CN102070480B - Method for synthesizing taxol side chains - Google Patents
Method for synthesizing taxol side chains Download PDFInfo
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- CN102070480B CN102070480B CN2010106069286A CN201010606928A CN102070480B CN 102070480 B CN102070480 B CN 102070480B CN 2010106069286 A CN2010106069286 A CN 2010106069286A CN 201010606928 A CN201010606928 A CN 201010606928A CN 102070480 B CN102070480 B CN 102070480B
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Abstract
The invention discloses a method for synthesizing taxol side chains, which comprises the concrete steps: 1. preparing compounds with the structural formula 2; 2. preparing compounds with the structural formula 3 through protecting group removal; and 3. preparing compounds with the structural formula 4 through acylation reaction. The method disclosed by the invention utilizes the asymmetric ring opening of cis epoxy compounds to generate chiral centers, the dismounting is not needed, and the requirement can be reached only through removing a small quantity of isomers by silica gel column chromatography, so the operation is simplified, and the loss of a large amount of the isomers is reduced. Thereby, the compound yield is improved, in addition, products with high optical purity can be obtained, and the production cost of the side chains is greatly reduced. The method disclosed the invention has the concrete reaction formula shown in the accompanying drawing.
Description
Technical field
The present invention relates to a kind of synthetic method of paclitaxel lateral chain.
Background technology
Taxol has extraordinary effect aspect oncotherapy; but the natural extract taxol is subjected to the restriction of various conditions; and cost an arm and a leg; and then the taxol overwhelming majority in the whole world turns to synthetic; but since mother nucleus structure complexity, polyfunctional group, many chiral centres etc.; complete synthesis difficulty is very big; so semi-synthetic preparation taxol of many now employings; and semisynthetic key is exactly the chiral side chain that obtains high-optical-purity, thereby realizes blocking docking of fourth III (10-DABIII) derivative with 10-deacetylation crust.
In the synthetic patent of existing paclitaxel lateral chain, it is by splitting preparation that several different methods is arranged, long but its shortcoming is a route, yield is low after splitting, and operates too loaded down with trivial detailsly, and the input on cost is too high, cause product price too high, be unfavorable for the reduction of disease treatment expenditure.It is by ammonia, nitrine compounds open loop of epoxy compound to be prepared that the partial synthesis method is also arranged, but the regioselectivity of this compounds open loop is low, produce a large amount of impurity and isomer, make that the purifying difficulty of back is very big, cause the low yield of product, because there is huge potential safety hazard in the nature of danger of triazo-compound in production operation, be not suitable for large-scale production simultaneously.
In existing antitumor medicine, taxol is comparatively effective for some treatment for cancer effect, but in under-developed country and most developing country, the medical expense of taxol is for bigger burden of common patient Lai Shuoshi, how could allow the general population break away from this predicament, one improves medical level exactly, and it two is the prices that reduce medicine.
Summary of the invention
Technical problem to be solved by this invention is at existing route long in existing numerous patents, needs to split, and yield is low, defect of high cost and the synthetic method of the lower paclitaxel lateral chain of a kind of production cost is provided.The present invention is by optimizing the production technique of paclitaxel lateral chain, promptly reduce synthesis step, reduce the production difficulty, improve yield, reach the production cost that reduces taxol, thereby reduce patient's medicine expenditure, make the patient have the ability to use this effective medicine to treat, both reduce the misery that slight illness is brought, also reduced the economic pressures that medical expense brings, benefited numerous cancer patientss.
Technical problem to be solved by this invention can be achieved through the following technical solutions:
The present invention adopts fluoroform sulphonamide (TfNH
2) structure of the attack open loop of cis epoxy compounds being come the establishing target compound, the a small amount of isomer that is produced can obtain the product of high chemical purity, high-optical-purity by purification by silica gel column chromatography, just can obtain target compound by simple structural modification again.
The synthetic method of paclitaxel lateral chain of the present invention, its concrete steps are as follows:
1, the preparation of the compound of structural formula 2
With the cis epoxy compounds of structural formula 1 compound with fluoroform sulphonamide prepared in reaction structural formula 2 under nitrogen protection;
2, the deprotection base prepares the compound of structural formula 3
A, liquefied ammonia joined be refrigerated among the cryogenic THF, under whipped state, add sodium bits preparation feedback liquid;
B, get the compound of the structural formula 2 of step 1 preparation, join among the THF, obtain the THF solution of the compound of structural formula 2, the THF solution of compound with the structural formula 2 of preparation joins in the reaction solution of steps A then, after reacting completely, add anhydrous methanol and will react cancellation in reaction solution, extraction, washing, drying, concentrating under reduced pressure, column purification make the compound of structural formula 3;
3, acylation reaction prepares the compound of structural formula 4
The compound of getting the structural formula 3 of step 2 preparation is dissolved in the compound solution that gets structural formula 3 in the benzene class solution, drips alkaline solution then in the compound solution of structural formula 3; Drip Benzoyl chloride again and the toluene wiring solution-forming reacts, after reacting completely, extract, the organic phase of extraction is through washing, exsiccant crude product, and the crude product recrystallization gets the compound white solid of structural formula 4;
Concrete reaction formula is as follows:
The present invention utilizes the asymmetric open loop of cis epoxy compounds to produce chiral centre, need not to split, can reach requirement as long as remove a spot of isomer by silica gel column chromatography, so just simplified operation, a large amount of losses of isomer have been reduced, thereby improved the yield of compound, and can obtain the product of high-optical-purity, reduced the production cost of side chain significantly.
The present invention adopts primary amine compounds nucleophilic attack, thus the introducing nitrogen atom avoided adopting the introducing of nitrine compounds and the danger that brings, make reaction safely, stablize, be easy to control.
The present invention's direct acidylate behind the highly basic deprotection promptly obtains the paclitaxel lateral chain ester, reacts easy, a large amount of minimizing intermediary production link, is beneficial to reduce cost.
The present invention compared with prior art.Have following advantage:
1. need not to split; the synthetic route of this patent does not need can obtain through fractionation the paclitaxel lateral chain of high-optical-purity; avoid generating a large amount of isomer; thereby making the isomer of 50% content effectively to utilize, all is very big improvement on molecule economics, environment protection and compound cost.
2. the productive rate height is optimized on synthetic route, reduced react fussy degree, need not to obtain high optical purity compound simultaneously through splitting, the less significantly loss of compound has obtained higher yield like this in the production of compound.
3. production technique is simple, and this patent synthetic route is short, and step is simplified, and has avoided fractionation simultaneously, does not also introduce nitrine class group, make whole synthetic route easy, safely, be easy to control.
Embodiment
Following examples are based on that following reaction formula describes:
Embodiment 1
1, the preparation of the compound of structural formula 2
Get an exsiccant single necked round bottom flask and place on the oil bath, with cis epoxy compounds 1 (1.78g, 10mmol, methyl esters), low-pressure refrigeration exsiccant Na
2CO
3(0.11g, 1mmol) and fluoroform sulphonamide (TfNH
2) (2.98g; 20mmol) add in the single port bottle, nitrogen protection is stirred down oil bath is warming up to about 120 ℃; TLC detects; when epoxy compounds disappears, then temperature of reaction is reduced to room temperature, in reaction flask, add the 100mL methylene dichloride; 5 minutes after-filtration of stir about; get solution decompression concentrate crude product, purification by silica gel column chromatography get structural formula 2 compound 2.5g (productive rate: 74%, ee:99.2%).
2, the deprotection base prepares the compound of structural formula 3
Liquefied ammonia (200mL) is joined among the THF (100mL) that is refrigerated to-40 ℃, stir down sodium bits (5.0g) are joined in the solution of ammonia, reaction solution becomes blueness very soon, get the compound (10.5g of structural formula 2,32.2mmol, methyl esters) THF (200mL) solution is added in the above-mentioned reaction solution, and reaction is 1 hour under this temperature.It is complete that TLC detects raw material reaction, in reaction solution, add anhydrous methanol (50mL) and will react cancellation, in reaction solution, add saturated NH4Cl solution (100mL) after being warming up to 0 ℃, ethyl acetate extraction, saturated common salt is washed to neutrality, dry back concentrating under reduced pressure, column purification gets the compound white powder 3.9g (productive rate: 62%) of structural formula 3.
3, acylation reaction prepares the compound of structural formula 4
Get a 100mL there-necked flask, (5.9g 30.2mmol) is dissolved in the 30mL toluene, places cold water to be cooled to about 5 ℃ reaction flask, drips the K of 30mL in solution with the compound white powder of structural formula 3
2CO
3Solution (3mol/L), stirred 15 minutes and keep solution temperature at about 5 ℃; get Benzoyl chloride (5mL; 43mmol) in reaction solution, drip; control reaction temperature is lower than 10 ℃; drip the back and continue to stir 3 hours, it is complete that TLC detects raw material reaction, and reaction solution is poured in the separating funnel; add the 50mL saturated aqueous common salt; ethyl acetate (50mL * 2) extraction merges organic phase, saturated common salt water washing; anhydrous sodium sulfate drying with 10mL toluene wiring solution-forming; concentrate crude product, recrystallization get structural formula 4 compound white solid 8.23g (productive rate: 91%, ee:99.2%).
Embodiment 2
1, the preparation of the compound of structural formula 2
With cis epoxy compounds 1 (89g, 0.5mol, methyl esters), low-pressure refrigeration exsiccant Na
2CO
3(5.3g, 50mmol) and fluoroform sulphonamide (TfNH
2) (149g 1.0mmol) adds in the exsiccant there-necked flask mechanical stirring 500rpm; and it is positioned on the oil bath, nitrogen protection is stirred down oil bath is warming up to about 120 ℃; TLC detects, and disappears until epoxy compounds, removes oil bath; temperature of reaction is reduced to room temperature; in reaction flask, add the 4L methylene dichloride, 15 minutes after-filtration of stir about, get solution decompression concentrate crude product; purification by silica gel column chromatography get structural formula 2 compound 117.8g (productive rate: 72%, ee:99%).
2, the deprotection base prepares the compound of structural formula 3
Liquefied ammonia (1.5L) is joined among the THF (1L) that is refrigerated to-40 ℃, stir down sodium bits (50g) are joined in the solution of ammonia, reaction solution becomes blueness very soon, get the compound (105g of structural formula 2,0.322mol, methyl esters) THF (2L) solution is added in the above-mentioned reaction solution, and reaction is 2 hours under this temperature.It is complete that TLC detects raw material reaction, in reaction solution, add anhydrous methanol (100mL) and will react cancellation, in reaction solution, add saturated NH4Cl solution (1L) after being warming up to 0 ℃, ethyl acetate extraction, saturated common salt is washed to neutrality, dry back concentrating under reduced pressure, column purification gets the compound white powder 40.8g (productive rate: 65%) of structural formula 3.
3, acylation reaction prepares the compound of structural formula 4
Get a 2L there-necked flask, (88.5g 0.45mol) is dissolved in the 450mL toluene, places cold water to be cooled to about 5 ℃ reaction flask, drips the K of 450mL in solution with the compound white powder of structural formula 3
2CO
3Solution (3mol/L), stirred 15 minutes and keep solution temperature at about 5 ℃; get Benzoyl chloride (75mL; 0.65mol) in reaction solution, drip; control reaction temperature is lower than 10 ℃; drip the back and continue to stir 3 hours, it is complete that TLC detects raw material reaction, and reaction solution is poured in the separating funnel; add saturated aqueous common salt 500mL; ethyl acetate (500mL * 2) extraction merges organic phase, saturated common salt water washing; anhydrous sodium sulfate drying with 150mL toluene wiring solution-forming; concentrate crude product, recrystallization get structural formula 4 compound white solid 121.2g (productive rate: 90%, ee:99%).
Embodiment 3
1, the preparation of the compound of structural formula 2
Get an exsiccant single necked round bottom flask and place on the oil bath, with cis epoxy compounds 1 (1.78g, 10mmol, methyl esters), low-pressure refrigeration exsiccant Na
2CO
3(0.11g, 1mmol) and fluoroform sulphonamide (TfNH
2) (2.98g; 20mmol) add in the single port bottle, nitrogen protection is stirred down oil bath is warming up to about 90 ℃; TLC detects; about 10 hours of reaction times epoxy compounds disappears, and temperature of reaction is reduced to room temperature, adds the 100mL methylene dichloride in reaction flask; 5 minutes after-filtration of stir about; get solution decompression concentrate crude product, purification by silica gel column chromatography get structural formula 2 compound 1.7g (productive rate: 51%, ee:96.5%).
2, the deprotection base prepares the compound of structural formula 3
Liquefied ammonia (200mL) is joined among the THF (100mL) that is refrigerated to-40 ℃, stir down sodium bits (5.0g) are joined in the solution of ammonia, reaction solution becomes blueness very soon, get the compound (10.5g of structural formula 2,32.2mmol, methyl esters) THF (200mL) solution is added in the above-mentioned reaction solution, and reaction is 1 hour under this temperature.It is complete that TLC detects raw material reaction, in reaction solution, add anhydrous methanol (50mL) and will react cancellation, in reaction solution, add saturated NH4Cl solution (100mL) after being warming up to 0 ℃, ethyl acetate extraction, saturated common salt is washed to neutrality, dry back concentrating under reduced pressure, column purification gets the compound white powder 4.1g (productive rate: 65.2%) of structural formula 3.
3, acylation reaction prepares the compound of structural formula 4
Get a 100mL there-necked flask, (5.9g 30.2mmol) is dissolved in the 30mL toluene, places cold water to be cooled to about 5 ℃ reaction flask, drips the K of 30mL in solution with the compound white powder of structural formula 3
2CO
3Solution (3mol/L), stir after 15 minutes and to keep solution temperature at about 5 ℃; get Benzoyl chloride (5mL; 43mmol) in reaction solution, drip; control reaction temperature is lower than 10 ℃; drip the back and continue to stir 3 hours, it is complete that TLC detects raw material reaction, and reaction solution is poured in the separating funnel; add the 50mL saturated aqueous common salt; ethyl acetate (50mL * 2) extraction merges organic phase, saturated common salt water washing; anhydrous sodium sulfate drying with 10mL toluene wiring solution-forming; concentrate crude product, recrystallization get structural formula 4 compound white solid 8.04g (productive rate: 89%, ee:96.5%).
Embodiment 4
1, the preparation of the compound of structural formula 2
Get an exsiccant single necked round bottom flask and place on the oil bath, with cis epoxy compounds 1 (3.82g, 20mmol, ethyl ester), low-pressure refrigeration exsiccant Na
2CO
3(0.21g, 2mmol) and fluoroform sulphonamide (TfNH
2) (5.96g; 40mmol) add in the single port bottle, nitrogen protection is stirred down oil bath is warming up to about 120 ℃; TLC detects; when epoxy compounds disappears, then temperature of reaction is reduced to room temperature, in reaction flask, add the 200mL methylene dichloride; 5 minutes after-filtration of stir about; get solution decompression concentrate crude product, purification by silica gel column chromatography get structural formula 2 compound 5.12g (productive rate: 75%, ee:99.4%).
2, the deprotection base prepares the compound of structural formula 3
Liquefied ammonia (350mL) is joined among the THF (200mL) that is refrigerated to-40 ℃, stir down sodium bits (10g) are joined in the solution of ammonia, reaction solution becomes blueness very soon, get the compound (22g of structural formula 2,64.4mmol, methyl esters) THF (400mL) solution is added in the above-mentioned reaction solution, and reaction is 1 hour under this temperature.It is complete that TLC detects raw material reaction, in reaction solution, add anhydrous methanol (50mL) and will react cancellation, in reaction solution, add saturated NH4Cl solution (200mL) after being warming up to 0 ℃, ethyl acetate extraction, saturated common salt is washed to neutrality, dry back concentrating under reduced pressure, column purification gets the compound white powder 8.4g (productive rate: 64.5%) of structural formula 3.
3, acylation reaction prepares the compound of structural formula 4
Get a 250mL there-necked flask, (12.6g 60.4mmol) is dissolved in the 60mL toluene, places cold water to be cooled to about 5 ℃ reaction flask, drips the K of 60mL in solution with the compound white powder of structural formula 3
2CO
3Solution (3mol/L), stirred 15 minutes and keep solution temperature at about 5 ℃; get Benzoyl chloride (10mL; 86mmol) in reaction solution, drip; control reaction temperature is lower than 10 ℃; drip the back and continue to stir 3 hours, it is complete that TLC detects raw material reaction, and reaction solution is poured in the separating funnel; add the 100mL saturated aqueous common salt; ethyl acetate (100mL * 2) extraction merges organic phase, saturated common salt water washing; anhydrous sodium sulfate drying with 20mL toluene wiring solution-forming; concentrate crude product, recrystallization get structural formula 4 compound white solid 17.1g (productive rate 90.1%, ee:99.4%).
Claims (2)
1. the synthetic method of paclitaxel lateral chain is characterized in that, concrete steps are as follows:
1), the preparation of the compound of structural formula 2
With the cis epoxy compounds of structural formula 1 compound with fluoroform sulphonamide prepared in reaction structural formula 2 under nitrogen protection, its temperature of reaction is 90 ℃ to 120 ℃;
2), the deprotection base prepares the compound of structural formula 3
A, liquefied ammonia joined be refrigerated among the cryogenic THF, under whipped state, add sodium bits preparation feedback liquid;
B, get the compound of the structural formula 2 of step 1 preparation, join in the THF solution, obtain the THF solution of the compound of structural formula 2, the THF solution of compound with the structural formula 2 of preparation joins in the reaction solution of steps A then, after reacting completely, add anhydrous methanol and will react cancellation in reaction solution, extraction, washing, drying, concentrating under reduced pressure, column purification make the compound of structural formula 3;
3), acylation reaction prepares the compound of structural formula 4
The compound of getting the structural formula 3 of step 2 preparation is dissolved in the compound solution that gets structural formula 3 in the benzene class solution, drips alkaline solution then in the compound solution of structural formula 3; Drip Benzoyl chloride again and the toluene wiring solution-forming reacts, after reacting completely, extract, the organic phase of extraction is through washing, dry crude product, and the crude product recrystallization gets the compound white solid of structural formula 4;
Concrete reaction formula is as follows:
Wherein, R=Me, Et.
2. the synthetic method of paclitaxel lateral chain as claimed in claim 1 is characterized in that, the temperature of reaction in the step 1) is 120 ℃.
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| CN2010106069286A CN102070480B (en) | 2010-12-27 | 2010-12-27 | Method for synthesizing taxol side chains |
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| CN2010106069286A CN102070480B (en) | 2010-12-27 | 2010-12-27 | Method for synthesizing taxol side chains |
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| CN102070480B true CN102070480B (en) | 2013-07-31 |
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| CN104177273B (en) * | 2014-09-09 | 2016-04-27 | 西安近代化学研究所 | A kind of method of synthesis of chiral 3-amino-3-phenyl-2-hydroxycarboxylic acid ester cpds |
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Non-Patent Citations (1)
| Title |
|---|
| penso，michele.Stereo- and regioselective opening of 3-phenylglycidates by trifluoromethanesulfonamide under solid-liquid heterogeneous conditions.《chemistry letters》.2001,第5卷全文. * |
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Address after: 201715 Shanghai city Qingpu District Liantang Town Mao Dian Road No. 508 Patentee after: Shanghai King bio Pharmaceutical Co., Ltd. Address before: 201716 Shanghai City Liantang Industrial Park Qingpu District A-4 Patentee before: Jinhe Biological Technology Co., Ltd., Shanghai |