CN111718309A - Synthesis method of paclitaxel side chain and analogues thereof - Google Patents
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Abstract
The invention discloses a synthesis method of a taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof shown in a formula (f), which takes cinnamaldehyde as a raw material and is synthesized into the taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and the analogues thereof through a series of reactions such as epoxidation, methyl esterification, ammonolysis, esterolysis, condensation, configuration inversion, condensation and hydrolysis. The method is optimized in the aspect of post-treatment operation, and has the advantages of short reaction time, high yield, good chiral selection, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of a taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof.
Background
Paclitaxel is a widely-recognized anticancer drug with strong activity in the world at present and has a unique anticancer mechanism. The clinical application proves that it has curative effect on various cancers, especially on uterine cancer, ovarian cancer and breast cancer. The sales volume of the medicine is increased year by year after the medicine is on the market, the sales volume of the medicine in the United states is the first of similar medicines at present, the medicine is a very good anti-tumor medicine, and the medicine has good application prospect. The paclitaxel is extracted from bark of natural plant Taxus chinensis, and has very low content (only 0.069% at most). This will destroy the ecological environment and wild resources, and the natural yew has a small quantity worldwide and a long growth period, which causes great difficulty in further development of taxol. Therefore, the extraction of paclitaxel from natural yew is far from meeting the requirement of people on paclitaxel, and the magical curative effect and the serious shortage of medicine sources of paclitaxel make the price of paclitaxel extremely expensive.
In order to solve the problem, chemists have made great progress in research on chemical total synthesis of paclitaxel in recent years, but the total synthesis is relatively complex and the cost is relatively high, so that the method has no practical value at present. Later scientists found a byproduct 10-deacetylbaccatin III in the research on the separation and purification of paclitaxel, and the byproduct can be extracted from the leaves of yew trees. Because the leaves of the taxus chinensis can be harvested for 4 times a year and can be regenerated, the source of the 10-deacetylbaccatin III is rich, and the taxol side chain can be introduced into the 10-deacetylbaccatin III molecule only by synthesizing a large amount of taxol side chains, so that the anticancer drug can be obtained by a semisynthesis method.
Disclosure of Invention
The invention discloses a synthesis method of a taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof, which are synthesized by taking cinnamaldehyde as a raw material through a series of reactions such as epoxidation, methyl esterification, aminolysis, esterlysis, condensation, configuration inversion, condensation, hydrolysis and the like. The method has the advantages of short reaction time, high yield (10-20%), good chiral selectivity (ee is more than 99%), suitability for industrial production and the like.
The novel taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and the analogue thereof are shown as a formula f, and the synthetic process is shown as a following route (A):
wherein the content of the first and second substances,
r is p-methoxybenzyl, isopropyl and the like;
preferably, it is p-methoxybenzyl.
The method comprises the following specific steps:
1) in an organic solvent, the cinnamaldehyde compound of the formula a and an oxidant generate chiral epoxidation reaction under the action of a ligand, then generate methyl esterification reaction under the action of a methyl esterification reagent, and finally generate ammonolysis reaction to obtain a compound of the formula b;
2) in an organic solvent, carrying out an esterification reaction on the compound shown in the formula b and micromolecular alcohol under the action of acid to obtain a compound shown in the formula c;
3) in a solvent, carrying out condensation reaction on the compound of the formula c and benzoyl chloride under the action of alkali to obtain a compound of a formula d;
4) in a solvent, carrying out dehydration reaction on the compound of the formula d under the action of a dehydration reagent and an acid to obtain a compound of a formula e;
5) in an organic solvent, the compound of the formula e and a condensation reagent are subjected to condensation reaction under the action of a catalyst, and then the compound of the formula f is obtained under the action of alkali.
In the step 1), the organic solvent is selected from one or more of dioxane, dichloromethane, 1, 2-dichloroethane, toluene, tetrahydrofuran, xylene, chlorobenzene and the like; but are not limited to the above-mentioned organic solvents; preferably dioxane, dichloromethane.
In the step 1), the oxidant is one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, chlorous acid and the like; preferably, hydrogen peroxide.
In the step 1), the ligand is (2S) -2- [ diphenyl [ (trimethylsilyl) oxy ] methyl ] -pyrrolidine.
In the step 1), the molar ratio of the compound of the formula a to the oxidant to the ligand is 1: 0.1-5: 0.05-0.5; preferably, it is 1: 1.2: 0.4.
In the step 1), the temperature of the chiral epoxidation reaction is 0-50 ℃; preferably, it is 25 ℃.
In the step 1), the methyl esterification reagent is one or more of NBS, sodium hypochlorite and the like; preferably, it is NBS.
In the step 1), the temperature of the methyl esterification reaction is 0-50 ℃; preferably, it is 25 ℃.
In the step 1), the methyl esterification reaction time is 2-10 h; preferably, it is 5 h.
In the step 1), the reagent required by the ammonolysis reaction is an alcohol solution of ammonia, wherein the alcohol is one or more of methanol, ethanol, propanol, butanol, isopropanol, tert-butanol and the like; preferably, it is methanol.
In the step 1), the temperature of the ammonolysis reaction is 50-100 ℃; preferably, it is 90 ℃.
In the step 1), the ammonolysis reaction time is 2-12 h; preferably, it is 6 h.
In the step 2), the organic solvent is selected from one or more of dichloromethane, methanol, ethanol, isopropanol and the like; preferably, it is methanol.
In the step 2), the acid is strong acid and is selected from one or more of sulfuric acid, hydrochloric acid, thionyl chloride and the like; preferably, thionyl chloride.
In the step 2), the small molecular alcohol is one or more of methanol, ethanol, isopropanol and the like; preferably, it is methanol.
In the step 2), the molar ratio of the compound in the formula b to the micromolecule alcohol to the acid is 1: 2-6: 1-10; preferably, it is 1: 6: 4.
In the step 2), the temperature of the esterification reaction is 20-110 ℃; preferably, it is 90 ℃.
In the step 2), the esterification reaction time is 2-11 h; preferably, it is 4 h.
In the step 3), the solvent is one or more of tetrahydrofuran, dioxane, dichloromethane, toluene and the like; preferably, dichloromethane.
In the step 3), the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like; preferably, it is sodium carbonate.
In the step 3), the molar ratio of the compound of the formula c, benzoyl chloride and alkali is 1: 1-5: 2-10; preferably, it is 1: 1.2: 2.
In the step 3), the temperature of the condensation reaction is 0-40 ℃; preferably, it is 25 ℃.
In the step 3), the condensation reaction time is 2-11 h; preferably, it is 4 h.
In the step 4), the dehydration reagent is selected from one or more of thionyl chloride, phosphorus oxychloride, sulfuric acid, phosphorus pentoxide and the like; preferably, thionyl chloride.
In the step 4), the acid is strong acid, and the strong acid is selected from one or more of hydrochloric acid, sulfuric acid and the like; preferably, hydrochloric acid.
In the step 4), the solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, methanol and the like; preferably, dichloromethane.
In the step 4), the temperature of the dehydration reaction is 50-150 ℃; preferably 50 deg.c.
In the step 4), the time of the dehydration reaction is 2-11 h; preferably, it is 6 h.
In the step 4), the molar ratio of the compound shown in the formula d to the dehydrating reagent is 1 to (10-50); preferably, it is 1: 4.
In the step 5), the organic solvent is one or more selected from toluene, xylene, chlorobenzene, tetrahydrofuran, ethyl acetate and the like; preferably, it is toluene.
In the step 5), the catalyst is one or more of PPDS, CSA and the like; preferably, it is PPDS.
In the step 5), the molar ratio of the compound of the formula e to the catalyst is (1-50) to (0.1-1); preferably, it is 1: 0.1.
In the step 5), the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like; preferably, sodium hydroxide.
In the step 5), the temperature of the condensation reaction is 0-140 ℃; preferably 130 deg.c.
In the step 5), the condensation reaction time is 2-11 h; preferably, it is 4 h.
In the step 5), the condensation reagent is PDA.
The main innovation points of the invention which are different from the prior art are as follows: 1. ligand catalyzed epoxidation improves chiral purity. 2. And the dehydration reagent and the acid configuration conversion method adopted in the step four are matched with the first step to obtain the configuration required by the invention, and the method is simple to operate and beneficial to industrialization.
In one embodiment, the paclitaxel side chain of formula (f) ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolinecarboxylic acid) and analogs thereof are synthesized as shown in scheme (A'),
wherein the content of the first and second substances,
r is p-methoxybenzyl, isopropyl and the like;
preferably, it is p-methoxybenzyl.
The invention also provides a taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof, which are prepared by the synthesis method.
The invention also provides a taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof, wherein the structure of the taxol side chain is shown as the following formula f:
wherein the content of the first and second substances,
r is p-methoxybenzyl, isopropyl and the like;
preferably, it is p-methoxybenzyl.
The method has the advantages of short reaction time, simple operation, less wastewater, high yield and good chiral selection, and is suitable for industrial mass production. Most importantly, the ligand is adopted to catalyze the epoxidation reaction, so that the generation of chiral isomers is reduced, the chiral purity of the product is improved, and the quality of the product is improved. The method for directly esterifying in the alcohol solvent avoids the synthesis of acyl chloride, has high efficiency and simple operation, and is beneficial to industrialization.
Corresponding full-name corresponding table used for short names in the specification
| Entry | Abbreviations | Full scale |
| 1 | NBS | N-bromosuccinimide |
| 2 | PPDS | 4-Methylbenzenesulfonic acid pyridine |
| 3 | CSA | Camphorsulfonic acid |
| 4 | PDA | Para-methoxybenzaldehyde dimethyl acetal |
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Synthesis of Compound b:
adding cinnamaldehyde (5.2g, 39.3mmol), ligand (1.1g, 3.1mmol) and DCM (52ml) into a three-neck flask at room temperature, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding H2O2(4.8g, 47.2mmol) is controlled to be lower than 5 ℃, stirred for 4h at room temperature after finishing dropping, a small amount of raw materials are not reacted by TLC detection, 25ml of water is added, layering is carried out, and the organic phase is washed by 20ml of saline; drying with anhydrous sodium sulfate, filtering, adding 10ml methanol, NBS (9.3g, 51.1mmol) and sodium carbonate (5.6g, 51.1mmol), stirring at room temperature for 16h, detecting reaction by TLC, adding 25ml brine, separating layers, extracting aqueous phase with 20ml DCM, combining organic phases, drying with anhydrous sodium sulfate, concentrating to obtain intermediate crude product, adding 7MNH into sealed tube3Heating alcohol (40ml) and the intermediate crude product to 110 ℃ for reaction for 3h, cooling to about 10 ℃, stirring for crystallization for 1h, filtering, rinsing a filter cake with ice methanol, and drying to obtain 3.1g of a product b with the yield of 43.6%.
1HNMR(DMS0-d6/D20)3.87(d，J＝3.3Hz，1H)，4.08(d，J＝3.3Hz，1H)，7.0-7.5(aromatic，5H)。
Example 2
Synthesis of Compound c:
in a 120ml stopcock, compound b (8.9g, 49.4mmol), SOCl was added2(23.1g, 197.5mmol) and methanol (600ml), heating to 85 deg.C and maintaining for 5h, HPLC shows complete reaction of the raw materials, concentrating, adding DCM 60ml and saturated potassium carbonate 30ml, stirring for 10min, separating, washing the organic phase with 30ml of sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 8.4g of product c, yield 87.2%.
1H NMR(400MHz，CHLOROFORM-d)ppm 2.29(br.s.，2H)3.69(s，3H)4.28(d，J＝3.67Hz，1H)4.38-4.50(m，1H)7.17-7.36(m，5H)
Example 3
Synthesis of Compound d:
DCM (75ml) and compound c (7.5g, 38.4mmol) were added to a three-necked flask at room temperature, sodium carbonate (8.4g, 80.7mmol) and water (43ml) were added under nitrogen, and the mixture was cooled to 0 ℃ in an ice-water bath. Dripping benzoyl chloride, keeping the temperature and stirring for 2h after dripping, detecting the complete reaction of the raw materials by TLC, adding 25ml of sodium bicarbonate solution into the reaction solution, stirring for 10min, layering, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 10.9g of a product c with the yield of 94.9%.
1H NMR(400MHz，CHLOROFORM-d)ppm 3.06(br.s.，1H)3.71(s，3H)4.70(d，J＝2.69Hz，1H)5.61(dd，J＝8.56，3.18Hz，1H)7.16(d，J＝8.07Hz，1H)7.26-7.55(m，8H)7.80(d，J＝7.34Hz，2H)
Example 4
Synthesis of Compound e:
DCM (100ml) and compound d (10g, 33.4mmol) were added to a three-necked flask at room temperature under nitrogen protection with SOCl2(9.93g, 83.5mmol), heating to reflux and stirring for 5h, detecting raw materials by TLC to completely react, concentrating to obtain a light yellow solid, adding 50ml of DCM, refluxing and stirring for 4h, cooling to room temperature, washing by 50ml of saturated sodium chloride, concentrating to obtain a white solid, adding methanol (230ml) and 1N hydrochloric acid (77ml), stirring and refluxing, detecting by TLC about 5h at the external temperature of 87 ℃, concentrating, adding 50ml of water and 50ml of 2DCM for extraction, combining organic phases, drying by anhydrous sodium sulfate, concentrating to obtain 8.5g of a white solid e, wherein the yield is 85.0%.
1H NMR(400MHz，DMSO-d6)ppm 3.51(s，3H)4.48(d，J＝4.89Hz，1H)5.41(dd，J＝8.80，5.38Hz，1H)7.14-7.60(m，8H)7.74-7.93(m，2H)8.56-8.79(m，1H)
Example 5
Synthesis of Compound f:
adding PPDS (0.13g, 0.6mmol), PDA (1.1g, 6mmol) and toluene (15ml) into a three-neck flask, refluxing under the protection of nitrogen, adding a compound e (1.5g, 5mmol) under the reflux condition, preserving heat and refluxing for 6h, detecting that raw materials react completely by TLC (thin layer chromatography), concentrating under reduced pressure to remove toluene, adding 5ml of tetrahydrofuran and 20ml of methanol, stirring, cooling to 0 ℃, and dropwise adding 1N sodium hydroxide solution (10 ml); reacting at 25 ℃ for 3h, detecting by TLC that the raw materials completely react, concentrating, adding 15ml of water, extracting with MTBE10ml x 2, discarding the organic phase, adjusting the pH of the aqueous phase to 1 by using 3N hydrochloric acid, extracting with DCM 10ml of 2, combining the organic phases, washing with 8ml of saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and pulping with 2ml of methanol to obtain 1.5g of a pure product f with the yield of 75%.
1H NMR(400MHz，DMSO-d6)6ppm 3.74(s，3H)4.92(s，1H)5.29(br.s.，1H)6.61(br.s.，1H)6.88(d，J＝7.83Hz，2H)7.09-7.48(m，12H)
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (10)
1. A method for synthesizing ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolinecarboxylic acid) and its analogues, wherein the reaction process is shown in scheme (A):
wherein R is p-methoxybenzyl and isopropyl;
the method comprises the following specific steps:
1) in an organic solvent, the cinnamaldehyde compound of the formula a and an oxidant generate chiral epoxidation reaction under the action of a ligand, then generate methyl esterification reaction under the action of a methyl esterification reagent, and finally generate ammonolysis reaction to obtain a compound of the formula b;
2) in an organic solvent, carrying out an esterification reaction on the compound shown in the formula b and micromolecular alcohol under the action of acid to obtain a compound shown in the formula c;
3) in a solvent, carrying out condensation reaction on the compound of the formula c and benzoyl chloride under the action of alkali to obtain a compound of a formula d;
4) in a solvent, carrying out dehydration reaction on the compound of the formula d under the action of a dehydration reagent and an acid to obtain a compound of a formula e;
5) in an organic solvent, the compound of the formula e and a condensation reagent are subjected to condensation reaction under the action of a catalyst, and then the compound of the formula f is obtained under the action of alkali.
2. The synthesis method according to claim 1, wherein in step 1), the organic solvent is selected from one or more of dioxane, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, xylene and chlorobenzene; and/or the oxidant is one or more of hydrogen peroxide, m-chloroperoxybenzoic acid and chlorous acid; and/or the ligand is (2S) -2- [ diphenyl [ (trimethylsilyl) oxy ] methyl ] -pyrrolidine; and/or the methyl esterification reagent is one of NBS and sodium hypochlorite.
3. The synthetic method of claim 1 wherein in step 1), the molar ratio of the compound of formula a to the oxidant to the ligand is 1: 0.1-5: 0.05-0.5; and/or the temperature of the chiral epoxidation reaction is 0-50 ℃; and/or the temperature of the methyl esterification reaction is 0-50 ℃.
4. The synthesis method of claim 1, wherein in step 1), the reagent required for ammonolysis reaction is an alcohol solution of ammonia, wherein the alcohol is one or more of methanol, ethanol, propanol, butanol, isopropanol and tert-butanol; and/or the temperature of the ammonolysis reaction is 50-100 ℃; and/or the time of the ammonolysis reaction is 2-12 h.
5. The synthesis method of claim 1, wherein in the step 2), the organic solvent is selected from one or more of dichloromethane, methanol, ethanol and isopropanol; and/or, the acid is strong acid and is selected from one or more of sulfuric acid, hydrochloric acid and thionyl chloride; and/or the small molecular alcohol is one or more of methanol, ethanol and isopropanol.
6. The synthetic method of claim 1, wherein in the step 2), the molar ratio of the compound of the formula b to the small molecule alcohol to the acid is 1 to (2-6) to (1-2); and/or the temperature of the esterification reaction is 20-110 ℃.
7. The synthesis method of claim 1, wherein in the step 3), the solvent is one or more of tetrahydrofuran, dioxane, dichloromethane and toluene; and/or the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate; and/or the molar ratio of the compound of the formula c, benzoyl chloride and alkali is 1 to (2-5) to (2-10); and/or the temperature of the condensation reaction is 0-40 ℃.
8. The synthesis method of claim 1, wherein in the step 4), the dehydration reagent is one or more selected from thionyl chloride, phosphorus oxychloride, sulfuric acid and phosphorus pentoxide; and/or the acid is strong acid, and the strong acid is selected from one or more of hydrochloric acid and sulfuric acid; and/or the solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene and methanol; and/or the temperature of the dehydration reaction is 50-150 ℃; and/or the molar ratio of the compound shown in the formula d to the dehydrating reagent is 1 to (10-50).
9. The synthesis method of claim 1, wherein in the step 5), the organic solvent is one or more selected from toluene, xylene, chlorobenzene, tetrahydrofuran and ethyl acetate; and/or the catalyst is one or two of PPDS and CSA; and/or the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate; and/or the molar ratio of the compound of the formula e to the catalyst is (1-50) to (0.1-1); and/or, the condensing agent is PDA; and/or the temperature of the condensation reaction is 0-140 ℃.
10. The taxol side chain ((4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and the analogues thereof are characterized in that the structure is shown as a formula f:
wherein R is p-methoxybenzyl and isopropyl.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025516A (en) * | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
| CN106632160A (en) * | 2016-12-21 | 2017-05-10 | 重庆市碚圣医药科技股份有限公司 | Methods for preparing semi-synthetic paclitaxel and intermediate thereof |
| CN107056767A (en) * | 2015-12-04 | 2017-08-18 | 江苏恩华络康药物研发有限公司 | Method and intermediate for preparing water-soluble taxane analog derivative |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025516A (en) * | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
| CN107056767A (en) * | 2015-12-04 | 2017-08-18 | 江苏恩华络康药物研发有限公司 | Method and intermediate for preparing water-soluble taxane analog derivative |
| CN106632160A (en) * | 2016-12-21 | 2017-05-10 | 重庆市碚圣医药科技股份有限公司 | Methods for preparing semi-synthetic paclitaxel and intermediate thereof |
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