reacts in next step without further purification.Above-mentioned crude product (6.67g, 0.0096mol) is dissolved in 40mlDMF
In, nitrogen displacement.Reaction solution is cooled to -25 DEG C.It is added sodium hydrogen (0.77g, 0.0193mol, 2eq).Finish, in -20 DEG C~-
25 DEG C of reaction 1h.DMF solution (4.84g, 0.0288mol, 3eq) 30ml of CDI is added dropwise.Drop finishes, and reacts in -20 DEG C~-25 DEG C
1h.After sample detection raw material fully reacting, ice water 90ml is added dropwise, temperature control is no more than 10 DEG C, there is solid precipitation.Drop finishes, stirring
15min is filtered, ice water elution.Filter cake is dissolved in 50ml ethyl acetate, saturated common salt water washing, and anhydrous sodium sulfate is dry.It takes out
Filter, 40 DEG C are spin-dried for, and obtain crude product light yellow solid 6.6g, MS=786.Column chromatographic purifying (silica gel 200-300 mesh, the Qingdao Huanghai Sea)
(petroleum ether: acetone=6:1+1% triethylamine) obtains compound as white solid VII6g.
Claims (13)
1. a kind of method for preparing rope Citropten, which is characterized in that method includes the following steps:
(1) prepare compound III,
1. compound II carries out fluoro-reaction, compound III is generated,
Or
2. compound VII first carries out fluoro-reaction, then reacts with carbonyl dimidazoles and generate compound III；
R is H or hydroxy-protecting agent in formula, and the hydroxyl protection base is acyl protecting groups；
(2) compound III is docked with the side chain ammonia of compound IV, is formed oxazole cycle compound V, is seen below formula:
Wherein CP is protection amino, and the step (2) carries out in organic solvent with water, and the organic solvent is selected from tetrahydro furan
It mutters, acetonitrile, N, one of N- dimethylamino formamide, dimethyl sulfoxide, methylene chloride, toluene or two or more mixing
Object；Compound V carries out Deprotection to obtain rope Citropten I after amino；See below formula:
2. preparing the method for rope Citropten according to claim 1, which is characterized in that the hydroxyl protection base is benzoyl
Base or acetyl group.
3. preparing the method for rope Citropten according to claim 1, which is characterized in that step (1) fluoro-reaction uses
Fluoro reagent be selected from N- fluoro bis benzene sulfonamide, the fluoro- benzene disulfonic acid amide of N- or the fluoro- 4- hydroxyl -1,4- diaza-bicyclo of 1- [2,2,
2] the double tetraphydro-borates of octane；
Fluoro reagent and compound II dosage molar ratio are 1~2；Fluoro reagent and compound VII dosage molar ratio are 1~2；Institute
Fluoro-reaction is stated to carry out at a temperature of -78 DEG C~30 DEG C；Reaction time 0.5h~4h.
4. preparing the method for rope Citropten according to claim 3, which is characterized in that fluoro reagent is rubbed with compound II dosage
You are than being 1.2~1.5；Fluoro reagent and compound VII dosage molar ratio are 1.2~1.5；The fluoro-reaction is at -20~0 DEG C
At a temperature of carry out；2~3h of reaction time.
5. preparing the method for rope Citropten according to claim 1, which is characterized in that step (1) fluoro-reaction uses
Organic solvent be selected from tetrahydrofuran, 2- methyltetrahydrofuran, toluene, 1,4- dioxane, N,N-dimethylformamide, acetic acid
One of ethyl ester or isopropyl acetate or two or more mixtures.
6. preparing the method for rope Citropten according to claim 5, which is characterized in that step (1) fluoro-reaction uses
Organic solvent be N,N-dimethylformamide and tetrahydrofuran mixed system.
7. preparing the method for rope Citropten according to claim 1, which is characterized in that the fluoro-reaction of the step (1) exists
Alkali promotes lower progress, and the alkali is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, tertiary fourth
Lithium alkoxide, sodium methoxide, sodium ethoxide, one of sodium hydrogen or NaHMDS or two or more mixtures.
8. preparing the method for rope Citropten according to claim 1, which is characterized in that the organic solvent is with water volume ratio
1~10:1；The reaction dissolvent consumption are as follows: the ratio of solvent and compound III are 5~30:1V/W；The reaction time is
0.5h~16h；Temperature is 50 DEG C~100 DEG C.
9. preparing the method for rope Citropten according to claim 8, which is characterized in that described organic molten in the step (2)
Agent and water volume ratio are 2:1；The reaction dissolvent consumption are as follows: the ratio of solvent and compound III are 5~7:1V/W.
10. preparing the method for rope Citropten according to claim 1, which is characterized in that the reaction of the step (2) is organic
Alkali promotes lower progress, and the organic base is selected from 1,8- diazabicylo, 11 carbon -7- alkene, dicyclohexylcarbodiimide, N, N-
One of lutidines amine, triethylenediamine or 1,5- diazabicyclo [4.3.0] -5- nonene are two or more mixed
Close object；The molar ratio of the compound III and compound IV is 1:1~3；Reaction temperature is 0 DEG C~100 DEG C.
11. preparing the method for rope Citropten according to claim 10, which is characterized in that in the step (2), the chemical combination
The molar ratio of object III and compound IV is 1:1~2；Reaction temperature is 20 DEG C~60 DEG C.
12. preparing the method for rope Citropten according to claim 1, which is characterized in that the step (2), reaction product is adopted
With acidolysis reaction Deprotection, rope Citropten is made；The acid of the acidolysis reaction is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrogen bromine
One or more of in acid, the protection amino is selected from Boc-NH, BsMoc-NH, Trityl-NH or MeOTrityl-NH；Temperature 20
DEG C~50 DEG C, time 0.5h~10h.
13. preparing the method for rope Citropten according to claim 1, which is characterized in that the compound II passes through following side
Method preparation:
Wherein R is sugared hydroxyl protection base；
Using clarithromycin 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, double hydroxyls are protected, carbonic ester is formed；Then oxidation hydroxyl forms carbonyl, and oxidation reaction can be with
It is realized using pyridinium chloro-chromate or polite oxidation；Compound II is finally formed under the action of carbonyl dimidazoles.
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| 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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