CN110143934A - A kind of fluorine-containing bearing taxanes and the preparation method and application thereof - Google Patents
A kind of fluorine-containing bearing taxanes and the preparation method and application thereof Download PDFInfo
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- CN110143934A CN110143934A CN201810995609.5A CN201810995609A CN110143934A CN 110143934 A CN110143934 A CN 110143934A CN 201810995609 A CN201810995609 A CN 201810995609A CN 110143934 A CN110143934 A CN 110143934A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 239000011737 fluorine Substances 0.000 title abstract description 18
- 229910052731 fluorine Inorganic materials 0.000 title abstract description 18
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title abstract description 17
- 229940123237 Taxane Drugs 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
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- 238000006243 chemical reaction Methods 0.000 claims description 129
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- -1 Propiono Chemical group 0.000 claims description 17
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052710 silicon Inorganic materials 0.000 claims description 15
- 239000010703 silicon Substances 0.000 claims description 15
- 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 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 238000003032 molecular docking Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
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- 239000002253 acid Substances 0.000 claims description 7
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- 201000001275 rectum cancer Diseases 0.000 claims description 5
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound 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 abstract description 24
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 abstract description 14
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- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
The invention discloses a kind of fluorine-containing bearing taxanes and the preparation method and application thereof.The general structure of the compound is shown in formula I.Pharmacological evaluation proves, a series of fluorine-containing taxane derivatives synthesized by the present invention, compared with taxol, for multidrug resistance type MCF-7 cell strainHJ2mm/Adr, Ovarian Cancer Cells NCI/Adr has the cytotoxicity better than taxol, and for the colon cancer cell line HCT-116 that tumor stem cell is overexpressed++Show the cytotoxicity better than taxol.
Description
Technical field
The present invention relates to a kind of fluorine-containing bearing taxanes and the preparation method and application thereof.
Background technique
Malignant tumour is to seriously threaten the principal disease of human life and quality of life.In recent decades, people are mutually secondary
The treatment that many high cell toxicant based chemotherapy drugs are clinically used as fiest-tire medication to be applied to kinds cancer is showed.Taxol
(Paclitaxel) it is listed from exploitation in 1992, the market sales revenue occupies rapidly first of antineoplastic, so far paclitaxel prodrugs
Still it is always maintained at 30% growth rate, the taxol volume of trade in the whole world is always held at 5,000,000,000 dollars or more at present.As
Another of Japanese yew class represents drug docetaxel (Docetaxel), and anti-tumor activity is more stronger than taxol, the market share by
Year rises.
The application of taxol at present clinically is administered by intravenous injection, since taxol soluble is very poor, by it
It is dissolved in the in the mixed solvent of Emulsifier EL-60 Chremophor EL and ethyl alcohol (1:1 specific gravity), the injection of taxol has been made
Agent, the entitled Taxol in market.Clinically application receives the restriction of several factors to Taxol: (1) being drug itself first to just
Normal histiocytic toxic side effect, dose limiting toxicity and bone marrow suppression (clinically needing to cooperate growth factor for treating), nothing
Method passes through blood-brain barrier etc.；(2) with the application of Chremophor EL, following problem: serious allergic reaction, original
Hair property hyperlipidemia, variation [ten Tije AJ, et al, the Clin of Central neurotoxicity and taxol pharmacokinetics
Pharmacokinet 42,655-685,2003；H.Gelderblom,et al,Eur.J.Cancer 37(13),1590-
1598,2001；van Zuylen L,et al,Invest New Drugs 19,125-141,2001；R.B.Weiss,et
al,J.Clin.Oncol.8(7),1263-1268,1990].(3) multidrug resistance caused by long-term administration.This is also taxol
The main reason for chemotherapy fails, while taxol itself waited colon cancer, brain tumor the cell strain activity of P- glycoprotein (P-gp)
It is very low, greatly limit its clinical application range.Application of the docetaxel in clinic is similarly big along with toxic side effect, more
The problems such as medicine drug resistance.
The Development Trend in taxanes anti-tumor drug future is no longer structural modification simply to find higher cell toxicant
Taxane molecule, but turning to is to overcome the problems, such as the multidrug resistance of taxone, still for multidrug resistance of tumor
Anticancer therapeutic is kept, blood-brain barrier easier can be passed through and there is the novel taxane class of good therapeutic effect to tumor in digestive tract
Molecule, to expand the clinical application range of taxane anti-tumor medicament and improve the therapeutic index to malignant tumour.In invention Hold
The object of the present invention is to provide a kind of fluorine-containing bearing taxanes and the preparation method and application thereof.
Fluorine-containing bearing taxanes provided by the invention, general structure are shown in formula I:
In the Formulas I, R is the alkyl for being 1-6 containing the carboxyl groups or carbon atom number for being no more than six atoms.
Specifically, the R is acetyl group, propiono, methoxycarbonyl base, N, N- dimethylcarbamoyl, cyclopropyl formoxyl
Or methyl；
Concretely any one in compound shown in following JY-01 to JY-06 of compound shown in the Formulas I:
JY-01
JY-02
JY-03
JY-04
JY-05
JY-06
The method provided by the invention for preparing compound shown in the Formulas I, includes the following steps:
The silicon-based protecting group that compound shown in formula 002 is sloughed to C2' obtains compound shown in the Formulas I；
In the above method, in the silicon-based protecting group step for sloughing C2', reaction condition is acid condition；
The pH value of the acid condition is 1-3；
The acid condition is specially to carry out in HF/Py solution；The volume ratio of the HF/Py is 3-4:1.
In the silicon-based protecting group step for sloughing C2', reaction dissolvent is the mixed liquor being made of acetonitrile and pyridine, four
At least one of hydrogen furans, methylene chloride, methanol and ethyl alcohol；In the mixed liquor being made of acetonitrile and pyridine, acetonitrile and pyrrole
The volume ratio of pyridine is specially 1:1-2；
Reaction temperature is room temperature to 0 DEG C；
Reaction time is 12-24h.
In addition, compound or its pharmaceutically acceptable salt shown in the Formulas I that aforementioned present invention provides are to prepare anti-multiple medicine resistance to
Pharmacological property product and/or the application in the active product that preparation inhibits the strain of tumor stem cell overexpressing cell, also belong to this hair
Bright protection scope.
Specifically, the anti-multidrug resistance and inhibit the strain of tumor stem cell overexpressing cell in, for tumour be cream
At least one of gland cancer, oophoroma, the carcinoma of the rectum, non-small cell lung cancer and melanoma.
In addition, midbody compound used when compound shown in a kind of preparation formula I is also claimed in the present invention, among this
The general structure of body compound as shown in formula 002,
The method of compound shown in preparation formula 002 provided by the invention, comprising:
Compound shown in formula 001 is reacted with the generation Hilton docking of compound shown in formula 11 and is obtained；
In the Hilton docking reaction step of the above method, compound shown in compound shown in formula 001 and formula 11
Equivalent proportion is 1:1~1:4；
The Hilton docking reaction carries out under alkaline condition；
The pH value of the alkaline condition is 7.5-9；
The alkaline condition is specially condition existing for lithium hexamethyldisilazide (LHMDS)；
The Hilton docking reaction carries out in a solvent；The solvent is chosen in particular from tetrahydrofuran, methylene chloride and two
At least one of six ring of oxygen；
The reaction temperature of the Hilton docking reaction is 0 DEG C to -40 DEG C；
Reaction time is 2-12h.
In the above method, compound shown in the formula 11 namely beta-lactam side chain precursor can synthesize as follows:
Benzyl protection is successively passed through using glycolic, tert-butyl carbonyl (Boc yl) protection generates boc-protected ethyl alcohol acid benzyl ester；It sloughs
Benzyl protection, free carboxylic acid is reacted with n-hydroxysuccinimide generates active intermediate, with trans- -2- phenyl -1-
Cyclohexanol esterification condensation forms compound 5, and methacrolein forms corresponding enamine compound 6, compound 5 with P-nethoxyaniline
Addition is carried out with compound 6 and generates chipal compounds 7, and then isobutene oxide base side chain forms aldehyde radical, and difluoroethylene replaces, and takes off
The protecting group gone on nitrogen-atoms is finally protected with tertbutyloxycarbonyl, and final beta-lactam side chain precursor is generated.
Compound shown in the formula 001 namely taxane nucleus part can synthesize as follows: with 10- deacetylate
Baccatin III is starting material, carries out silated protection to C7 hydroxyls first, then carry out acylation protection to C10 hydroxyls,
Slough C7 silicon-based protecting groups, free hydroxyl generates sulphonic acid ester, under the action of high temperature highly basic, and faces a C6 generation
Elimination reaction, generates C6, and the structure of C7 double bond carries out addition with HF, obtains final mother nucleus structure.
Wherein, C10 hydroxyls be acylated protecting and be specifically included: when R is acetyl group, and propiono replaces, institute
The reaction being related to is under the action of cerous chloride, and tetrahydrofuran is as solvent, at room temperature, is reacted with corresponding acid anhydrides.
(acid anhydrides includes acetic anhydride and propionic andydride).When R be methoxycarbonyl base, N, N- dimethylcarbamoyl, cyclopropyl formoxyl replace when,
Related reaction is especially optimal with lithium hexamethyldisilazide (LHMDS), tetrahydrofuran under alkaline condition, dichloromethane
Alkane, dioxane as solvent, be especially with tetrahydrofuran it is optimal, room temperature is especially optimal with 0 DEG C at a temperature of 0 DEG C, and corresponding
Acyl chlorides is reacted.(acyl chlorides includes: methoxycarbonyl chlorine, N, N- dimethyl methyl acyl chlorides, Cyclopropyl carbonyl chloride.) taken for methyl as R
Dai Shi, related reaction is especially optimal with lithium hexamethyldisilazide (LHMDS), tetrahydrofuran under alkaline condition, two
Chloromethanes, dioxane as solvent, especially with tetrahydrofuran be it is optimal, it is especially optimal with -40 DEG C at a temperature of 0 DEG C to -70 DEG C,
It is reacted with Methyl triflate.
The present invention is by the way that simultaneously to taxol C6, C7, C10, the substituent group in the more a sites C3' is transformed, and synthesis obtains
Especially 6 novel fluorine-containing taxane compounds shown in Formulas I, by investigate in vitro its to multidrug resistance tumor cells strain with
And the cytotoxic activity test of the cell strain of tumor stem cell overexpression, the experimental results showed that the anti-multidrug resistance of 6 compounds
Activity is superior to taxol.Therefore, this kind of fluorine-containing taxane compounds of the invention are a kind of potential anti-multidrug resistances of tool
Tumour medicine.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited to following embodiments.Institute
State method is conventional method unless otherwise instructed.The raw material can obtain unless otherwise instructed from public commercial source.
The preparation of embodiment 1, JY-01
1) preparation of compound 11
A. the preparation of compound 1
Glycolic (7.60g, 0.10mol) is dissolved in the acetonitrile of 10mL, into solution add cylite (13.60g,
0.08mol), it is to be mixed uniformly after at 0 DEG C, DBU (12.16g, 0.08mol) is slowly added dropwise into reaction solution, is dripped
Bi Hou, the reaction solution are stirred at room temperature overnight.Reacted solution is poured into ice water, is extracted with ethyl acetate, is associated with
Machine phase successively uses 1M hydrochloric acid solution, and saturated common salt water washing is dry with anhydrous magnesium sulfate, and concentrated by rotary evaporation obtains yellow oil
Compound 1.
B. the preparation of compound 2
Compound 1 (12.5g, 75.3mmol) is dissolved in 100mL methylene chloride, and 4-dimethylaminopyridine is added into solution
(1.04g, 8.42mmol) and triethylamine (14.1mL, 101mmol) is added dropwise 1M's after mixing evenly at 0 DEG C into reaction solution
Tri isopropyl chlorosilane (22.3mL, 101mmol).Stirred overnight at room temperature reaction, TLC monitoring reaction carries out, to after completion of the reaction,
25mL saturated ammonium chloride solution is added into reaction solution, is filtered to remove the white solid of generation, filtrate passes through ethyl acetate repeatedly
Washing merges organic phase, and after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentrated by rotary evaporation and obtains yellow oily
Close object.
C. the preparation of compound 3
Compound 2 (5g, 15.53mmol) is dissolved in 50mL ethyl acetate, and 10% palladium carbon is added into reaction solution
(82.5mg,0.775mmol).The air in reaction flask is emptied, the continuous hydrogen make-up into reaction flask is reacted 4 hours, TLC
Monitoring reaction carries out, to which after reaction, filtering and concentrating obtains yellow oily compound 3.
D. the preparation of compound 4
Compound 3 (3.6g, 15.5mmol) is dissolved in the methylene chloride of 50mL, and 1- (3- diformazan is added into reaction solution
Aminopropyl) -3- ethyl carbodiimide (EDC) (3.03g, 15.5mmol) and n-hydroxysuccinimide (NHS) (2.18g,
18.6mmol), overnight, TLC monitoring reaction carries out for reaction at room temperature, to after reaction, methylene chloride repeatedly extracts, is associated with
Machine phase, after saturated common salt water washing, anhydrous magnesium sulfate, which dries, filters, is concentrated to get compound 4.
E. the preparation of compound 5
Trans- 2- phenylcyclohexanol (1.95g, 11.08mmol) and 4-dimethylaminopyridine (DMAP) (1.37g,
It 11.08mmol) is dissolved in 25mL toluene, compound 4 (4.38g, 13.3mmol) is slowly added into reaction solution.In room temperature
Under reacted, TLC monitoring reaction carries out, and to after reaction, 20mL saturated salt solution, ethyl acetate are added into reaction solution
Repeatedly extraction merges organic phase, and anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain compound 5.
F. the preparation of compound 6
P-nethoxyaniline (0.31g, 2.51mmol) is dissolved in 10mL methylene chloride, and a small amount of nothing is added into reaction solution
Water magnesium sulfate.Then to the dropwise addition 3- methyl -2- butyraldehyde into reaction solution.It is protected from light 4 hours, TLC monitoring reaction carries out, to anti-
After answering, filtering and concentrating obtains compound 6.
G. the preparation of compound 7
Compound 5 (0.65g, 1.67mmol) is dissolved in the tetrahydrofuran of 4mL, is added dropwise at -78 DEG C into reaction solution
Compound 6 is added dropwise into reaction solution after reaction 0.5 hour for the lithium diisopropylamine (2.5mL, 2.50mmol) of 1M
(2.50mmol) is dissolved in 3mL tetrahydrofuran, and after reaction 2.5 hours, reaction was completed, and 5mL is added into reaction solution and is saturated chlorine
Change ammonium salt solution, reaction solution is repeatedly extracted with ethyl acetate, merge organic phase, after saturated common salt water washing, anhydrous magnesium sulfate is dry
Dry, filtering and concentrating, column separation purifies to obtain compound 7.
H. the preparation of compound 8
Compound 7 (485mg, 1.20mmol) is dissolved in the methylene chloride of 10mL, and O is continually fed into reaction solution3,
It is reacted 0.5 hour at -78 DEG C, is revealed as to solution light blue, the dimethyl sulfide of 2mL is added into reaction solution, reaction is 3 small
Shi Hou, concentration of reaction solution, column separation purify to obtain compound 8.
I. the preparation of compound 9
Compound 8 (230mg, 0.61mmol), the chloro- 2- difluoroacetic acid sodium (285mg, 1.83mmol) of 2- and triphenyl phosphorus
(485mg, 1.83mmol) is dissolved in 10mL n,N-Dimethylformamide.After 90-100 DEG C is reacted 2 hours, to reaction solution
It is slightly cooling, 20mL water is added into reaction solution, is repeatedly extracted with ethyl acetate, merges organic phase, after saturated common salt water washing,
Anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain compound 9.
J. the preparation of compound 10
Compound 9 (124mg, 0.30mmol) is dissolved in 10mL acetonitrile/water (4:1), at -10 DEG C, adds into reaction solution
Enter ammonium ceric nitrate (575mg, 1.05mmol), react 2 hours, to after reaction, 30mL be added into reaction solution and is saturated sulfurous
Sour sodium, water phase are repeatedly extracted with ethyl acetate, merging organic phase, and after saturated common salt water washing, anhydrous magnesium sulfate is dry, mistake
Filter concentration, column separation obtain compound 10.
K. the preparation of compound 11
Compound 10 (270mg, 0.89mmol), triethylamine (0.75mL, 5.38mmol) and 4-dimethylaminopyridine
(43mg, 0.35mmol) is dissolved in the methylene chloride of 10mL, and di-tert-butyl dicarbonic acid ester is added into reaction solution at room temperature
(398mg, 1.77mmol), reaction overnight, to after reaction, reaction solution is repeatedly extracted with ethyl acetate, merge organic
Phase, after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain compound 11.
2) preparation of the fluoro- 7- deoxidation -10- acetyl group baccatin III of 6-
A.7- the preparation of triethyl group silicon substrate -10- deacetylate baccatin III
10-DAB (0.55g, 1.01mmol) and imidazoles (0.21g, 3.03mmol) are dissolved in the N of 10mL, N- dimethylamino
In formamide DMF, at 0 DEG C, chlorotriethyl silane TESCl (0.52mL, 3.03mmol) is added dropwise into reaction solution, reaction 1 is small
When, after reaction, the water of 25mL is added into reaction solution, is repeatedly extracted with ethyl acetate, merges organic phase, saturated salt solution
After washing, after anhydrous magnesium sulfate is dry, filtering and concentrating, column separation purifies to obtain product
B.10- acetyl group -7- triethyl group silicon substrate-baccatin III preparation
It is molten that compound 12 (658mg, 1.0mmol) and cerous chloride (4.9mg, 0.02mmol) are dissolved in 10mL tetrahydrofuran
In liquid, aceticanhydride (1.88mL, 20.0mmol) is added dropwise into reaction solution at room temperature, TLC monitoring reaction carries out, to the end of reacting
Afterwards, 20mL water is added into reaction solution, is repeatedly extracted with ethyl acetate, organic phase is merged, after saturated common salt water washing,
Anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
C.10- acetyl group-baccatin III preparation
10- acetyl group -7- triethyl group silicon substrate-baccatin III (586mg, 1.0mmol) be dissolved in 10mL acetonitrile/pyridine (1:
1) in, it is cooled to 0 DEG C, 3mL70%HF/Py solution, reaction overnight, after reaction, into reaction solution are added dropwise into reaction solution
The sodium bicarbonate solution of saturation is added, neutralizes excessive HF, is then repeatedly extracted with ethyl acetate, merges organic phase, reaction is used
The washing of copper/saturated copper sulphate solution, removes excessive pyridine, finally uses saturated common salt water washing, anhydrous magnesium sulfate dries, filters dense
Contracting, column separation purify to obtain product.
D.10- the preparation of acetyl group -7- triflate baccatin III
10- acetyl group-baccatin III of 1 equivalent is dissolved in dry methylene chloride, the pyridine of 5 equivalents is added, 0
It is stirred at DEG C, then is added dropwise to the Methyl triflate of 2 equivalents into reaction solution, after reaction 3 hours, reaction solution is poured into water
In, it is extracted with dichloromethane, merges organic phase, successively use the hydrochloric acid solution of 0.1M, saturated sodium bicarbonate, saturated common salt aqueous solution
Washing, rotates, column separation obtains product by dry filter.
E.10- the preparation of acetyl group -6,7- double bond baccatin III
10- acetyl group -7- triflate the Bakating III of 1 equivalent is dissolved in dioxane/tetrahydrofuran (10:1)
In the mixed solvent 1,8- diazabicylo, the 11 carbon -7- alkene DBU of 2 equivalents is added dropwise into reaction solution, instead at 100 DEG C
After answering 1 hour, reaction solution is poured into the saturated ammonium chloride of ice bath and the mixed liquor of ethyl acetate, the organic phase being obtained by extraction
It is concentrated through dry filter, column separation obtains product.
F.10- the preparation of the fluoro- 7- deoxidation baccatin III of acetyl group -6-
10- acetyl group -6,7- double bond baccatin III of 1 equivalent is dissolved in tetrahydrofuran, is added in hydrogen kettle,
At 40 DEG C, the CH of 2atm is poured into reactor3OCH35HF gas, after reaction 4 hours, reaction was completed, and column separation is concentrated
Obtain product.
3) preparation of JY-01
The beta-lactam side chain precursor of the parent nucleus of 1 equivalent and 2 equivalents is dissolved in suitable tetrahydrofuran, at -40 DEG C
Under, the lithium hexamethyldisilazide (LHMDS) of 1.5 equivalents is added dropwise into reaction solution, TLC monitoring reaction carries out, wait react knot
Shu Hou is added suitable saturated ammonium chloride solution, is repeatedly extracted with ethyl acetate, and merges organic phase, and drying is concentrated to give crude product.It will
The crude product that previous step is reacted is dissolved in the mixed solution of suitable acetonitrile/pyridine (1:1), at 0 DEG C, to reaction solution
Middle that suitable 70%HF/Py solution is added, reaction overnight, after reaction, the sodium bicarbonate that saturation is added into reaction solution are molten
Liquid neutralizes excessive HF, is then repeatedly extracted with ethyl acetate, and merges organic phase, and reaction is washed with copper/saturated copper sulphate solution, removed
Excessive pyridine is removed, saturated common salt water washing is finally used, anhydrous magnesium sulfate dries, filters concentration, column separation purifying
Object JY-01 is closed, final products purity reaches 95% or more.
M.p.=163-164 DEG C；1H NMR(500MHz,CDCl3)δ1.03(m,2H),1.17(m,2H),1.19(s,3H),
1.29(s,3H),1.38(s,9H),1.70(s,3H),1.77(s,3H),1.81(s,3H),1.83(m,1H),1.90(m,1H),
1.93 (s, 3H), 2.37 (s, 3H), 2.38-2.43 (m, 2H), 2.59 (m, 1H), 2.63 (s, br, 1H), 3.84 (d, J=
7.0Hz, 1H), 3.90 (s, 3H), 4.22 (m, 2H), 4.38 (d, J=8.5Hz, 1H), 4.76 (m, 1H), 4.80 (m, 1H),
5.00 (d, J=8.0,1H), 5.35 (m, 1H), 5.69 (d, J=7.0Hz, 1H), 6.21 (t, J=8.0Hz, 1H), 6.33 (s,
1H), 7.18 (dd, J=8.0,2.0Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.67 (s, 1H), 7.73 (d, J=7.5Hz,
1H)；13C NMR(125MHz,CDCl3)δ9.24,9.49,9.53,13.06,15.02,18.56,21.98,22.44,23.74,
26.72,28.23,35.56,35.58,43.21,45.63,51.52,55.34,58.58,72.24,72.40,73.71,
75.14,75.47,76.47,79.14,80.05,81.12,84.44,114.61,120.16,120.64,122.56,129.67,
130.49,132.90,137.93,142.70,155.42,159.65,166.83,170.05,173.18,175.18,203.96.
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The preparation of embodiment 2, JY-02
1) preparation of compound 11
The preparation method of compound 11 is identical with shown in step 1) in specific embodiment 1, referring to step in embodiment 1
1) reaction.
2) preparation of the fluoro- 7- deoxidation -10- propiono baccatin III of 6-
It is basic shown in step 2) in the preparation method and specific embodiment 1 of the fluoro- 7- deoxidation -10- propiono baccatin III of 6-
It is identical, in addition to b step difference, remaining step referring to step 2) in embodiment 1 reaction.
B.10- the preparation of propiono -7- triethyl group silicon substrate baccatin III
It is molten that compound 12 (658mg, 1.0mmol) and cerous chloride (4.9mg, 0.02mmol) are dissolved in 10mL tetrahydrofuran
In liquid, propionic andydride (1.92mL, 20.0mmol) is added dropwise into reaction solution at room temperature, TLC monitoring reaction carries out, to the end of reacting
Afterwards, 20mL water is added into reaction solution, is repeatedly extracted with ethyl acetate, organic phase is merged, after saturated common salt water washing,
Anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
3) preparation of JY-02
Process in JY-02 step 3) and 3 in specific embodiment 1) reaction process is identical, referring in specific embodiment 1
Step 3).Final products purity reaches 95% or more.
M.p.=168-169 DEG C；1H NMR(500MHz,CDCl3) δ 1.16 (s, 3H), 1.22 (t, J=7.5Hz, 3H),
1.26(s,3H),1.35(s,9H),1.68(s,3H),1.74(s,3H),1.77(s,3H),1.88(m,1H),1.90(s,3H),
2.34-2.41 (m, 2H), 2.36 (s, 3H), 2.46-2.60 (m, 4H), 3.49 (s, br, 1H), 3.83 (d, J=7.0Hz, 1H),
3.88 (s, 3H), 4.20 (m, 2H), 4.35 (d, J=8.5Hz, 1H), 4.44 (m, 1H), 4.74 (m, 1H), 4.78 (m, 1H),
4.98 (d, J=8.5Hz, 1H), 5.33 (m, 1H), 5.67 (d, J=7.0Hz, 1H), 6.18 (t, J=9.0Hz, 1H), 6.32
(s, 1H), 7.15 (dd, J=8.0,2.0Hz, 1H), 7.38 (t, J=8.0HZ, 1H), 7.65 (s, 1H), 7.71 (d, J=
7.5Hz,1H)；13C NMR(125MHz,CDCl3)δ9.06,9.56,14.97,18.55,21.88,22.43,25.73,26.64,
27.60,28.22,29.72,35.54,43.20,45.66,51.53,55.38,58.56,72.19,72.38,73.71,
73.13,75.46,76.47,79.08,79.99,81.12,84.45,114.62,120.14,120.64,122.55,129.67,
130.45,132.93,137.90,142.50,155.44,159.63,166.81,170.09,173.19,174.67,203.86.
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The preparation of embodiment 3, JY-03
1) preparation of compound 11
The preparation method of compound 11 is identical with shown in step 1) in specific embodiment 1, referring to step in embodiment 1
1) reaction.
2) preparation of the fluoro- 7- deoxidation -10- methoxycarbonyl base baccatin III of 6-
In the preparation method and specific embodiment 1 of the fluoro- 7- deoxidation -10- methoxycarbonyl base baccatin III of 6- shown in step 2)
It is essentially identical, in addition to b step difference, remaining step referring to step 2) in embodiment 1 reaction.
B.10- the preparation of methoxycarbonyl base -7- triethyl group silicon substrate baccatin III
Compound 12 (658mg, 1.0mmol) is dissolved in 10mL tetrahydrofuran solution, at 0 DEG C, is dripped into reaction solution
Add the LHMDS (1.5mL, 1.5mmol) of 1M that methoxycarbonyl chlorine (1.5mmol) is added dropwise into reaction solution after reaction 0.5 hour,
TLC monitoring reaction merges organic to after reaction, 20mL water be added into reaction solution, is repeatedly extracted with ethyl acetate
Phase, after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
3) preparation of JY-03
Process in JY-03 step 3) and 3 in specific embodiment 1) reaction process is identical, referring in specific embodiment 1
Step 3).Final products purity reaches 95% or more.
M.p.=165-167 DEG C；1H NMR(500MHz,CDCl3)δ0.82–0.98(m,2H),1.14(s,3H),1.23
(t, J=7.8Hz, 3H), 1.25 (s, 3H), 1.34 (s, 9H), 1.65 (s, 1H), 1.67 (s, 3H), 1.73 (s, 1H), 1.75
(s,3H),1.76(s,3H),1.87(m,1H),1.89(s,3H),2.36(s,3H),2.40(m,1H),2.42(s,3H),
2.48-2.62 (m, 4H), 3.38 (d, J=6.9Hz, 1H), 3.81 (d, J=7.2Hz, 1H), 4.13-4.22 (m, 2H), 4.31
(d, J=7.8Hz, 1H), 4.42 (m, 1H), 4.73-4.80 (m, 2H), 4.97 (d, J=9.6Hz, 1H), 5.33 (d, J=
8.1Hz, 1H), 5.65 (d, J=6.6Hz, 1H), 6.16 (t, J=8.7Hz), 6.31 (s, 1H), 7.30-7.42 (m, 2H),
7.90 (d, J=7.5Hz, 1H), 7.93 (s, 1H)；13C NMR(125MHz,CDCl3)δ9.06,9.56,14.99,18.59,
21.38,21.88,22.38,25.74,26.64,27.60,28.23,35.58,43.20,45.68,51.57,58.57,
72.25,72.45,73.75,74.92,75.47,76.49,79.16,79.97,91.10,84.43,120.65,127.32,
128.54,129.12,130.83,132.93,134.48,137.89,138.36,142.51,153.43,167.08,170.04,
173.17,174.68,203.86.
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The preparation of embodiment 4, JY-04
1) preparation of compound 11
The preparation method of compound 11 is identical with shown in step 1) in specific embodiment 1, referring to step in embodiment 1
1) reaction.
2) preparation of fluoro- 7- deoxidation -10-N, N- the dimethyl carbamoyl baccatin III of 6-
It is walked in the preparation method and specific embodiment 1 of fluoro- 7- deoxidation -10-N, N- the dimethyl carbamoyl baccatin III of 6-
It is rapid 2) shown in it is essentially identical, in addition to b step difference, remaining step referring to step 2) in embodiment 1 reaction.
B.10-N, the preparation of N- formyl-dimethylamino -7- triethyl group silicon substrate baccatin III
Compound 12 (658mg, 1.0mmol) is dissolved in 10mL tetrahydrofuran solution, at 0 DEG C, is dripped into reaction solution
Add the LHMDS (1.5mL, 1.5mmol) of 1M that N, N- dimethylcarbamyl chloride are added dropwise into reaction solution after reaction 0.5 hour
(1.5mmol), TLC monitoring reaction, to after reaction, 20mL water be added into reaction solution, is repeatedly extracted with ethyl acetate
It takes, merges organic phase, after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
3) preparation of JY-04
Process in JY-04 step 3) and 3 in specific embodiment 1) reaction process is identical, referring in specific embodiment 1
Step 3).Final products purity reaches 95% or more.
M.p.=161-162 DEG C；1H NMR(400MHz,CDCl3)δ1.23(s,3H),1.30(s,3H),1.36(m,1H),
1.42(s,9H),1.74(s,3H),1.79(m,1H),1.81(s,6H),1.96(m,1H),2.11(s,3H),2.43(s,3H),
2.46 (m, 1H), 2.60 (m, 1H), 3.03 (s, 3H), 3.11 (s, 3H), 3.28 (d, J=3.6Hz, 1H), 3.43 (m, 1H),
2.88 (d, J=6.9Hz, 1H), 4.20 (m, 2H), 4.27 (d, J=8.4Hz, 1H), 4.38 (d, J=8.4Hz, 1H), 4.53
(m, 1H), 4.81 (m, 1H), 5.05 (d, J=7.8Hz, 1H), 5.73 (d, J=6.9Hz, 1H), 5.25 (t, 1H), 6.33 (s,
1H), 7.54 (t, J=7.2Hz, 2H), 7.68 (t, J=7.2,1H), 8.18 (d, J=7.2Hz, 2H)13C NMR(125MHz,
CDCl3)δ9.33,10.14,14.28,18.64,21.31,22.40,25.78,26.92,28.30,35.46,35.75,
36.01,36.68,43.27,45.68,58.50,59.31,72.46,72.52,73.85,75.28,76.51,79.34,
80.02,81.21,84.73,120.76,128.59,129.36,130.22,133.70,133.59,156.21,166.93,
130.02,205.76.
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The preparation of embodiment 5, JY-05
1) preparation of compound 11
The preparation method of compound 11 is identical with shown in step 1) in specific embodiment 1, referring to step in embodiment 1
1) reaction.
2) preparation of the fluoro- 7- deoxidation -10- cyclopropyl formyl baccatin III of 6-
In the preparation method and specific embodiment 1 of the fluoro- 7- deoxidation -10- cyclopropyl formyl baccatin III of 6- shown in step 2)
It is essentially identical, in addition to b step difference, remaining step referring to step 2) in embodiment 1 reaction.
B.10- the preparation of cyclopropyl formyl -7- triethyl group silicon substrate baccatin III
Compound 12 (658mg, 1.0mmol) is dissolved in 10mL tetrahydrofuran solution, at 0 DEG C, is dripped into reaction solution
Add the LHMDS (1.5mL, 1.5mmol) of 1M that Cyclopropyl carbonyl chloride (1.5mmol) is added dropwise into reaction solution after reaction 0.5 hour,
TLC monitoring reaction merges organic to after reaction, 20mL water be added into reaction solution, is repeatedly extracted with ethyl acetate
Phase, after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
3) preparation of JY-05
Process in JY-05 step 3) and 3 in specific embodiment 1) reaction process is identical, referring in specific embodiment 1
Step 3).Final products purity reaches 95% or more.
mp 155-156℃；1H NMR(300MHz,CDCl3)δ1.08(m,2H),1.20(m,1H),1.23(s,3H),
1.33(s,3H),1.42(s,9H),1.74(s,3H),1.79(s,1H),1.83(s,6H),1.90(m,1H),1.97(s,3H),
2.11 (s, 1H), 2.42 (s, 3H), 2.45 (m, 1H), 2.60 (m, 1H), 2.65 (m, 1H), 3.45 (d, J=6.6Hz, 1H),
3.88 (d, J=6.9Hz, 1H), 4.24 (m, 2H), 4.38 (d, 8.4Hz, 1H) 4.48 (m, 1H), 4.83 (m, 2H), 5.03 (d,
7.8H),5.38(m,1H),5.74(d,7.2Hz,1H),6.24(t,1H),6.37(s,1H),7.54(t,7.2,2H),7.68
(t,7.5Hz,1H),8.17(d,7.2Hz,2H).13C NMR(125MHz,CDCl3)δ9.19,9.43,9.51,13.04,
14.98,18.56,21.35,21.45,22.35,25.71,26.69,28.2 2,35.54,43.19,45.66,51.56,
58.56,72.24,72.41,73.73,74.95,75.44,79.17,79.95,81.11,84.44,120.67,127.31,
128.57,129.14,139.81,132.94,134.45,137.56,138.34,142.64,155.41,167.07,170.01,
173.14,175.14,203.56.。
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The preparation of embodiment 6, JY-06
1) preparation of compound 11
The preparation method of compound 11 is identical with shown in step 1) in specific embodiment 1, referring to step in embodiment 1
1) reaction.
2) preparation of the fluoro- 7- deoxidation -10- methyl baccatin III of 6-
The preparation method and basic phase shown in step 2) in specific embodiment 1 of the fluoro- 7- deoxidation -10- methyl baccatin III of 6-
Together, in addition to b step difference, remaining step referring to step 2) in embodiment 1 reaction.
B.10- the preparation of methyl -7- triethyl group silicon substrate baccatin III
Compound 12 (658mg, 1.0mmol) is dissolved in 10mL tetrahydrofuran solution, at -40 DEG C, into reaction solution
The LHMDS (1.5mL, 1.5mmol) of 1M is added dropwise, Methyl triflate is added dropwise into reaction solution after reaction 0.5 hour
(2mmol), TLC monitoring reaction, to after reaction, 20mL water be added into reaction solution, is repeatedly extracted with ethyl acetate,
Merge organic phase, after saturated common salt water washing, anhydrous magnesium sulfate dries, filters concentration, and column separation purifies to obtain product.
3) preparation of JY-06
Process in JY-06 step 3) and 3 in specific embodiment 1) reaction process is identical, referring in specific embodiment 1
Step 3).Final products purity reaches 95% or more.
M.p.=172-174 DEG C；1H NMR(400MHz,CDCl3)δ1.02(m,2H),1.61(m,2H),1.18(s,3H),
1.28(s,3H),1.38s,9H),1.67(s,3H),1.77(s,3H),1.81(s,3H),1.85(m,1H),1.89(m,1H),
1.92 (s, 3H), 2.37 (s, 3H), 2.42 (m, 1H), 2.45 (s, 3H), 2.52-2.61 (m, 2H), 3.82 (d, J=6.8Hz,
1H), 3.90 (s, br, 1H), 4.22 (d, J=8.4Hz, 1H), 4.24 (m, 1H), 4.33 (d, J=8.4Hz, 1H), 4.75-
4.83 (m, 2H), 4.78 (m, 1H), 4.99 (d, J=8.0Hz, 1H), 5.34 (d, J=8.0Hz, 1H), 5.66 (d, J=
6.8Hz, 1H), 6.19 (t, J=8.4Hz, 1H), 6.32 (s, 1H), 7.37 (t, J=7.6Hz, 1H), 7.43 (d, J=7.6Hz,
1H), 7.92 (d, J=7.6Hz, 1H), 7.95 (s, 1H)；13C NMR(125MHz,CDCl3)δ9.19,9.43,9.51,13.04,
14.98,18.56,21.35,21.45,22.35,25.71,26.69,28.2 2,35.54,43.19,45.66,51.56,
58.56,72.24,72.41,73.73,74.95,75.44,79.17,79.95,81.11,84.44,120.67,127.31,
128.57,129.14,139.81,132.94,134.45,137.56,138.34,142.64,155.41,167.07,170.01,
173.14,175.14,203.93.
From the foregoing, it will be observed that the product structure is correct, it is target compound.
The application of embodiment 7, fluorine-containing bearing taxanes in terms of anti-multidrug resistance
The pharmacological evaluation of the fluorine-containing bearing taxanes of the present invention
1) cell toxicity test is carried out to human tumor cell line
Using taxol as positive control drug, fluorine-containing taxane compounds are investigated to 3 tumor cell lines (packet using mtt assay
Include responsive type MCF-7 cell strainHJ2mm, multidrug resistance type MCF-7 cell strainHJ2mm/Adr, multidrug resistance type people's ovum
Nest cancer cell line NCI/Adr) cytotoxicity, experimental result is shown in Table 1.
Table 1, fluorine-containing taxane compounds vitro cytotoxicity test (IC50nM)
aResistance factor=(IC50for drug resistant cell line,R)/(IC50for drug-
sensitive cell line,S).
Preliminary activation evaluation show this kind of fluorine-containing Taxane derivative be not only directed to responsive type tumor cell line activity it is excellent
In taxol, the activity better than positive control Taxol, resistance factor are also shown for the tumor cell line of multidrug resistance type
(R/S value) shows 4.5-45 times and is better than taxol.The experimental results showed that this kind of fluorine-containing Taxane derivative of the present invention
With the good activity for inhibiting responsive type and multidrug resistance type tumor cell line.
2) cytotoxicity test for the tumor cell line that tumor stem cell is overexpressed
Using taxol as positive control drug, fluorine-containing taxane compounds are investigated to tumor stem cell (cancer using mtt assay
Stem cells, CSCs) be overexpressed people's rectum cancer cell strain HCT-116++Cytotoxicity, experimental result is shown in Table 2.
Table 2, fluorine-containing taxane compounds are directed to people's rectum cancer cell strain HCT-116 that CSC is overexpressed++Proliferation inhibition rate
(IC50nM)
The experimental results showed that this kind of fluorine-containing taxane compounds are directed to people's rectum cancer cell strain that tumor stem cell is overexpressed
HCT-116++Cytotoxicity be better than 40-120 times of positive control drug taxol, have good inhibition tumor stem cell overexpression
The active function of cell strain.
Claims (10)
1. compound shown in Formulas I or its pharmaceutically acceptable salt,
In the Formulas I, R is the alkyl for being 1-6 containing the carboxyl groups or carbon atom number for being no more than six atoms.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: the R be acetyl group,
Propiono, methoxycarbonyl base, N, N- dimethylcarbamoyl, cyclopropyl formoxyl or methyl；
Compound shown in the Formulas I is any one in compound shown in following JY-01 to JY-06:
3. a kind of method for preparing compound shown in any Formulas I of claims 1 or 2, includes the following steps:
The silicon-based protecting group that compound shown in formula 002 is sloughed to C2' obtains compound shown in the Formulas I；
4. according to the method described in claim 3, it is characterized by: being reacted in the silicon-based protecting group step for sloughing C2'
Condition is acid condition；
The pH value of the acid condition is 1-3；
The acid condition is specially to carry out in HF/Py solution；The volume ratio of the HF/Py is 3-4:1.
5. the method according to claim 3 or 4, it is characterised in that: in the silicon-based protecting group step for sloughing C2',
Reaction dissolvent is at least one of mixed liquor, tetrahydrofuran, methylene chloride, methanol and the ethyl alcohol being made of acetonitrile and pyridine；Institute
It states in the mixed liquor being made of acetonitrile and pyridine, the volume ratio of acetonitrile and pyridine is specially 1:1-2；
Reaction temperature is room temperature to 0 DEG C；
Reaction time is 12-24h.
6. compound shown in any Formulas I of claims 1 or 2 or its pharmaceutically acceptable salt are preparing anti-multidrug resistance
Product and/or the application in the active product that preparation inhibits the strain of tumor stem cell overexpressing cell.
7. application according to claim 6, it is characterised in that: the anti-multidrug resistance and inhibition tumor stem cell cross table
Up in cell strain, for tumour be at least one of breast cancer, oophoroma, the carcinoma of the rectum, non-small cell lung cancer and melanoma.
8. compound shown in formula 002,
9. a kind of method of compound shown in preparation formula 002, comprising:
Compound shown in formula 001 is reacted with the generation Hilton docking of compound shown in formula 11 and is obtained；
10. according to the method described in claim 9, it is characterized by: the Hilton is docked in reaction step, shown in formula 001
The equivalent proportion of compound shown in compound and formula 11 is 1:1~1:4；Specially 1:2；
The Hilton docking reaction carries out under alkaline condition；
The pH value of the alkaline condition is 7.5-9；
The alkaline condition is specially condition existing for lithium hexamethyldisilazide；
The Hilton docking reaction carries out in a solvent；The solvent is chosen in particular from tetrahydrofuran, methylene chloride and dioxy six
At least one of ring；
The reaction temperature of the Hilton docking reaction is 0 DEG C to -40 DEG C；
Reaction time is 2-12h.
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