CN108129525B - A kind of preparation method of Etoposide intermediate - Google Patents
A kind of preparation method of Etoposide intermediate Download PDFInfo
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- CN108129525B CN108129525B CN201711465169.4A CN201711465169A CN108129525B CN 108129525 B CN108129525 B CN 108129525B CN 201711465169 A CN201711465169 A CN 201711465169A CN 108129525 B CN108129525 B CN 108129525B
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Abstract
The invention discloses a kind of preparation methods of Etoposide intermediate.This method is with 4; 6-O- acetal-D-Glucose is that starting material reacts in the presence of acid binding agent with benzyl chloroformate; high yield obtains 4; 6-O- acetal -1-O- benzyloxycarbonyl group-β-D-Glucose, then through 2,2- dichloroacetyl chloride double esterification; most Etoposide intermediate 2 is obtained through palladium carbon catalysis reduction afterwards; bis--the O- of 3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose.Raw material of the present invention is cheap and easy to get, easy to operate, reaction condition is mild, and reaction yield is high, and product purity is high, and environmental pollution is few, is suitable for industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to a kind of Etoposide intermediate --- 2,3- bis--O- (2,
2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose preparation method.
Background technique
Etoposide is cell cycle specific anti-tumor drug, acts on DNA topoisomerase II, forms drug-enzyme-
DNA stable invertibity compound hinders DNA to repair.Experiment finds that this compound can be reversed with the removing of drug, makes to damage
DNA repaired, reduce cytotoxicity.Therefore, extend the administration time of drug, improve anti-tumor activity.2017
October 27, the carcinogenic substance inventory edit reference that international cancer research institution, the World Health Organization announces, Etoposide exist
A kind of antineoplastic in a kind of carcinogenic substance inventory.The structural formula of Etoposide is as follows:
2,3- bis--O- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose, are anticarcinogen Etoposides
Key intermediate, English name 4,6-O-ethylidene-2,3-di-O- (2,2-dichloroacetate)-β-D-
Glucopyranose, No. CAS is 149403-65-6, structural formula are as follows:
Kurabayashi, Katsuhiko et al. report formula (1) compound 2 in the clear 59-98098 of JP, the bis--O- of 3- (2,
2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose synthesis technology, synthetic route is as follows:
The synthesis technology uses D-Glucose for starting material, and raw material is cheap and easy to get, but upper benzyloxycarbonyl group protects step, makes
With water as solvent, sodium hydroxide does acid binding agent, and reaction process and post-processing smell are larger, yield be only 35% or so and purity compared with
It is low, product purification difficult.During above-mentioned hydrogenation deprotection, catalyst is made using palladium carbon, it is easy to generate a large amount of structure
Formula is the α configurational isomer (reaction equation is as follows) of formula (5), is caused in the synthesis of Etoposide because cannot be higher
The intermediate of formula (1) compound of purity and generate a large amount of isomer impurities and other impurities so that the purifying of Etoposide is difficult
Degree increases, yield is lower, and production cost greatly improved.
Tadashi Fujii, Iwatsuki et al. are reported in US4757138 with 4,6-O- acetal -1-O- benzyloxy carbonyl
Base-β-D-Glucose (Formula (3)) is the method for raw material preparation formula (1) compound, and synthetic route is as follows:
Although the yield of document preparation formula (4) compound and formula (1) compound is all larger than 90%, it is in preparation formula (4)
During compound, using 1 class solvent dichloroethanes being more toxic, this prepares pharmaceutical intermediate now and should be avoided,
According to Formula (4) prepared by document, fusing point consistent with document is 150~151 DEG C, but HPLC purity is merely greater than 98%, is used
Its compound further prepared (1), purity is about 93% or so, and not only α configurational isomer is larger, and other impurities are also very big.
Using ethyl acetate as hydrogenation solvent in Chinese patent CN102180920, Pd/C is carried out as catalyst
Reaction, and product is obtained with petroleum ether crystallization.But formula obtained in the patent (1) although compound isomers 1% or so,
Other impurities are larger, always miscellaneous to have reached 5% or so, still reach to less than the requirement for simplifying Etoposide technique.
Etoposide is classified as a kind anti-cancer drugs by the World Health Organization, indicates that the dosage of the drug can be increasing, and
And the dosage of key intermediate also can gradually increase.Enhancing year by year with Chinese Government to environmental protection consciousness, develops one kind
Low cost, high yield, the bis--O- of 2 environmental-friendly, 3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose
Synthetic method is known as our new research topics.
Summary of the invention
The present invention overcomes above-mentioned the deficiencies in the prior art, provide Etoposide intermediate --- 2,3- bis--O- (2,2-
Dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose preparation method, this method is with 4,6-O- acetal-D-Glucose
It is reacted in the presence of acid binding agent with benzyl chloroformate for starting material, high yield obtains 4,6-O- acetal -1-O- benzyl
Oxygen carbonyl-β-D-Glucose, then through 2,2- dichloroacetyl chloride double esterification, most afterwards through palladium carbon catalysis reduction obtain the bis--O- of 2,3- (2,
2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose.Raw material of the present invention is cheap and easy to get, easy to operate, reaction condition
Mildly, reaction yield is high, and product purity is high, and environmental pollution is few, is suitable for industrialized production.
The technical scheme is that a kind of Etoposide intermediate --- 2,3- bis--O- (2,2- dichloro-acetyl) -4,
The preparation method of 6-O- ethylidene-β-D- glucopyranose, characterized in that
1) in the in the mixed solvent of DMF and tetrahydrofuran, formula (2) compound and acid binding agent is added, benzyl chloroformate is added dropwise,
Drop is stirred to react after finishing；Tetrahydrofuran is recovered under reduced pressure after the reaction was completed, methylene chloride (or chloroform) and water is added in residue,
By extracting liquid separation, organic layer washing obtains methylene chloride (or chloroform) solution of formula (3) compound after dry；
2) acid binding agent will be added in methylene chloride (or chloroform) solution of formula (3) compound that step 1) obtains, drips
Add 2,2- dichloroacetyl chloride, drop is stirred to react after finishing, added water and stirred liquid separation after the reaction was completed, organic layer through washing, drying and
Evaporated under reduced pressure obtains the crude product of formula (4) compound, then is refining to obtain highly finished product by ethyl alcohol；
3) palladium carbon catalytic hydrogenation deprotection base, filtering in acetone by the dissolution of formula (4) compound represented, is added
Palladium carbon is recycled, acetone is recycled by vacuum distillation, remaining solid is refining to obtain in Etoposide shown in formula (1) by isopropyl ether
Mesosome 2, the bis--O- of 3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose.
Reaction equation of the invention are as follows:
Wherein formula (2) compound is 4,6-O- acetal-D-Glucose, and formula (3) compound is 4,6-O- acetal -1-O-
Benzyloxycarbonyl group-β-D-Glucose；Formula (4) compound is the bis--O- of 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-
O- ethylidene-β-D- glucopyranose.
The mass ratio of mixed solvent DMF and tetrahydrofuran in the step 1) are 1:0.5~1:5, preferably 1:2, mixing
The mass ratio of solvent and formula (2) compound is 2~10:1, preferably 3:1；Reaction dissolvent is very little, is unfavorable for reaction heat dissipation, reacts molten
Agent is too many, is unfavorable for environmental protection.
The step 1) or 2) in acid binding agent be triethylamine, diisopropylethylamine or pyridine, preferably triethylamine.
Reaction temperature control is at 0~40 DEG C in the step 1), and preferably 20~30 DEG C.
The preferred methylene chloride of extractant in the step 1)；In bulk pharmaceutical chemicals dissolvent residual, methylene chloride allows most
High threshold is far longer than chloroform, and safety is higher, therefore preferred methylene chloride.
The yield of methylene chloride (or chloroform) solution of step 1) Chinese style (3) compound is based on 100%, directly
Investment is reacted in next step.
Reaction temperature control is at -10~10 DEG C in the step 2), and preferably -5~5 DEG C.
Ethyl alcohol purification in the step 2) are as follows: alcohol reflux to solid is added and dissolves, cool down crystallization, by filtering, drying
It is dry to obtain formula (4) compound.
Palladium carbon content in the step 3) is 10%, the mass ratio of formula (4) compound and 10% palladium carbon for 1:0.05~
0.5, preferably 1:0.01~1:0.2.
Hydrogenation in the step 3) is passed through Hydrogen Vapor Pressure in 0.1~0.5MPa, and reaction temperature is -10~0 DEG C,
It is preferred that -5~0 DEG C.
Step 1) the end of reaction steams tetrahydrofuran, it can be achieved that recovery, the step 2) by being concentrated under reduced pressure
In dichloromethane or chloroform after vacuum distillation recycling, be directly used in step 1), realize recovery, be conducive to environment
Protection.Palladium carbon used in the step 3) is directly used in next batch reaction, palladium carbon applies number by filtering, acetone washing
About 50 times, acetone is re-used by recycling.Therefore the pollution of anti-response environment can be further reduced.
Preferably, in the step 1), the molar ratio of formula (2) compound, benzyl chloroformate and acid binding agent be 1:1.0~
1.2:1.1~1.5.
Preferably, in the step 2), the molar ratios of 2,2- dichloroacetyl chlorides, acid binding agent and formula (2) compound is 1.0~
1.2:1.1~1.5:1.
Step 1) uses water as solvent in the clear 59-98098 document of JP, and sodium hydroxide does acid binding agent, although cost is relatively low,
Because benzyl chloroformate is not soluble in water, react for heterogeneous reaction, with the progress of reaction, formula (3) compound of generation can be wrapped
Remaining benzyl chloroformate is wrapped up in, reaction is caused no longer to carry out, and in formula (3) compound being obtained by filtration, because comprising a large amount of
Benzyl chloroformate, cause the unstable of product, largely decomposed being further processed process, cause yield lower.The present invention adopts
With mixed solvent, it is in order to which heterogeneous reaction is become homogeneous reaction, reaction process is without solid that organic base liquid base, which does acid binding agent,
It is precipitated, benzyl chloroformate completely consumes during the reaction, and last handling process will not cause formula (3) chemical combination because of the change of pH value
The decomposition of object substantially increases the yield and purity of formula (3) compound.
The beneficial effects of the present invention are:
1, the synthesis of formula (3) compound is dissolved into solvent using homogeneous reaction, raw material and product in organic solvent,
And realize the recycling of tetrahydrofuran.The step three wastes are few and processed, and almost quantitative and product purity is high for product yield, reaction
Mild condition, extraction solution are suitble to industrialized production directly as next step reaction solution.
2, the preparation process of formula (4) compound is changed using the methylene chloride as solvent being more toxic in document, because upper
Formula (3) compound purity of single step reaction preparation is high, formula (4) compound HPLC purity of step preparation 99.5% with
On, formula (1) compound prepared by hydrogenating reduction, not only for α configurational isomer less than 0.5%, other impurities are smaller.For into
One step prepares Etoposide and provides formula (1) compound of high-purity, greatly reduces the complexity of subsequent reaction.
3, acetone solvent used by formula (1) preparation of compounds, palladium-carbon catalyst recycle re-using, reduce
Environmental protection pressure.
4, preparation method raw material of the invention is cheap and easy to get, easy to operate, reaction condition is mild, and reaction yield is high (total to receive
Rate >=85%), product purity is high, and (HPLC detects α configuration impurity less than 0.5%, and always miscellaneous less than 1%), environmental pollution is few, fits
Together in industrialized production.
Specific embodiment
The present invention will be further explained combined with specific embodiments below, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1:
1) 4,6-O- acetal -1-O- benzyloxycarbonyl group-β-D-Glucose preparation
500g 4,6-O- acetal-D-Glucose (2.4mol) is added to equipped with churned mechanically 5000ml reaction flask
In, 500g DMF, 1000g tetrahydrofuran and 303g triethylamine (3.0mol) are added, stirring to solid is dissolved.By 443.5g chlorine
Dropping funel is added in benzyl formate (2.6mol, content 98%), and water-bath controls 20~30 DEG C of reaction temperature, and chloro-carbonic acid benzyl is added dropwise
Ester, drop Bi Jixu are stirred 1 hour, and tetrahydrofuran is recovered under reduced pressure after the reaction was completed, 1000ml water and 2000ml is added in residue
Methylene chloride, liquid separation, organic phase 1000ml*2 water washing, anhydrous magnesium sulfate dry, filter, and filtrate direct plunges into anti-in next step
It answers, reaction yield is based on 100%).
2) bis--O- of 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose
Preparation
Upper step dichloromethane solution is added to equipped in churned mechanically 5000ml reaction flask, 303g triethylamine is added
(3.0mol) is cooled to -5~5 DEG C, and 412.7g 2,2- dichloroacetyl chloride (2.8mol, content is added dropwise in control at this temperature
99%), drop Bi Jixu is stirred to react 1 hour at such a temperature, and 1000ml water is added, and stirs liquid separation, and organic phase uses 1000ml* again
2 water washings are to neutrality, and anhydrous magnesium sulfate is dry, and recycling methylene chloride is concentrated under reduced pressure, and residue is added 2000g dehydrated alcohol, adds
Heat is back to solid dissolution, is cooled to room temperature crystallization, and by filtering, drying obtains 1214g white solid, two step yields
90.0%, HPLC purity 99.8%, m.p.154~155.5 DEG C (150~151 DEG C of document).
3) bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose preparation
By the bis--O- of 500g1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyra
Sugared (0.89mol) is added in 5000ml autoclave pressure, adds 3000g acetone and 50g palladium carbon (content 10%), it is cooled to -5~
0 DEG C, lead to nitrogen displacement twice, then be passed through hydrogen, keeps 0.1~0.5MPa of reaction pressure to hydrogen is no longer inhaled, filter, palladium carbon recycling
It applies, reaction solution evaporated under reduced pressure, 1500g isopropyl ether is added in residue, is heated to solid dissolution, is cooled to 0~5 DEG C of crystallization, leads to
It is obtained by filtration 365.7g white solid, yield 96.1%, HPLC detects α configuration impurity less than 0.5%, total miscellaneous less than 1%.
Embodiment 2
1) preparation of 4,6-O- acetal -1-O- benzyloxycarbonyl group-b-D- glucose
100kg DMF, 200kg tetrahydrofuran and 60.6kg triethylamine are added in 1000L reaction kettle, adds 100kg
4,6-O- acetals-D-Glucose, stirring to solid are dissolved.88.7kg benzyl chloroformate (content 98%) is added to head tank
In, 20~30 DEG C of reaction temperature are controlled, benzyl chloroformate is added dropwise, drop Bi Jixu is stirred 1 hour, and tetrahydrofuran is recovered under reduced pressure, remains
300kg water and 400kg methylene chloride are added in excess, liquid separation, organic phase 200kg*2 water washing, anhydrous magnesium sulfate is dry, mistake
Filter, filtrate direct plunges into be reacted in next step, and reaction yield is based on 100%)
2) bis--O- of 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose
Preparation
Upper step dichloromethane solution is added in 1000L reaction kettle, 60.6kg triethylamine is added, is cooled to -5~5
DEG C, 82.5kg 2,2- dichloroacetyl chloride (content 99%) is added dropwise in control at this temperature, and drop Bi Jixu is stirred to react at such a temperature
1 hour, 300kg water is added, stirs liquid separation, organic phase uses 200kg*2 water washing to neutrality again, and anhydrous magnesium sulfate is dry, decompression
400kg dehydrated alcohol is added in concentration and recovery methylene chloride, residue, is heated to reflux to solid and dissolves, is cooled to room temperature crystallization, leads to
Filtering, drying obtain 250.9kg white solid, two step yields 93.0%, HPLC purity 99.7%, m.p.154~155.5
℃。
3) bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose preparation
By the bis--O- of 50kg 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyra
Sugar is added in 1000L autoclave pressure, is added 300kg acetone and 5kg palladium carbon (content 10%), is cooled to -5~0 DEG C, and nitrogen is led to
Displacement twice, then is passed through hydrogen displacement twice, leads to hydrogen and 0.1~0.5MPa of reaction pressure is kept to return to hydrogen, filtering, palladium carbon is no longer inhaled
Receipts are applied, reaction solution evaporated under reduced pressure, and 150kg isopropyl ether is added in residue, are heated to solid dissolution, are cooled to 0~5 DEG C of crystallization,
By being obtained by filtration 37.2kg white solid, yield 97.2%, HPLC detects α configuration impurity less than 0.5%, total miscellaneous less than 1%.
Embodiment 3
1) preparation of 4,6-O- acetal -1-O- benzyloxycarbonyl group-b-D- glucose
Preparation method and inventory are made extractant using chloroform substitution methylene chloride and are reacted, obtained with example 1
To the chloroform soln of 4,6-O- acetal -1-O- benzyloxycarbonyl group-b-D- glucose.
2) bis--O- of 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose
Preparation
Preparation method and inventory are reacted with example 1 using the chloroform soln of upper step, with equivalent molar ratio
Pyridine substitution triethylamine reacted, drying obtains 1208g white solid, two step yields 89.8%, HPLC purity 99.7%,
M.p.154~155.5 DEG C.
3) bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose preparation
Preparation method and inventory with example 1, using recycling palladium carbon do catalyst reacted to obtain 366.0g white it is solid
Body, yield 96.2%, HPLC detection α configuration impurity are total miscellaneous less than 1% less than 0.5%.
Claims (9)
1. a kind of preparation method of Etoposide intermediate, characterized in that the following steps are included:
1) in the in the mixed solvent of DMF and tetrahydrofuran, formula (2) compound and acid binding agent is added, benzyl chloroformate is added dropwise, drop finishes
After be stirred to react；Tetrahydrofuran is recovered under reduced pressure after the reaction was completed, residue is added water and dichloromethane or chloroform, passes through extraction
Liquid separation is taken, organic layer washing obtains the dichloromethane or chloroform solution of formula (3) compound after dry；
2) acid binding agent will be added in the dichloromethane or chloroform solution of formula (3) compound that step 1) obtains, be added dropwise 2,2-
Dichloroacetyl chloride, drop are stirred to react after finishing, and are added water and stirred liquid separation after the reaction was completed, and organic layer is steamed through washing, drying and decompression
The dry crude product for obtaining formula (4) compound, then highly finished product are refining to obtain by ethyl alcohol；
3) palladium carbon in acetone by the dissolution of formula (4) compound represented, is added and carries out catalytic hydrogenation deprotection base, filtering
Palladium carbon is recycled, acetone is recycled by vacuum distillation, remaining solid is refining to obtain Etoposide intermediate 2 by isopropyl ether, and 3- is bis--
O- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranose；
Wherein, formula (2) compound is 4,6-O- acetal-D-Glucose, and formula (3) compound is 4,6-O- acetal -1-O- benzyl
Oxygen carbonyl-β-D-Glucose；Formula (4) compound is the bis--O- of 1-O- benzyloxycarbonyl group -2,3- (2,2- dichloro-acetyl) -4,6-O-
Ethylidene-β-D- glucopyranose；
The mass ratio of mixed solvent DMF and tetrahydrofuran in the step 1) are 1:2；
Acid binding agent in the step 1) or step 2) is triethylamine, diisopropylethylamine or pyridine.
2. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that mixing in the step 1)
The mass ratio of solvent and formula (2) compound is 2~10:1.
3. a kind of preparation method of Etoposide intermediate as claimed in claim 2, characterized in that mixing in the step 1)
The mass ratio of solvent and formula (2) compound is 3:1.
4. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that reaction in the step 1)
Temperature is controlled at 0~40 DEG C.
5. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that reaction in the step 2)
Temperature is controlled at -10~10 DEG C.
6. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that the second in the step 2)
Alcohol purification are as follows: alcohol reflux to solid is added and dissolves, cool down crystallization, obtains formula (4) compound by filtering, drying.
7. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that the palladium in the step 3)
Carbon is 10% palladium carbon, and the mass ratio of formula (4) compound and 10% palladium carbon is 1:0.05~0.5.
8. a kind of preparation method of Etoposide intermediate as described in claim 1, characterized in that the hydrogen in the step 3)
Change reaction, is passed through Hydrogen Vapor Pressure in 0.1~0.5Mpa, reaction temperature is -10~0 DEG C.
9. a kind of preparation method of Etoposide intermediate as described in any one of claim 1-8, characterized in that described
The tetrahydrofuran withdrawal that step 1) steams is applied；The dichloromethane or chloroform recovery steamed in the step 2)；
Palladium carbon used in step 3) is directly used in next batch reaction by filtering, acetone washing；It is re-used after acetone recycling.
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| 抗癌药VP16-213合成工艺的改进;王学勤 等;《淮海工学院学报》;19990930;第8卷(第3期);第42-44,55页 * |
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