CN108129525A - A kind of preparation method of Etoposide intermediate - Google Patents
A kind of preparation method of Etoposide intermediate Download PDFInfo
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- CN108129525A CN108129525A CN201711465169.4A CN201711465169A CN108129525A CN 108129525 A CN108129525 A CN 108129525A CN 201711465169 A CN201711465169 A CN 201711465169A CN 108129525 A CN108129525 A CN 108129525A
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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 are starting material, in the presence of acid binding agent, are reacted with benzyl chloroformate; in high yield obtain 4; 6 O acetals, 1 O benzyloxycarbonyl group β D glucose, then through 2,2 dichloroacetyl chloride double esterifications; most Etoposide intermediate 2 is obtained through palladium carbon catalysis reduction afterwards; 3 pairs of 4,6 O ethylidene β D glucopyranoses of O (2,2 dichloro-acetyl).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-acetyls) -4,6-O- ethylidene-β-D- glucopyranoses preparation method.
Background technology
Etoposide is cell cycle specific antitumor drug, acts on DNA topoisomerase II, formed drug-enzyme-
The invertibity compound that DNA stablizes hinders DNA to repair.Experiment finds that this compound can be reversed with the removing of drug, makes damage
DNA repaired, reduce cytotoxicity.Therefore, extend the administration time of drug, improve antitumor activity.2017
October 27, the carcinogenic substance inventory edit reference that international cancer research institution of 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- glucopyranoses, 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, and structural formula is：
Kurabayashi, Katsuhiko et al. report formula (1) compound 2 in the clear 59-98098 of JP, the bis--O- of 3- (2,
2- dichloro-acetyls) -4,6-O- ethylidene-β-D- glucopyranoses synthesis technology, synthetic route is as follows：
The synthesis technology uses D-Glucose, and for starting material, raw material is cheap and easy to get, but upper benzyloxycarbonyl group protection 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 isomers (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 relatively low, and production cost greatly improved.
Tadashi Fujii, Iwatsuki et al. are reported in US4757138 with 4,6-O- acetal -1-O- benzyloxy carbonyls
Base-β-D-Glucose (Formula (3)) is the method for raw material formula (1) compound, and synthetic route is as follows：
Although the yield of document formula (4) compound and formula (1) compound is all higher than 90%, it is in formula (4)
During compound, using the 1 class solvent dichloroethanes that toxicity is larger, this prepares pharmaceutical intermediate and should be avoided now,
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 isomers are 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 obtain product with petroleum ether crystallization.But the formula (1) that is obtained in the patent 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.With year by year enhancing of the Chinese Government to environmental protection consciousness, exploitation is a kind of
It is inexpensive, the bis--O- of 2,3- in high yield, environmental-friendly (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
Synthetic method is known as our new research topics.
Invention content
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- glucopyranoses preparation method, this method is with 4,6-O- acetals-D-Glucose
For starting material, in the presence of acid binding agent, reacted with benzyl chloroformate, in high yield obtain 4,6-O- acetal -1-O- benzyls
Oxygen carbonyl-β-D-Glucose, then through 2,2- dichloroacetyl chloride double esterifications, most afterwards through palladium carbon catalysis reduction obtain the bis--O- of 2,3- (2,
2- dichloro-acetyls) -4,6-O- ethylidene-β-D- glucopyranoses.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- glucopyranoses, it is characterized in that,
1) in the in the mixed solvent of DMF and tetrahydrofuran, formula (2) compound and acid binding agent are added in, benzyl chloroformate is added dropwise,
Drop is stirred to react after finishing；Tetrahydrofuran is recovered under reduced pressure after the completion of reaction, residue adds in dichloromethane (or chloroform) and water,
By extracting liquid separation, organic layer washing obtains dichloromethane (or chloroform) solution of formula (3) compound after dry；
2) acid binding agent is added in dichloromethane (or chloroform) solution of formula (3) compound obtained step 1), is dripped
Add 2,2- dichloroacetyl chlorides, drop is stirred to react after finishing, reaction complete after through plus water stirring liquid separation, organic layer through washing, dry 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 by the dissolving of formula (4) compound represented in acetone, are added in
Palladium carbon is recycled, acetone is recycled by vacuum distillation, remaining solid is refining to obtain by isopropyl ether in the Etoposide shown in formula (1)
Mesosome 2, the bis--O- of 3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses.
The present invention reaction equation be：
Wherein formula (2) compound is 4,6-O- acetals-D-Glucose, and formula (3) compound is 4,6-O- acetals -1-O-
Benzyloxycarbonyl group-β-D-Glucose；Formula (4) compound is the bis--O- of 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-
O- ethylidene-β-D- glucopyranoses.
The mass ratio of mixed solvent DMF and tetrahydrofuran in the step 1) are 1:0.5~1:5, preferably 1:2, mixing
Solvent and the mass ratio of formula (2) compound are 2~10:1, preferably 3:1；Reaction dissolvent is very little, is unfavorable for reaction heat dissipation, and reaction is molten
Agent is too many, is unfavorable for environmental protection.
The step 1) or 2) in acid binding agent for triethylamine, diisopropylethylamine or pyridine, preferred triethylamine.
Reaction temperature control is at 0~40 DEG C in the step 1), preferably 20~30 DEG C.
The preferred dichloromethane of extractant in the step 1)；In bulk pharmaceutical chemicals dissolvent residual, dichloromethane allows most
High threshold is far longer than chloroform, and safety is higher, therefore preferred dichloromethane.
The yield of dichloromethane (or chloroform) solution of step 1) Chinese style (3) compound is based on 100%, directly
Input is reacted in next step.
Reaction temperature control is at -10~10 DEG C in the step 2), preferably -5~5 DEG C.
Ethyl alcohol in the step 2), which refines, is：It adds in alcohol reflux to solid to dissolve, cool down crystallization, by filtering, drying
It is dry to obtain formula (4) compound.
Palladium carbon content in the step 3) is 10%, and the mass ratio of formula (4) compound and 10% palladium carbon is 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 reaction is finished by being concentrated under reduced pressure, and steams tetrahydrofuran, it can be achieved that recovery, the step 2)
In dichloromethane or chloroform after vacuum distillation is recycled, be directly used in step 1), realize recovery, be conducive to environment
Protection.The palladium carbon used in the step 3) is washed by filtering, acetone, is directly used in next batch reaction, palladium carbon applies mechanically number
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 is 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 for 1.0~
1.2：1.1~1.5：1.
Step 1) does acid binding agent using water as solvent, sodium hydroxide in the clear 59-98098 documents of JP, 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 wrap
Remaining benzyl chloroformate is wrapped up in, reaction is caused no longer to carry out, and in the formula by being obtained by filtration (3) compound, because comprising a large amount of
Benzyl chloroformate, cause the unstable of product, largely decomposed being further processed process, cause yield relatively low.The present invention adopts
With mixed solvent, organic base liquid base does acid binding agent, is in order to which heterogeneous reaction is become homogeneous reaction, reaction process is without solid
It is precipitated, benzyl chloroformate completely consumes during the reaction, and last handling process will not cause formula (3) chemical combination due to the change of pH value
The decomposition of object substantially increases the yield and purity of formula (3) compound.
The beneficial effects of the invention are as follows：
1st, the synthesis of formula (3) compound is dissolved into using homogeneous reaction, raw material and product in organic solvent in 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.
2nd, the preparation process of formula (4) compound is changed using the methylene chloride as solvent that toxicity is larger in document, because upper
Formula (3) compound purity prepared by single step reaction is high, formula (4) compound HPLC purity which prepares 99.5% with
On, by formula (1) compound of hydrogenating reduction preparation, not only for α configurational isomers less than 0.5%, other impurities are smaller.For into
One step prepares formula (1) compound that Etoposide provides high-purity, greatly reduces the complexity of subsequent reaction.
3rd, acetone solvent used by formula (1) preparation of compounds, palladium-carbon catalyst recycle re-using, reduce
Environmental protection pressure.
4th, 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 detection α configurations impurity is less than 0.5%, and always miscellaneous to be less than 1%), environmental pollution is few, fits
Together in industrialized production.
Specific embodiment
The present invention is further described with reference to specific embodiment, 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) preparation of 4,6-O- acetals -1-O- benzyloxycarbonyl groups-β-D-Glucose
500g 4,6-O- acetals-D-Glucose (2.4mol) is added to equipped with churned mechanically 5000ml reaction bulbs
In, 500g DMF, 1000g tetrahydrofurans and 303g triethylamines (3.0mol) are added, stirs to solid and dissolves.By 443.5g chlorine
Benzyl formate (2.6mol, content 98%) adds in dropping funel, and chloro-carbonic acid benzyl is added dropwise in 20~30 DEG C of water-bath controlling reaction temperature
Ester, drop Bi Jixu are stirred 1 hour, and tetrahydrofuran is recovered under reduced pressure after the completion of reaction, 1000ml water and 2000ml are added in residue
Dichloromethane, liquid separation, organic phase 1000ml*2 water washings, anhydrous magnesium sulfate drying, filtering, filtrate direct plunge into anti-in next step
Should, reaction yield is based on 100%).
2) bis--O- of 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
It prepares
Upper step dichloromethane solution is added to equipped in churned mechanically 5000ml reaction bulbs, adds 303g triethylamines
(3.0mol) is cooled to -5~5 DEG C, and 412.7g 2,2- dichloroacetyl chlorides (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, adds in 1000ml water, stirs liquid separation, and organic phase uses 1000ml* again
Recycling dichloromethane is concentrated under reduced pressure in 2 water washings to neutrality, anhydrous magnesium sulfate drying, and residue adds in 2000g absolute ethyl alcohols, adds
Heat is back to solid dissolving, is cooled to room temperature crystallization, and by filtering, drying obtains 1214g white solids, two step yields
90.0%, HPLC purity 99.8%, m.p.154~155.5 DEG C (150~151 DEG C of document).
3) preparation of the bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
By the bis--O- of 500g1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyras
Sugared (0.89mol) is added in 5000ml autoclave pressures, adds 3000g acetone and 50g palladium carbons (content 10%), it is cooled to -5~
0 DEG C, lead to nitrogen displacement twice, then be passed through hydrogen, 0.1~0.5MPa of reaction pressure is kept to be filtered to hydrogen is no longer inhaled, palladium carbon recycling
It applies mechanically, reaction solution evaporated under reduced pressure, residue adds in 1500g isopropyl ethers, is heated to solid dissolving, is cooled to 0~5 DEG C of crystallization, leads to
365.7g white solids, yield 96.1% is obtained by filtration, HPLC detects α configurations impurity less than 0.5%, always miscellaneous to be less than 1%.
Embodiment 2
1) preparation of 4,6-O- acetals -1-O- benzyloxycarbonyl groups-b-D- glucose
100kg DMF, 200kg tetrahydrofurans and 60.6kg triethylamines are added in 1000L reaction kettles, adds 100kg
4,6-O- acetals-D-Glucose are stirred to solid and are dissolved.88.7kg benzyl chloroformates (content 98%) are added to head tank
In, benzyl chloroformate is added dropwise in 20~30 DEG C of controlling reaction temperature, and drop Bi Jixu is stirred 1 hour, and tetrahydrofuran is recovered under reduced pressure, remains
300kg water and 400kg dichloromethane, liquid separation, organic phase 200kg*2 water washings, anhydrous magnesium sulfate drying, mistake are added in excess
Filter, filtrate direct plunges into be reacted in next step, and reaction yield is based on 100%)
2) bis--O- of 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
It prepares
Upper step dichloromethane solution is added in 1000L reaction kettles, 60.6kg triethylamines is added, is cooled to -5~5
DEG C, 82.5kg 2,2- dichloroacetyl chlorides (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 in, stirs liquid separation, organic phase is again with 200kg*2 water washings to neutrality, anhydrous magnesium sulfate drying, decompression
Concentration and recovery dichloromethane, residue add in 400kg absolute ethyl alcohols, are heated to reflux to solid dissolving, are cooled to room temperature crystallization, lead to
Filtering, drying obtain 250.9kg white solids, two step yields 93.0%, HPLC purity 99.7%, m.p.154~155.5
℃。
3) preparation of the bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
By the bis--O- of 50kg 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyras
Sugar is added in 1000L autoclave pressures, is added 300kg acetone and 5kg palladium carbons (content 10%), is cooled to -5~0 DEG C, leads to nitrogen
Displacement twice, then is passed through hydrogen displacement twice, and logical hydrogen keeps 0.1~0.5MPa of reaction pressure to be filtered, palladium carbon is returned to hydrogen is no longer inhaled
Receipts are applied mechanically, reaction solution evaporated under reduced pressure, and residue adds in 150kg isopropyl ethers, are heated to solid dissolving, are cooled to 0~5 DEG C of crystallization,
By the way that 37.2kg white solids, yield 97.2% is obtained by filtration, HPLC detects α configurations impurity less than 0.5%, always miscellaneous to be less than 1%.
Embodiment 3
1) preparation of 4,6-O- acetals -1-O- benzyloxycarbonyl groups-b-D- glucose
Preparation method, with example 1, is made extractant using chloroform replacement dichloromethane and is reacted, obtained with inventory
To the chloroform soln of 4,6-O- acetal -1-O- benzyloxycarbonyl group-b-D- glucose.
2) bis--O- of 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
It prepares
Preparation method, with example 1, is reacted, with equivalent molar ratio with inventory using the chloroform soln of upper step
Pyridine substitute triethylamine and reacted, drying obtains 1208g white solids, two step yields 89.8%, HPLC purity 99.7%,
M.p.154~155.5 DEG C.
3) preparation of the bis--O- of 2,3- (2,2- dichloro-acetyl) -4,6-O- ethylidene-β-D- glucopyranoses
Preparation method and inventory are made catalyst and are carried out 366.0g whites are obtained by the reaction and consolidated with example 1 using recycling palladium carbon
Body, yield 96.2%, HPLC detection α configurations impurity are always miscellaneous to be less than 1% less than 0.5%.
Claims (10)
1. a kind of preparation method of Etoposide intermediate, it is characterized in that, include the following steps：
1) in the in the mixed solvent of DMF and tetrahydrofuran, formula (2) compound and acid binding agent are added in, benzyl chloroformate is added dropwise, drop finishes
After be stirred to react；Tetrahydrofuran is recovered under reduced pressure after the completion of reaction, residue adds in water and dichloromethane or chloroform, passes through extraction
Liquid separation is taken, organic layer washing obtains the dichloromethane or chloroform soln of formula (3) compound after dry；
2) acid binding agent is added in the dichloromethane or chloroform soln of formula (3) compound that obtain step 1), is added dropwise 2,2-
Dichloroacetyl chloride, drop are stirred to react after finishing, and reaction is passed through after completing plus water stirring liquid separation, and organic layer is through washing, drying and depressurizing steaming
It is dry to obtain the crude product of formula (4) compound, then highly finished product are refining to obtain by ethyl alcohol；
3) it by the dissolving of formula (4) compound represented in acetone, adds in palladium carbon 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- glucopyranoses；
Wherein, formula (2) compound is 4,6-O- acetals-D-Glucose, and formula (3) compound is 4,6-O- acetal -1-O- benzyls
Oxygen carbonyl-β-D-Glucose；Formula (4) compound is the bis--O- of 1-O- benzyloxycarbonyl groups -2,3- (2,2- dichloro-acetyl) -4,6-O-
Ethylidene-β-D- glucopyranoses.
2. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, it is mixed in the step 1)
The mass ratio of bonding solvent DMF and tetrahydrofuran is 1:0.5~1:5；Mixed solvent and the mass ratio of formula (2) compound are 2~10:
1。
3. a kind of preparation method of Etoposide intermediate as claimed in claim 2, it is characterized in that, it is mixed in the step 1)
The mass ratio of bonding solvent DMF and tetrahydrofuran is 1:2, the mass ratio of mixed solvent and formula (2) compound is 3:1.
4. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, the step 1) or step
2) acid binding agent in is triethylamine, diisopropylethylamine or pyridine.
5. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, it is reacted in the step 1)
Temperature is controlled at 0~40 DEG C.
6. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, it is reacted in the step 2)
Temperature is controlled at -10~10 DEG C.
7. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, the second in the step 2)
Alcohol, which refines, is：It adds in alcohol reflux to solid to dissolve, cool down crystallization, and formula (4) compound is obtained by filtering, drying.
8. a kind of preparation method of Etoposide intermediate as described in claim 1, it is 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.
9. a kind of preparation method of Etoposide intermediate as described in claim 1, it is characterized in that, the hydrogen in the step 3)
Change reaction, be passed through Hydrogen Vapor Pressure in 0.1~0.5Mpa, reaction temperature is -10~0 DEG C.
10. a kind of preparation method of Etoposide intermediate as described in any one in claim 1-9, it is characterized in that, institute
The tetrahydrofuran withdrawal that step 1) steams is stated to apply mechanically；The dichloromethane steamed or chloroform recovery set in the step 2)
With；The palladium carbon used in step 3) is washed by filtering, acetone, is directly used in next batch reaction；It is re-used after acetone recycling.
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| EP0111058A1 (en) * | 1982-11-26 | 1984-06-20 | Nippon Kayaku Kabushiki Kaisha | Process for producing 4'-demethyl-epipodophyllotoxin-beta-D-ethylidene-glucoside and acyl-derivative thereof |
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| CN115197281A (en) * | 2021-04-09 | 2022-10-18 | 四川汇宇制药股份有限公司 | Preparation method of etoposide intermediate |
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