CN102516281B - 10-deacetylbaccatin III and method for methoxylation of its derivative - Google Patents
10-deacetylbaccatin III and method for methoxylation of its derivative Download PDFInfo
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- CN102516281B CN102516281B CN201110321031.3A CN201110321031A CN102516281B CN 102516281 B CN102516281 B CN 102516281B CN 201110321031 A CN201110321031 A CN 201110321031A CN 102516281 B CN102516281 B CN 102516281B
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- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000006198 methoxylation reaction Methods 0.000 title claims abstract description 8
- 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 title abstract 4
- YWLXLRUDGLRYDR-UHFFFAOYSA-N 10-deacetylbaccatin Chemical compound CC(=O)OC12COC1CC(O)C(C(C(O)C1=C(C)C(O)CC3(O)C1(C)C)=O)(C)C2C3OC(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-UHFFFAOYSA-N 0.000 claims abstract description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- -1 methoxy compound Chemical class 0.000 claims abstract description 16
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 230000001035 methylating effect Effects 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 8
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 238000003381 deacetylation reaction Methods 0.000 claims description 6
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- MNSBLWANOCYPMT-UHFFFAOYSA-N butyl(diphenyl)silane Chemical group C=1C=CC=CC=1[SiH](CCCC)C1=CC=CC=C1 MNSBLWANOCYPMT-UHFFFAOYSA-N 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 238000000151 deposition Methods 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- QUBBAXISAHIDNM-UHFFFAOYSA-N ethyldimethylbenzene Natural products CCC1=CC=CC(C)=C1C QUBBAXISAHIDNM-UHFFFAOYSA-N 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000006884 silylation reaction Methods 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 abstract description 12
- 229960001573 cabazitaxel Drugs 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)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 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 abstract description 7
- 229960003668 docetaxel Drugs 0.000 abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 abstract description 5
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 239000012022 methylating agents Substances 0.000 abstract 1
- 239000003208 petroleum Substances 0.000 abstract 1
- 239000012071 phase Substances 0.000 abstract 1
- 239000012266 salt solution Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 0 C*[C@@](C([C@@]1(*)C(C[C@@]2OC)OC1)[C@]2(C)C([C@@](C(C1(C)C)=C(C)[C@](C2)OC([C@@]([C@](c3ccccc3)NC(OC(C)(C)C)=O)O)=O)OC)=O)[C@@]12O Chemical compound C*[C@@](C([C@@]1(*)C(C[C@@]2OC)OC1)[C@]2(C)C([C@@](C(C1(C)C)=C(C)[C@](C2)OC([C@@]([C@](c3ccccc3)NC(OC(C)(C)C)=O)O)=O)OC)=O)[C@@]12O 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to 10-deacetylbaccatin III and a method for methoxylation of its derivative, which belongs to the medicine synthesis technical field. The invention is characterized in that the under the condition that 10-DAB, the 7 position and the 10 position of its derivative are hydroxy or one of them is hydroxyl, a phase transfer catalyst quaternary ammonium salt N<+>R4X<-> is added under the existence of a methylating agent, and dissolved according to a weight ratio of 1:10-100 of solute to organic solvent, and reacted with low temperature, a lower layer water phase is separated after finishing the reaction, an organic phase is washed by a saturated salt solution, and the organic phase is concentrated by concentrated acid, a petroleum ether is added for completely deposing, filtered, deposed and dried to obtain the product. The invention provides a simple and easy method for preparing the 10-DAB and a methoxy compound of the 7 position and the 10 position hydroxy of its derivative. The method for large scale intermediate preparation enables possibility of preparation of docetaxel with large dosage, and is a key step for preparing cabazitaxel.
Description
Technical field
The present invention relates to a kind of method of 10-deacetylation bar card fourth III and derivative methoxylation thereof, belong to technical field of medicine synthesis.
Background technology
In June, 2010, the U.S. ratified to have gone on the market antiprostate cancer Cabazitaxel cabazitaxel (JEVTANA), i.e. cabazitaxel (No. CAS: 183133-96-2; Molecular formula: C
45h
57nO
14), its structural formula is as follows:
The difference of Cabazitaxel and docetaxel docetaxel is only 7, the difference of No. 10 positions, and as shown in structure above, the position, No. 10, No. 7 positions of docetaxel is for hydroxyl and No. 7 positions of Cabazitaxel and No. 10 positions are methoxyl group.The synthesis technique of docetaxel since listing in 94 years, existing many ripe synthesis routes being applicable to (feather weight) in enormous quantities.The synthesis of Cabazitaxel can use docetaxel synthesis thinking to carry out completely, and then by 7, methylating of 10 hydroxyls is introduced.Therefore the methoxyl group of 7,10 hydroxyls changes into the gordian technique point of Synthesis Card Ba Tasai.The methoxylation of traditional hydroxyl is at alkali (as: NaH, NaOH, KH, Na, K, LiBu by methylating reagent (as: methyl iodide, methyl-sulfate, Methyl triflate)
4, LiHMDS etc.) effect under the selection of hydrogen solvent of sloughing on hydroxyl be generally aprotic polar solvent as dimethyl formamide DMF, after methyl-sulphoxide DMSO.
The preparation technology of this compound that can inquire at present be using 10-deacetylation bar card fourth III (hereinafter referred to as: 10-DAB) as starting raw material; through 7; 13 hydroxyl protection-10DAB, 10 HM-7,13 protecting group-10DAB, 7; 13 hydroxyls go protection acquisition 10 to methylate-10DAB; 7 HMs obtain 7,10-and to methylate-10-DAB again, then are coupled through side chain; go protection two step to obtain Cabazitaxel, synthetic route is as follows:
Use NaH in this synthesis road, MeI is as the methylation reaction of hydroxyl.Because 10-deacetylation bar card fourth III and the structure of derivative comparatively complicated, so 10-DAB time stable under alkaline environment can not be oversize, its 7, No. 10 position hydroxyls are sterically hindered larger.Reaction can be caused to carry out fast smoothly.This is also the batch little (tens of micrograms level) all very why this patent system is standby.Wherein the synthesis technique of key intermediate 7,10-dimethoxy-10-DAB becomes the committed step preparing Cabazitaxel.
Summary of the invention
The object of this invention is to provide a kind of 10-DAB, and 7 of derivative, the efficient methoxylation of No. 10 position hydroxyls.This preparation feedback can apply to Cabazitaxel key intermediate 7,10-dimethoxy-10-DAB.
Technical scheme of the present invention: a kind of method of 10-deacetylation bar card fourth III and derivative methoxylation thereof, step is as follows:
Described reactant is 10-DAB and derivative thereof, No. 7 positions of the derivative of described 10-DAB, No. 10 positions be simultaneously hydroxyl or one of them be hydroxyl;
By above-mentioned at reactant in 10-DAB and derivative thereof: organic solvent weightmeasurement ratio be 1: 10 ~ 100 ratio be suspended in organic solvent, 10-DAB and derivative thereof in molar ratio: methylating reagent 1: 1 ~ 10,10-DAB and derivative thereof: Phase-transfer catalyst quaternary ammonium salt class N
+r
4x
-be 1: 0.01 ~ 10,10-DAB and derivative thereof: dehydrating agent 1: 1.5 ~ 30 adds methylating reagent, Phase-transfer catalyst quaternary ammonium salt class N
+r
4x
-and dehydrating agent, at low temperature-70 ~ 5 DEG C reaction 0.5 ~ 4h, isolate lower floor's aqueous phase after completion of the reaction; get saturated common salt water washing organic phase; and organic phase is concentrated into 20% ~ 60% of original volume; add sherwood oil to precipitating completely; after filtering-depositing drying, namely obtain product; or organic phase is concentrated into ointment shape, with silica gel column chromatography, eluent proportioning is ethyl acetate: sherwood oil, normal hexane, No. six oil or pentane volume ratio 1: 1 ~ 7; concentrated; obtain the derivative of product 7,10-dimethoxy-10-DAB or 7,10-dimethoxy-10-DAB;
The derivant structure formula of described 7,10-dimethoxy-10-DAB is as follows:
Wherein R
1, R
2one of be methyl, another is ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, allyl group, tertiary butyl or benzyl, R
3for hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, tertiary butyl diphenyl silane base, allyl group, tertiary butyl, benzyl, or side-chain structure as follows:
Wherein R
4, R
5for alkyl, methoxyl group, the oxyethyl group of hydrogen atom and carbonatoms 1-4, or the combination of p-methoxyphenyl.
Described methylating reagent is methyl iodide, methyl-sulfate, Methyl triflate, methyl iodide, methylcarbonate, triazonmethane or trimethyl phosphite 99.
Described Phase-transfer catalyst quaternary ammonium salt class N
+r
4x
-in R to be carbon atom number be the saturated of 1-20 or unsaturation alkyl and benzene, toluene or dimethylbenzene.
Described organic solvent is the ether after anhydrous process, toluene, ethyl acetate, dimethylbenzene or benzene.
Described dehydrating agent is NaH, NaOH, KH, Na metal, and karat gold belongs to, n-Butyl Lithium or LHMDS.
Described 10-DAB and derivant structure as follows:
R
1for hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, phenylbenzene tertiary butyl silylation, allyl group, tertiary butyl, benzyl, or side-chain structure as follows:
Wherein R
4, R
5for hydrogen atom, the alkyl of carbonatoms 1 ~ 4, methoxyl group, oxyethyl group, or the combination of p-methoxyphenyl.
R ', R " be hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, tertiary butyl diphenyl silane base, allyl group, tertiary butyl or benzyl.
Described methylating reagent is according to methylating reagent: ether weightmeasurement ratio is 1: 1 ~ 5 be dissolved in solvent and be added dropwise in reactant again.
Described 10-DAB and derivative thereof: dehydrating agent molar ratio is 1: 10 ~ 30.
Beneficial effect of the present invention: the present invention has prepared 10-DAB by a kind of simple method, and 7 of derivative, the methoxyl group compound of No. 10 position hydroxyls, this method can preparing intermediate on a large scale makes heavy dose prepare docetaxel possibility, is the committed step preparing Cabazitaxel.
Embodiment
Embodiment 1
In the reaction flask of 5L, 100.0g (0.15mol) 13-triethyl silyl-10-DAB is dissolved in the anhydrous diethyl ether of 2.5L, in churned mechanically situation, add 1g (0.003mol) Tetrabutyl amonium bromide, subcooling is to-40 degrees Celsius.Then the 200mL anhydrous ether solution of methyl-sulfate (1mol, 126g) is dropped in reaction flask.Again by NaH 134.7g (3.3mol) powder adding 60% in filling tube in batches.1 hours adds complete, and feed rate to control in reaction flask reacting liquid temperature below-15 degrees Celsius.Stir 1 hour recession deicing salt bath again; According to the detection of TLC to starting material after completion of the reaction, leave standstill after being added dropwise to the hydrochloric acid of 1000mL 0.5mol/L when opening ice bath and separate lower floor's aqueous phase, then the hydrochloric acid soln adding 1000mL0.5mol/L stir after separate lower floor's aqueous phase.Then through the washing of 500mL saturated aqueous common salt, organic phase solution is concentrated into 600mL.There is a large amount of white precipitates in the sherwood oil adding 3L after cooling.Its filtration drying is obtained product 10-methoxyl group-7,13-triethyl silyl-DAB white powder 88.5g yield 86%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
Embodiment 2
By 100.0g (0.18mol) in the reaction flask of 5L, 10-DAB is suspended in the anhydrous diethyl ether of 2.5L, adds 1g Tetrabutyl amonium bromide in churned mechanically situation, cryosel water-bath to 0 degree Celsius.Then the 200mL anhydrous ether solution of methyl-sulfate (1mol, 126g) is dropped in reaction flask.Again by NaH 134.7g (3.3mol) powder adding 60% in filling tube in batches.1 hours adds complete, and feed rate to control in reaction flask reacting liquid temperature below 5 degrees Celsius.Stir 1 hour recession deicing salt bath again; According to the detection of TLC to starting material after completion of the reaction, leave standstill after being added dropwise to the hydrochloric acid of 1000mL 0.5mol/L when opening ice bath and separate lower floor's aqueous phase, then the hydrochloric acid soln adding 1000mL 0.5mol/L stir after separate lower floor's aqueous phase.Then through the washing of 500mL saturated aqueous common salt, organic phase solution is concentrated into 600mL.There is a large amount of white precipitates in the sherwood oil adding 3L after cooling.Filtered to obtain filter cake, by filter cake through chromatography dry product 7,10-dimethoxy-10-DAB white powder 93.1g yield 89%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
Embodiment 3
By 100.0g (0.18mol) in the reaction flask of 10L, 10-DAB is suspended in the dry toluene of 2.5L, adds 1g Tetrabutyl amonium bromide in churned mechanically situation, cryosel water-bath to 0 degree Celsius.Then the 1000mL anhydrous toluene solution of methyl-sulfate (0.5mol, 63g) is dropped in reaction flask.Again by the NaH pressed powder 6.58g (0.24mol) adding 90% in filling tube in batches.1 hours adds complete, and feed rate to control in reaction flask reacting liquid temperature below 5 degrees Celsius.Stir 1 hour recession deicing salt bath again; According to the detection of TLC to starting material after completion of the reaction, leave standstill after being added dropwise to the hydrochloric acid of 1000mL 0.5mol/L when opening ice bath and separate lower floor's aqueous phase, then the hydrochloric acid soln adding 1000mL 0.5mol/L stir after separate lower floor's aqueous phase.Then through the washing of 500mL saturated aqueous common salt, organic phase solution is concentrated into 600mL.There is a large amount of white precipitates in the sherwood oil adding 3L after cooling.Filtered to obtain filter cake, by filter cake through chromatography dry product 7,10-dimethoxy-10-DAB white powder 93.1g yield 89%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
Claims (1)
1. a method for 10-deacetylation bar card fourth III and derivative methoxylation thereof, is characterized in that: step is as follows:
Reactant is 10-DAB or derivatives thereof, No. 7 positions of the derivative of described 10-DAB, No. 10 positions be simultaneously hydroxyl or one of them be hydroxyl;
Above-mentioned reactant is suspended in organic solvent in the ratio that 10-DAB or its Yan Sheng Wu ︰ organic solvent weightmeasurement ratio are 1 ︰ 10 ~ 100g/ml, 10-DAB or its Yan Sheng Wu ︰ methylating reagent 1 ︰ 1 ~ 10 in molar ratio, 10-DAB or its Yan Sheng Wu ︰ Tetrabutyl amonium bromide are 1 ︰ 0.01 ~ 10, 10-DAB or its Yan Sheng Wu ︰ dehydrating agent 1 ︰ 1.5 ~ 30 adds methylating reagent, Tetrabutyl amonium bromide and dehydrating agent, at low temperature-70 ~ 5 DEG C reaction 0.5 ~ 4h, isolate lower floor's aqueous phase after completion of the reaction, get saturated common salt water washing organic phase, and organic phase is concentrated into 20% ~ 60% of original volume, add sherwood oil complete to precipitation, namely product is obtained after filtering-depositing drying, or organic phase is concentrated into ointment shape, with silica gel column chromatography, eluent proportioning is Yi Suan Yi Zhi ︰ sherwood oil, Yi Suan Yi Zhi ︰ normal hexane, Yi Suan Yi Zhi ︰ No. six oil or Yi Suan Yi Zhi ︰ pentane volume ratio 1:1 ~ 7, concentrated, obtain product 7, 10-dimethoxy-10-DAB or 7, the derivative of 10-dimethoxy-10-DAB,
The derivant structure formula of described 7,10-dimethoxy-10-DAB is as follows:
Wherein R
1, R
2one of be methyl, another is ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, allyl group, tertiary butyl or benzyl, R
3for hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, tertiary butyl diphenyl silane base, allyl group, tertiary butyl, benzyl, or side-chain structure as follows:
Wherein R
4, R
5for alkyl, methoxyl group, the oxyethyl group of hydrogen atom and carbonatoms 1-4, or the combination of p-methoxyphenyl;
Described methylating reagent is methyl iodide, methyl-sulfate, Methyl triflate, methylcarbonate, triazonmethane or trimethyl phosphite 99;
Described organic solvent is the ether after anhydrous process, toluene, ethyl acetate, dimethylbenzene or benzene;
Described dehydrating agent is NaH, NaOH, KH, Na metal, and karat gold belongs to, n-Butyl Lithium or LHMDS;
Described 10-DAB and derivant structure as follows:
R ' " be hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, phenylbenzene tertiary butyl silylation, allyl group, tertiary butyl, benzyl, or side-chain structure as follows:
Wherein R
4, R
5for hydrogen atom, the alkyl of carbonatoms 1-4, methoxyl group, oxyethyl group, or the combination of p-methoxyphenyl;
R', R " be hydrogen atom, ethanoyl, benzoyl, TMS, triethyl silyl, tertiary butyl dimethylsilyl, tertiary butyl diphenyl silane base, allyl group, tertiary butyl or benzyl;
Described methylating reagent is that 1 ︰ 1 ~ 5g/ml is dissolved in solvent and is added dropwise in reactant again according to methyl Shi Ji ︰ ether weightmeasurement ratio.
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| WO2014184807A2 (en) * | 2013-05-13 | 2014-11-20 | Msn Laboratories Private Limited | PROCESS FOR THE PREPARATION OF (2α,5β,7β,10β,13α)-4-ACETOXY-13-({(2R,3S)-3-[(TERT-BUTOXYCARBONYL)AMINO]-2-HYDROXY-3-PHENYLPROPANOYL}OXY)-1-HYDROXY-7,10-DIMETHOXY-9-OXO-5,20-EPOXYTAX-11-EN-2-YL BENZOATE |
| CN106632158B (en) * | 2013-08-28 | 2018-11-06 | 江苏恒瑞医药股份有限公司 | The preparation method of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs |
| CN104109142A (en) * | 2014-06-22 | 2014-10-22 | 南京工业大学 | Method for preparing cabazitaxel by taking baccatin III as raw material |
| CN106892883A (en) * | 2017-04-19 | 2017-06-27 | 成都百特万合医药科技有限公司 | A kind of preparation method of Cabazitaxel intermediate |
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