CN105503947B - A kind of preparation method and antitumor application thereof of the phosphate derivatives containing amino acid fragment - Google Patents
A kind of preparation method and antitumor application thereof of the phosphate derivatives containing amino acid fragment Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 title claims abstract description 13
- 125000003275 alpha amino acid group Chemical group 0.000 title claims 2
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 20
- 150000001413 amino acids Chemical group 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- -1 phosphonate compound Chemical class 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 238000004440 column chromatography Methods 0.000 claims description 16
- 239000005457 ice water Substances 0.000 claims description 16
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002475 indoles Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229960003742 phenol Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 claims description 2
- 108090000958 Thiopurine S-methyltransferases Proteins 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims description 2
- 150000008301 phosphite esters Chemical class 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 1
- 239000012346 acetyl chloride Substances 0.000 claims 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 238000007876 drug discovery Methods 0.000 abstract description 4
- 150000002611 lead compounds Chemical class 0.000 abstract description 4
- 229910052697 platinum Inorganic materials 0.000 abstract description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 4
- 230000004224 protection Effects 0.000 abstract description 3
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 2
- 239000012634 fragment Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- PEHQDSOLLVMPLB-UHFFFAOYSA-N OOP(O)=O Chemical compound OOP(O)=O PEHQDSOLLVMPLB-UHFFFAOYSA-N 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 10
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- SULWMEGSVQCTSK-UHFFFAOYSA-N diethyl hydrogen phosphite Chemical class CCOP(O)OCC SULWMEGSVQCTSK-UHFFFAOYSA-N 0.000 description 4
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical class FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- 150000008566 D-phenylalanines Chemical class 0.000 description 2
- 150000008547 L-phenylalanines Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 0 *C(C(OC(C(C(C1O*)O)C1=O)c1ccccc1)=O)N Chemical compound *C(C(OC(C(C(C1O*)O)C1=O)c1ccccc1)=O)N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of phosphate derivatives containing amino acid fragment（I）Preparation method and its antitumor application thereof, belong to antitumor drug research field.Using the drug discovery method based on segment, the phosphonate compound of early-stage study is optimized, finds antitumor lead compound.The present invention devises the phosphate derivatives of serial brand new, preparation method：It using amino acid as raw material, is protected by Boc, obtains intermediate, then occur to react at ester with hydroxy phosphonate intermediate, finally take off Boc protections, be made（I）Shown phosphate derivatives.The analog derivative has different inhibited proliferations to tumour cell.Which part compound on tumor cell A 549, SGC 7901 and EC 109 have notable antiproliferative effect, close with comparison medicine cis-platinum, can be used as antitumor lead compound application.
Description
Technical field
The present invention relates to a kind of antitumor drug, the preparation side of specially a kind of phosphate derivatives containing amino acid fragment
Method and antitumor application thereof.
Background technology
Tumour is to endanger one of the disease of human health and life most serious now, therefore find structure novel, new role
Mechanism antitumor drug is of great importance.For phosphonate ester compound as derivative of organic phosphorus, Recent study is extremely wide,
Key player is play in drug design synthesis, research shows that the analog derivative has antitumor, antibacterial, antiviral etc. a variety of heavy
The physiological activity wanted is widely used in medicine and pesticide field.
We designed and synthesized different series phosphate derivatives early period, and biological activity test finds that inhomogeneity compound has
Potential antitumor activity.The structure-activity relationship for analyzing a few class compounds is found：Shared phosphonic acids ester structure may be that its is antitumor
Pharmacophore.Therefore, using phosphonate ester as the structural modification of skeleton, optimization and its antitumor action further investigate very it is necessary to.
It is well known that amino acid is important physiological activator, be biological internal synthetic peptide, protein, hormone, enzyme and
The raw material of antibody participates in a variety of Biochemical processes activities.Wherein class peptides amino acid derivativges because molecular weight it is small, exist interior more
Property target spot in source has good compatibility with cell and nucleic acid, easily penetrates tumour cell, improve immune response, inhibits tumour
The features such as vascularization, growth and metastasis of tumours, has become the new hot spot of antitumor drug research.Amino acid fragment is introduced
It into drug molecule, is more advantageous to drug molecule and is combined with tumor cell tissue, and play antitumor action.Expert it is thought that
One developing direction got a good chance of of antitumor drug.
Therefore, phosphonate ester active fragment is combined with amino acid fragment, using the drug discovery method based on segment, design
The phosphate derivatives containing amino acid fragment of a kind of brand new carry out antitumor activity, and acquisition has antitumor guideization
Object is closed, there is good foreground.
Invention content
The present invention is on the basis of previous research work, using the drug discovery method based on segment, by phosphonate ester activity
Segment is combined with amino acid fragment, is prepared a kind of phosphate derivatives containing amino acid fragment, is obtained promising antitumor
Primer.
In order to achieve the above objectives, the technical solution used for：The structure of object phosphate derivatives containing amino acid fragment
General formula isR is the alkyl of 1-5 carbon；R1For H or the alkyl of halogen or nitro or 1-3 carbon；R2For H
Or the alkyl or benzyl or indoles -2- methyl or methylol or thiopurine methyltransferase or para hydroxybenzene methyl or carbamyl first of 1-5 carbon
Base or carbamoylethyl or CH2CH2CH2Or HOCH (CH3)；Configuration：With R2The carbon atom being connected directly is R or S configurations.It is closed
It is at reaction equation：
Its prepare the specific steps are：
1) intermediate 1 is prepared：Amino acid is dissolved in tetrahydrofuran, ice-water bath, the bicarbonate of 1-3 times of amount of amino acid is added
Then 1-2 times of (Boc) measured is added in sodium or triethylamine2O, ice-water bath reacts 30-60min, then reacts at room temperature 15-20h, reacts
Liquid is extracted with ethyl acetate, and discards upper layer, is adjusted with acid pH, then extracted with dichloromethane, merges lower layer's organic phase, with anhydrous sulphur
The drying of sour sodium, concentrated solvent to get；
2) intermediate 2 is prepared：By phosphite ester and aromatic aldehyde (1:1.5 molar ratios feed intake) it is added in three-necked bottle, then add
Enter the 1-2 times of triethylamine measured, 40-80 DEG C of reaction 1.5h, then room temperature reaction for 24 hours, remove triethylamine, recrystallization to get；
3) intermediate 3 is prepared：Take intermediate 1 and intermediate 2 (1:1 molar ratio feeds intake), it is added in reaction bulb, ice salt bath adds
Enter 1 times of condensing agent (DCC/DMAP or EDCI/DMAP or HBTU/DIPEA, preferred EDCI/DMAP) measured, is with dichloromethane
Solvent, dissolve condensing agent, react at room temperature 10-12h, remove insoluble matter, concentrated solvent, column chromatography isolate and purify to get；
4) prepare compound (I)：Reaction bulb is taken, ethyl acetate is added as solvent, sequentially adds the methanol and 1 of 1 times of amount
The chloroacetic chloride of amount again reacts 3-5h, then the intermediate 3 that 0.5-1 times is measured is dissolved in ethyl acetate, and reaction bulb, ice water is added
Bath is lower to react 8-10h, is concentrated under reduced pressure, obtains thick liquid, column chromatography isolates and purifies, and is dried in vacuo to get object (I).
This kind of phosphate derivatives containing amino acid fragment are designed using the drug discovery method based on segment, are
The phosphonate compound of early-stage study is optimized.The analog derivative has different inhibited proliferations to tumour cell.Having
Have in the object (I) of same amino acid structure, L-configuration has apparent antitumor activity compared with D amino acids compounds.Part
Compound on tumor cell A-549, SGC-7901 and EC-109 have notable antiproliferative effect, close with comparison medicine cis-platinum, can make
It is studied for antitumor lead compound.
Specific implementation mode
It is further described the present invention with reference to embodiment, but the present invention is not limited only to following embodiments, it is anticipated that this
For field technology personnel in the case where combining the prior art, there may be many variations for performance.
The general structure of object phosphate derivatives isR is the alkyl of 1-5 carbon；R1For H or
The alkyl of halogen or nitro or 1-3 carbon；R2For the alkyl or benzyl or indoles -2- methyl or methylol or mercapto of H or 1-5 carbon
Methyl or para hydroxybenzene methyl or carbamoyl methyl or carbamoylethyl or CH2CH2CH2Or HOCH (CH3)；Configuration：With R2
The carbon atom being connected directly is R or S configurations.Its synthetic reaction formula is：
Specific implementation mode
Embodiment 1：O, O'- diethyl-α-(2- fluorophenyls)-α-(L-2- aminobenzenes propionyloxy) methyl phosphonate (I
A) preparation.
10m mol L-phenylalanines are dissolved in 50mL tetrahydrofurans, sodium bicarbonate 20m is added to 0 DEG C or so in ice-water bath
mol.Then by 12m mol (Boc)2O is slowly dropped into above-mentioned solution.0 DEG C or so, 40min is reacted, then react at room temperature 15-
20h, reaction finish.Reaction solution is extracted with ethyl acetate 2-3 times, discards upper layer, is adjusted with acid pH, then extract 2- with dichloromethane
3 times.Merge lower layer's organic phase, is dried with anhydrous sodium sulfate, concentrated solvent, obtain intermediate 1；
2mmol diethyl phosphites and 3mmol o fluorobenzaldehydes are added in 50ml three-necked bottles, are sufficiently mixed, then will
1.1mmol triethylamines are added dropwise in mixed liquor.After 10min, temperature is increased, 3h is stirred to react at 60 DEG C.It is stirred at room temperature again
Reaction is for 24 hours.Reaction finishes, and triethylamine is removed under reduced pressure, and uses ether：Petroleum ether=1：1 recrystallization, obtains intermediate 2.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds DMAP
(4.1mmol), with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
EDCI (4.1mmol, anhydrous methylene chloride 15mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 10h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:1) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (0.8mmoL) and chloroacetic chloride (0.8mmoL) maintain the temperature, react about 3h.Then by intermediate 3, (0.5mmoL uses 5mL
Anhydrous ethyl acetate dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 8h under ice-water bath, is concentrated under reduced pressure, obtains viscous
Thick liquid, column chromatography (chloroform：Methanol=8：1) it isolates and purifies, is dried in vacuo, obtains compound (Ia), yield 50.5%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.05~1.14 (m,
6H,CH3),1.84(s,2H,NH2), 2.80~2.94 (m, 2H, CH2), Ar 3.84~4.01 (m, 4H, OCH2),4.58(s,1H,
), NCH 6.34 (dd, 1H, J=24Hz PCH), 6.86~7.42 (m, 9H, Ar-H)；13C NMR(100MHz,CDCl3),δ:
16.1,16.2,37.6,54.3,63.2,63.3,65.0,115.1,120.6,124.3,128.3,129.0,135.5,135.8,
158.6,170.1.IR(KBr)v:3303,2915,2854,1669,1465,1201,1030cm- 1。
Embodiment 2：O, O'- diethyl-α-(2- fluorophenyls)-α-(D-2- aminobenzenes propionyloxy) methyl phosphonate (I
B) preparation.
10m mol D-phenylalanines are dissolved in 50mL tetrahydrofurans, triethylamine 20m is added to 0 DEG C or so in ice-water bath
mol.Then by 15m mol (Boc)2O is slowly dropped into above-mentioned solution.0 DEG C or so, 60min is reacted, then react at room temperature 15h, instead
It should finish.Reaction solution is extracted with ethyl acetate 2-3 times, discards upper layer, is adjusted with acid pH, then extracted 2-3 times with dichloromethane.It closes
And lower layer's organic phase, it is dried with anhydrous sodium sulfate, concentrated solvent, obtains intermediate 1；
2mmol diethyl phosphites and 2mmol o fluorobenzaldehydes are added in 50ml three-necked bottles, are sufficiently mixed, then will
1.5mmol triethylamines are added dropwise in mixed liquor.After 10min, temperature is increased, 1.5h is stirred to react at 80 DEG C.It is stirred again in room temperature
Mix reaction for 24 hours.Reaction finishes, and triethylamine is removed under reduced pressure, and uses ether：Petroleum ether=1：1 recrystallization, obtains intermediate 2.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds DCC
(4.1mmol), with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
DMAP (4.1mmol, anhydrous methylene chloride 15mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 12h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:1) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (1mmoL) and chloroacetic chloride (1mmoL) maintain the temperature, react about 3h.Then by intermediate 3 (0.5mmoL, it is anhydrous with 5mL
Ethyl acetate dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 10h under ice-water bath, is concentrated under reduced pressure, obtains sticky
Liquid, column chromatography (chloroform：Methanol=8：1) it isolates and purifies, is dried in vacuo, obtains compound (Ib), yield 48.0%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.06~1.15 (m,
6H,CH3),1.82(s,2H,NH2), 2.85~2.98 (m, 2H, CH2), Ar 3.86~4.03 (m, 4H, OCH2),4.59(s,1H,
), NCH 6.02 (dd, 1H, J=20Hz PCH), 6.86~7.38 (m, 9H, Ar-H)；13C NMR(100MHz,CDCl3),δ:
16.0,16.1,37.7,54.4,63.3,63.4,69.4,115.2,126.5,128.1,129.0,129.6,135.5,135.8,
154.9,155.1,170.4.IR(KBr)v:3302,2981,2855,1671,1538,1207,1033cm- 1。
Embodiment 3：O, O'- diethyl-α-(4- fluorophenyls)-α-(L-2- aminobenzenes propionyloxy) methyl phosphonate (I
C) preparation.
10m mol L-phenylalanines are dissolved in 50mL tetrahydrofurans, triethylamine 20m is added to 0 DEG C or so in ice-water bath
mol.Then by 12mmol (Boc)2O is slowly dropped into above-mentioned solution.0 DEG C or so, 40min is reacted, then react at room temperature 15h, instead
It should finish.Reaction solution is extracted with ethyl acetate 2-3 times, discards upper layer, is adjusted with acid pH, then extracted 2-3 times with dichloromethane.It closes
And lower layer's organic phase, it is dried with anhydrous sodium sulfate, concentrated solvent, obtains intermediate 1；
2mmol diethyl phosphites and 2mmol 4-Fluorobenzaldehydes are added in 50ml three-necked bottles, are sufficiently mixed, then will
1.5mmol triethylamines are added dropwise in mixed liquor.After 10min, temperature is increased, 1.5h is stirred to react at 80 DEG C.It is stirred again in room temperature
Mix reaction for 24 hours.Reaction finishes, and triethylamine is removed under reduced pressure, and uses ether：Petroleum ether=1：1 recrystallization, obtains intermediate 2.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds HBTU
(4.1mmol), with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
DIPEA (4.1mmol, anhydrous methylene chloride 15mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 12h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:1) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (1mmoL) and chloroacetic chloride (1mmoL) maintain the temperature, react about 3h.Then by intermediate 3 (0.5mmoL, it is anhydrous with 5mL
Ethyl acetate dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 10h under ice-water bath, is concentrated under reduced pressure, obtains sticky
Liquid, column chromatography (chloroform：Methanol=7：1) it isolates and purifies, is dried in vacuo, obtains compound (Ic), yield 52.3%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.08~1.12 (m,
6H,CH3),1.87(s,2H,NH2), 2.88~3.11 (m, 2H, CH2), Ar 3.84~3.95 (m, 4H, OCH2),4.60(s,1H,
), NCH 6.01 (dd, 1H, J=8Hz PCH), 6.90~7.33 (m, 9H, Ar-H)；13C NMR(100MHz,CDCl3),δ:
16.2,16.3,37.7,54.4,63.3,63.4,71.4,115.5,126.8,128.1,128.8,129.3,129.6,135.6,
135.9,155.0,161.5,170.7.IR(KBr)v:3301,2958,2855,1672,1539,1208,1031cm- 1。
Embodiment 4：O, O'- diethyl-α-(4- fluorophenyls)-α-(D-2- aminobenzenes propionyloxy) methyl phosphonate (I
D) preparation.
10m mol D-phenylalanines are dissolved in 50mL tetrahydrofurans, triethylamine 20m is added to 0 DEG C or so in ice-water bath
mol.Then by 12m mol (Boc)2O is slowly dropped into above-mentioned solution.0 DEG C or so, 40min is reacted, then react at room temperature 15h, instead
It should finish.Reaction solution is extracted with ethyl acetate 2-3 times, discards upper layer, is adjusted with acid pH, then extracted 2-3 times with dichloromethane.It closes
And lower layer's organic phase, it is dried with anhydrous sodium sulfate, concentrated solvent, obtains intermediate 1；
2mmol diethyl phosphites and 2mmol 4-Fluorobenzaldehydes are added in 50ml three-necked bottles, are sufficiently mixed, then will
1.5mmol triethylamines are added dropwise in mixed liquor.After 10min, temperature is increased, 1.5h is stirred to react at 80 DEG C.It is stirred again in room temperature
Mix reaction for 24 hours.Reaction finishes, and triethylamine is removed under reduced pressure, and uses ether：Petroleum ether=1：1 recrystallization, obtains intermediate 2.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds EDCI
(4.1mmol), with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
DMAP (4.1mmol, anhydrous methylene chloride 15mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 12h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:1) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (1mmoL) and chloroacetic chloride (1mmoL) maintain the temperature, react about 3h.Then by intermediate 3 (0.5mmoL, it is anhydrous with 5mL
Ethyl acetate dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 10h under ice-water bath, is concentrated under reduced pressure, obtains sticky
Liquid, column chromatography (chloroform：Methanol=9：1) it isolates and purifies, is dried in vacuo, obtains compound (Id), yield 49.7%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.08~1.10 (m,
6H,CH3),1.87(s,2H,NH2), 288~3.12 (m, 2H, CH2), Ar 3.86~4.03 (m, 4H, OCH2),4.61(s,1H,
), NCH 6.03 (dd, 1H, J=12Hz PCH), 6.92~7.36 (m, 9H, Ar-H)；13C NMR(100MHz,CDCl3),δ:
16.1,16.3,37.8,54.4,63.2,63.5,65.2,115.2,115.3,124.4,126.8,128.3,128.4,129.0,
129.2,129.5,130.6,135.8,135.9,158.5,161.0,170.3.IR(KBr)v:3300,2915,2854,1690,
1461,1201,1028cm- 1。
Embodiment 5：O, O'- diethyl-α-(4- fluorophenyls)-α-(L-2- nafoxidines formyloxy) methyl phosphonate (I
E) preparation.
The preparation of intermediate 1 and intermediate 2 is the same as 4 method of embodiment.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds EDCI
(4.5mmol), with anhydrous methylene chloride (20mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
DMAP (4.5mmol, anhydrous methylene chloride 20mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 12h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:2) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (1mmoL) and chloroacetic chloride (1mmoL) maintain the temperature, react 2h.Then by the (0.8mmoL, with the anhydrous second of 5mL of intermediate 3
Acetoacetic ester dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 10h under ice-water bath, is concentrated under reduced pressure, obtains viscous fluid
Body, column chromatography (chloroform：Methanol=8：1) it isolates and purifies, is dried in vacuo, obtains compound (Ie), m.p.85-87 DEG C, yield
44.1%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.06~1.13 (m,
6H,CH3), 1.79~1.81 (m, 2H, CH2),1.96(s,1H,NH),2.14(s,1H,CCH2),2.43(s,1H,CCH2),
3.27~3.43 (m, 2H, NCH2), 3.88~4.03 (m, 2H, NCH2), 4.23~4.36 (m, H, CH2CO),6.35(dd,1H,J
=12Hz PCH), 6.94~7.48 (m, 4H, Ar-H)；13C NMR(100MHz,CDCl3),δ:16.1,16.2,27.7,30.5,
46.1,58.5,62.7,62.8,64.5,115.1,115.3,120.7,124.2,128.9,161.0,171.1.IR(KBr)v:
3425,2960,2843,1675,1600,1523,1452,1201,1035cm- 1。
Embodiment 6：O, O'- diethyl-α-(4- fluorophenyls)-α-(D-2- nafoxidines formyloxy) methyl phosphonate (I
F) preparation.
The preparation of intermediate 1 and intermediate 2 is the same as 4 method of embodiment.
Intermediate 1 (4mmoL) and intermediate 2 (4mmol) are taken, is added in 50mL there-necked flasks, adds EDCI
(4.2mmol), with anhydrous methylene chloride (20mL) for solvent, stirring and dissolving under ice salt bath (- 5~0 DEG C), is leaked with constant pressure addition
DMAP (4.2mmol, anhydrous methylene chloride 20mL dissolving) is slowly added dropwise in bucket, and 30min is added dropwise, and reacts at room temperature 12h, filters,
Remove insoluble matter, concentrated solvent, column chromatography (ethyl acetate：Petroleum ether=1:1) it isolates and purifies, obtains intermediate 3.
Anhydrous ethyl acetate (4mL) is added in reaction bulb, is sufficiently stirred under ice salt bath (- 5~0 DEG C), sequentially adds first
Alcohol (1mmoL) and chloroacetic chloride (1mmoL) maintain the temperature, react 2h.Then by the (0.6mmoL, with the anhydrous second of 5mL of intermediate 3
Acetoacetic ester dissolves), it is slowly added in reaction system, TLC tracking, is stirred to react 10h under ice-water bath, is concentrated under reduced pressure, obtains viscous fluid
Body, column chromatography (chloroform：Methanol=10：1) it isolates and purifies, is dried in vacuo, obtains compound (If), m.p.66-68 DEG C, yield
45.8%.
(c=0.01g/mL, methanol)1H NMR(400MHz,CDCl3),δ:1.04~1.19 (m,
6H,CH3), 1.71~1.82 (m, 2H, CH2),1.96(s,1H,NH),2.12(s,1H,CCH2),2.48(s,1H,CCH2),
3.24~3.47 (m, 2H, NCH2), 3.89~4.03 (m, 2H, NCH2), 4.23~4.34 (m, H, CH2CO),6.34(dd,1H,J
=8Hz PCH), 6.97~7.48 (m, 4H, Ar-H)；13C NMR(100MHz,CDCl3),δ:16.1,16.3,27.8,30.3,
46.1,58.9,63.2,63.3,64.5,115.2,115.4,120.7,124.2,129.3,158.4,171.1.IR(KBr)v:
3421,2955,2850,1653,1598,1462,1208,1022cm- 1。
Antitumor activity is tested：
It is control with cis-platinum using mtt assay, measures target compound to tumour cell A-549, SGC-7901 and EC-109
Inhibited proliferation, two-point method (Reed and Muench methods) calculates its IC50Value, above-mentioned each group embodiment object resist
Tumor promotion data such as following table：
IC of the 1 embodiment compound of table to different tumour cells50It is worth (μm ol/L)
As can be seen from the above table, such compound on tumor cell A-549, SGC-7901, EC-109 has potential proliferation
Inhibiting effect.Notable antitumor activity is presented in part of compounds, close with comparison medicine cis-platinum.It can be used as antitumor lead compound
Research.
Meanwhile the L-configuration of identical structural object compound (I) has notable antitumor activity compared with D amino acids derivatives.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Any one skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (2)
1. a kind of preparation method of the phosphate derivatives containing amino acid fragment, characteristic reaction formula are as follows：
Reaction condition a. sodium bicarbonates or triethylamine, b.Et3N, c.DCC/DMAP or EDCI/DMAP or HBTU/DIPEA,
d.CH3OH and CH3COCl；Wherein, R is the alkyl of 1-5 carbon, R1For H or the alkyl of halogen or nitro or 1-3 carbon, R2For H
Or the alkyl or benzyl or indoles -2- methyl or methylol or thiopurine methyltransferase or para hydroxybenzene methyl or carbamyl first of 1-5 carbon
Base or carbamoylethyl or CH2CH2CH2Or HOCH (CH3), with R2The carbon atom being connected directly is R or S configurations.
2. preparation method according to claim 1, it is characterized in that：Preparation process is：
1) intermediate 1 is prepared：Amino acid is dissolved in tetrahydrofuran, ice-water bath, the bicarbonate of -3 times of moles of amino acid 1 is added
Then sodium or triethylamine are added (Boc) of 1-2 times of mole2O, ice-water bath reacts 30-60min, then reacts at room temperature 15-20h,
Reaction solution is extracted with ethyl acetate, and discards upper layer, is adjusted with acid pH, then extracted with dichloromethane, merges lower layer's organic phase, with nothing
Aqueous sodium persulfate dry, concentrated solvent to get；
2) intermediate 2 is prepared：Phosphite ester and aromatic aldehyde are pressed 1:1.5 molar ratios, which feed intake, to be added in three-necked bottle, and 1-2 is then added
The triethylamine of times mole, 40-80 DEG C of reaction 1.5h, then room temperature reaction for 24 hours, remove triethylamine, recrystallization to get；
3) intermediate 3 is prepared：Take intermediate 1 and intermediate 2 by 1:1 molar ratio feeds intake, and is added in reaction bulb, and ice salt bath is added 1
The condensing agent DCC/DMAP or EDCI/DMAP or HBTU/DIPEA of times mole dissolve condensing agent using dichloromethane as solvent,
React at room temperature 10-12h, remove insoluble matter, concentrated solvent, column chromatography isolate and purify to get；
4) target compound (I) is prepared：Reaction bulb is taken, ethyl acetate is added as solvent, sequentially adds the first of 1 times of mole of proportion
The chloroacetic chloride of alcohol and 1 times of mole reacts 3-5h, then the intermediate 3 of 0.5-1 times of mole is dissolved in ethyl acetate, is added
Enter reaction bulb, 8-10h reacted under ice-water bath, be concentrated under reduced pressure, obtain thick liquid, column chromatography isolates and purifies, vacuum drying to get
Target compound (I).
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