CN111718309B - Synthesis method of paclitaxel side chain and analogues thereof - Google Patents
Synthesis method of paclitaxel side chain and analogues thereof Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 229930012538 Paclitaxel Natural products 0.000 title abstract description 16
- 229960001592 paclitaxel Drugs 0.000 title abstract description 16
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical group O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 9
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 9
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 8
- 238000009833 condensation Methods 0.000 claims abstract description 7
- 230000005494 condensation Effects 0.000 claims abstract description 7
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 229940117916 cinnamic aldehyde Drugs 0.000 claims abstract description 5
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 10
- 238000006297 dehydration reaction Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- -1 p-methoxybenzyl Chemical group 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 101100272974 Panax ginseng CYP716A47 gene Proteins 0.000 claims description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- RSUHWMSTWSSNOW-IBGZPJMESA-N [diphenyl-[(2s)-pyrrolidin-2-yl]methoxy]-trimethylsilane Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O[Si](C)(C)C)[C@@H]1CCCN1 RSUHWMSTWSSNOW-IBGZPJMESA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940077239 chlorous acid Drugs 0.000 claims description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000003384 small molecules Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000035484 reaction time Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- HYJVYOWKYPNSTK-UONOGXRCSA-N (2r,3s)-3-benzamido-2-hydroxy-3-phenylpropanoic acid Chemical compound N([C@H]([C@@H](O)C(O)=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 HYJVYOWKYPNSTK-UONOGXRCSA-N 0.000 abstract description 6
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000010931 ester hydrolysis Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 241001116500 Taxus Species 0.000 description 2
- 241001149649 Taxus wallichiana var. chinensis Species 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- MRDAXWGGWWDUKL-VKJPNVGWSA-N 3-O-Caffeoylshikimic acid Chemical compound O[C@H]1[C@H](O)CC(C(O)=O)=C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 MRDAXWGGWWDUKL-VKJPNVGWSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
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- 239000000203 mixture Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention discloses a paclitaxel side chain ((4S,5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) shown in a formula (f) and a synthesis of analogues thereofThe synthesis method comprises the steps of taking cinnamaldehyde as a raw material, and carrying out a series of reactions such as epoxidation, methyl esterification, ammonolysis, ester hydrolysis, condensation, configuration inversion, condensation and hydrolysis to synthesize a taxol side chain ((4S,5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazoline carboxylic acid) and analogues thereof. 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 paclitaxel side chain ((4S,5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolinecarboxylic 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 10-deacetylbaccatin III has rich sources, and the anti-cancer medicament can be obtained by a semisynthesis method by only synthesizing a large amount of paclitaxel side chains and then introducing the paclitaxel side chains into the 10-deacetylbaccatin III molecules.
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,
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,
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,
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 H 2 O 2 (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 tube 3 Heating 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%.
1 HNMR(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 added 2 (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%.
1 H NMR(400MHz，CHLOROFORM-d)δppm 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%.
1 H NMR(400MHz，CHLOROFORM-d)δppm 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 SOCl 2 (9.93g, 83.5mmol), heating to reflux and stirring for 5h, detecting by TLC that the raw materials react completely, concentrating to obtain light yellow solid, adding 50ml DCM, refluxing and stirring for 4h, cooling to room temperature, washing with 50ml saturated sodium chloride, concentrating to obtain white solid, adding methanol (230ml) and 1N hydrochloric acid(77ml) was stirred under reflux, the external temperature was 87 ℃ and the reaction was complete after about 5h of TLC detection, concentrated, extracted with 50ml of water and 50ml of 2DCM, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 8.5g of a white solid e, 85.0% yield.
1 H NMR(400MHz，DMSO-d 6 )δppm 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%.
1 H NMR(400MHz，DMSO-d 6 )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 (9)
1. A method for synthesizing ((4S,5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolinecarboxylic acid), wherein the reaction process is shown in scheme (A):
route (a);
wherein R 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; the ligand is (2S) -2- [ diphenyl [ (trimethylsilyl) oxy ] methyl ] -pyrrolidine; the oxidant is one or more of hydrogen peroxide, m-chloroperoxybenzoic acid and chlorous acid; the methyl esterification reagent is one of NBS and sodium hypochlorite;
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; the dehydration reagent is one or more of thionyl chloride, phosphorus oxychloride, sulfuric acid and phosphorus pentoxide;
5) in an organic solvent, carrying out a condensation reaction on a compound of a formula e and a condensation reagent under the action of a catalyst, and then obtaining a compound of a formula f under the action of alkali; the catalyst is one or two of PPDS and CSA; the condensing agent is PDA.
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.
3. The 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); the temperature of the chiral epoxidation reaction is 0-50 ℃; 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; the temperature of the ammonolysis reaction is 50-100 ℃; 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 two of dichloromethane and methanol; the acid is strong acid and is selected from one or more of sulfuric acid, hydrochloric acid and thionyl chloride; the small molecular alcohol is methanol.
6. The synthesis 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: (2-6): (1-2); 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; the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate; the molar ratio of the compound of formula c, benzoyl chloride and base is 1: (2-5): (2-10); the temperature of the condensation reaction is 0-40 ℃.
8. The synthesis method of claim 1, wherein in the step 4), the acid is a strong acid selected from one or more of hydrochloric acid and sulfuric acid; the solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene and methanol; the temperature of the dehydration reaction is 50-150 ℃; the molar ratio of the compound of formula d to the dehydrating reagent is 1: (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; the alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate; the molar ratio of the compound of formula e to the catalyst is (1-50): (0.1-1); the temperature of the condensation reaction is 0-140 ℃.
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