CN105503947A - Preparation method of phosphonate derivative containing amino acid fragments and antineoplastic application - Google Patents
Preparation method of phosphonate derivative containing amino acid fragments and antineoplastic application Download PDFInfo
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- CN105503947A CN105503947A CN201511015744.1A CN201511015744A CN105503947A CN 105503947 A CN105503947 A CN 105503947A CN 201511015744 A CN201511015744 A CN 201511015744A CN 105503947 A CN105503947 A CN 105503947A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 125000003275 alpha amino acid group Chemical group 0.000 title claims abstract 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract 4
- 230000000118 anti-neoplastic effect Effects 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 150000001413 amino acids Chemical class 0.000 claims abstract description 15
- -1 phosphonate compound Chemical class 0.000 claims abstract description 14
- 150000002611 lead compounds Chemical class 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- 238000006243 chemical reaction Methods 0.000 claims description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 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 22
- 230000000259 anti-tumor effect Effects 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 16
- 239000005457 ice water Substances 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 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
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 8
- 239000012346 acetyl chloride Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims description 8
- 238000001291 vacuum drying Methods 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 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000012467 final product 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 claims description 3
- 108090000958 Thiopurine S-methyltransferases Proteins 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229960003742 phenol Drugs 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 238000000034 method Methods 0.000 abstract description 8
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 239000012634 fragment Substances 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 238000007876 drug discovery Methods 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
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 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
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 230000006837 decompression Effects 0.000 description 4
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 150000003008 phosphonic acid esters Chemical group 0.000 description 4
- 238000013461 design Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000013543 active substance Substances 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 230000000844 anti-bacterial 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
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 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
- 238000011835 investigation Methods 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
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 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
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000005760 tumorsuppression Effects 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 preparation method of a phosphonate derivative (I) containing amino acid fragments and antineoplastic application thereof, and belongs to the field of anticancer drug research. By adopting a drug discovery method based on fragments, a phosphonate compound of preliminary study is optimized, and an antineoplastic lead compound is found. A series of phosphonate derivatives with new structures are designed, the preparation method comprises the steps of taking amino acid as a raw material, obtaining a midbody through Boc protection, then generating esterification with a hydroxy phosphonate midbody, finally removing Boc protection to obtain the phosphonate derivative shown in (I). The derivative has different anti-proliferative effects on tumor cells. A part of compounds has remarkable anti-proliferation on tumor cells A-549, SGC-7901 and EC-109, is approximated with a reference drug cis-platinum, and can be used as the antineoplastic lead compound. The chemical formula is shown in the description.
Description
Technical field
The present invention relates to a kind of antitumor drug, be specially a kind of preparation method of the phosphate derivatives containing amino acid fragment and antitumor application.
Background technology
Tumour is one of the most serious disease of current harm humans health and lives, therefore finds novel structure, novel mechanism antitumor drug is of great importance.Phosphonate ester compound is as derivative of organic phosphorus, Recent study is very extensive, in medicinal design synthesis, play key player, research shows that this analog derivative has the multiple important physiologically actives such as antitumor, antibacterial, antiviral, is widely used in medicine and pesticide field.
Early stage our design and synthesis different series phosphate derivatives, biological activity test finds that inhomogeneity compound has a potential anti-tumor activity.The structure activity relationship analyzing a few compounds finds: total phosphonic acid ester structure may be its antitumor pharmacophore.Therefore, take phosphonic acid ester as the structural modification of skeleton, optimization and antitumor action further investigation thereof be extremely necessary.
As everyone knows, amino acid is important physiologically active substance, is the raw material of synthetic peptide in organism, protein, hormone, enzyme and antibody, participates in multiple Biochemical processes activity.Wherein class peptide amino acid derivative because of molecular weight little, there is endogenous target spot more, with cell and nucleic acid, there is good affinity, very easily penetrate tumour cell, improve immunne response, the features such as Tumor suppression vascularization, growth and metastasis of tumours, have now become the new focus of antitumor drug research.Amino acid fragment is incorporated in drug molecule, is more conducive to drug molecule and is combined with tumor cell tissue, and play antitumor action.Expert thinks that this is antitumor drug developing direction got a good chance of.
Therefore, be combined with amino acid fragment by phosphonic acid ester active fragments, adopt the drug discovery method based on fragment, the phosphate derivatives containing amino acid fragment designing a class brand new carries out antitumor activity, acquisition has antitumor lead compound, has good prospect.
Summary of the invention
The present invention, on the basis of previous research work, adopts the drug discovery method based on fragment, by phosphonic acid ester active fragments be combined with amino acid fragment, prepare a class containing the phosphate derivatives of amino acid fragment, obtain promising antitumor primer.
For achieving the above object, the technical scheme of employing is: target compound containing the general structure of amino acid fragment phosphate derivatives is
, R is the alkyl of 1-5 carbon or the alkoxyl group of 1-5 atom; R
1for H or the alkyl of halogen or a nitro 1-3 carbon or the alkoxyl group of 1-3 atom; R
2for the alkyl of H or 1-5 carbon or phenmethyl or indoles-2-methyl or methylol or thiopurine methyltransferase or para hydroxybenzene methyl or carbamoyl methyl or carbamoylethyl or CH
2cH
2cH
2or HOCH (CH
3); Configuration: with R
2the carbon atom be directly connected is R or S configuration.Its building-up reactions formula is:
its concrete steps prepared are:
1) prepare intermediate 1: be dissolved in by amino acid in tetrahydrofuran (THF), ice-water bath, add sodium bicarbonate or the triethylamine of 1-3 times of amount of amino acid, then add (Boc) of 1-2 times amount
2o, ice-water bath reaction 30-60min, then room temperature reaction 15-20h, reaction solution is extracted with ethyl acetate, and discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction, merges lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, to obtain final product;
2) intermediate 2 is prepared: add in three-necked bottle by phosphorous acid ester and aromatic aldehyde (1:1.5 mol ratio feeds intake), then add the triethylamine of 1-2 times amount, 40-80 DEG C of reaction 1.5h, then at room temperature reaction 24h, removing triethylamine, recrystallization, to obtain final product;
3) intermediate 3 is prepared: get intermediate 1 and intermediate 2(1:1 mol ratio feeds intake), add in reaction flask, cryosel bath adds the condensing agent (DCC/DMAP or EDCI/DMAP or HBTU/DIPEA, preferred EDCI/DMAP) of 1 times amount, take methylene dichloride as solvent, dissolve condensing agent, room temperature reaction 10-12h, removing insolubles, concentrated solvent, column chromatography separation and purification, to obtain final product;
4) compound (I) is prepared: get reaction flask, add ethyl acetate as solvent, add the methyl alcohol of 1 times amount and the Acetyl Chloride 98Min. of 1 times amount successively, reaction 3-5h, then the intermediate 3 of 0.5-1 times amount is dissolved in ethyl acetate, add reaction flask, react 8-10h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography separation and purification, vacuum-drying, obtains target compound (I).
This kind of phosphate derivatives containing amino acid fragment adopts the drug discovery method based on fragment to design, and is be optimized the phosphonate compound of early-stage Study.This analog derivative has different inhibited proliferation to tumour cell.In the target compound (I) with same amino acid structure, L configuration comparatively D amino acids compound has obvious anti-tumor activity.Part of compounds has remarkable antiproliferative effect to tumour cell A-549, SGC-7901 and EC-109, and medicine cis-platinum is close with contrasting, and can be used as the research of antitumor lead compound.
Embodiment
Introduce the present invention further below in conjunction with embodiment, but the present invention is not limited only to following embodiment, can predict those skilled in the art when in conjunction with prior art, performance may produce many variations.
The general structure of target compound phosphate derivatives is
, R is the alkyl of 1-5 carbon or the alkoxyl group of 1-5 atom; R
1for H or the alkyl of halogen or a nitro 1-3 carbon or the alkoxyl group of 1-3 atom; R
2for the alkyl of H or 1-5 carbon or phenmethyl or indoles-2-methyl or methylol or thiopurine methyltransferase or para hydroxybenzene methyl or carbamoyl methyl or carbamoylethyl or CH
2cH
2cH
2or HOCH (CH
3); Configuration: with R
2the carbon atom be directly connected is R or S configuration.Its building-up reactions formula is:
Embodiment
The preparation of embodiment 1:O, O'-diethyl-α-(2-fluorophenyl)-α-(L-2-amino-benzene propionyloxy) methylphosphonate (Ia).
10mmolL-phenylalanine is dissolved in 50mL tetrahydrofuran (THF), about ice-water bath to 0 DEG C, adds sodium bicarbonate 20mmol.Then by 12mmol (Boc)
2o slowly instills to above-mentioned solution.About 0 DEG C, reaction 40min, then room temperature reaction 15-20h, react complete.Reaction solution is extracted with ethyl acetate 2-3 time, discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction 2-3 time.Merge lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, obtain intermediate 1;
2mmol diethyl phosphite and 3mmol o fluorobenzaldehyde are added in 50ml three-necked bottle, fully mixes, then 1.1mmol triethylamine is dropwise added in mixed solution.After 10min, raised temperature, at 60 DEG C of stirring reaction 3h.Again at stirring at room temperature reaction 24h.React complete, decompression removing triethylamine, with ether: sherwood oil=1:1 recrystallization, obtains intermediate 2.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add DMAP (4.1mmol) again, with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip EDCI (4.1mmol, anhydrous methylene chloride 15mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 10h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:1) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (0.8mmoL) and Acetyl Chloride 98Min. (0.8mmoL) successively, maintain this temperature, react about 3h.Then by intermediate 3 (0.5mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 8h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography (chloroform: methyl alcohol=8:1) separation and purification, vacuum-drying, obtain compound (Ia), productive rate 50.5%.
=-30.6°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.05～1.14(m,6H,CH
3),1.84(s,2H,NH
2),2.80～2.94(m,2H,CH
2Ar),3.84～4.01(m,4H,OCH
2),4.58(s,1H,NCH),6.34(dd,1H,J=24HzPCH),6.86～7.42(m,9H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
The preparation of embodiment 2:O, O'-diethyl-α-(2-fluorophenyl)-α-(D-2-amino-benzene propionyloxy) methylphosphonate (Ib).
10mmolD-phenylalanine is dissolved in 50mL tetrahydrofuran (THF), about ice-water bath to 0 DEG C, adds triethylamine 20mmol.Then by 15mmol (Boc)
2o slowly instills to above-mentioned solution.About 0 DEG C, reaction 60min, then room temperature reaction 15h, react complete.Reaction solution is extracted with ethyl acetate 2-3 time, discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction 2-3 time.Merge lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, obtain intermediate 1;
2mmol diethyl phosphite and 2mmol o fluorobenzaldehyde are added in 50ml three-necked bottle, fully mixes, then 1.5mmol triethylamine is dropwise added in mixed solution.After 10min, raised temperature, at 80 DEG C of stirring reaction 1.5h.Again at stirring at room temperature reaction 24h.React complete, decompression removing triethylamine, with ether: sherwood oil=1:1 recrystallization, obtains intermediate 2.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add DCC (4.1mmol) again, with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip DMAP (4.1mmol, anhydrous methylene chloride 15mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 12h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:1) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (1mmoL) and Acetyl Chloride 98Min. (1mmoL) successively, maintain this temperature, react about 3h.Then by intermediate 3 (0.5mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 10h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography (chloroform: methyl alcohol=8:1) separation and purification, vacuum-drying, obtain compound (Ib), productive rate 48.0%.
=+31.3°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.06～1.15(m,6H,CH
3),1.82(s,2H,NH
2),2.85～2.98(m,2H,CH
2Ar),3.86～4.03(m,4H,OCH
2),4.59(s,1H,NCH),6.02(dd,1H,J=20HzPCH),6.86～7.38(m,9H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
The preparation of embodiment 3:O, O'-diethyl-α-(4-fluorophenyl)-α-(L-2-amino-benzene propionyloxy) methylphosphonate (Ic).
10mmolL-phenylalanine is dissolved in 50mL tetrahydrofuran (THF), about ice-water bath to 0 DEG C, adds triethylamine 20mmol.Then by 12mmol (Boc)
2o slowly instills to above-mentioned solution.About 0 DEG C, reaction 40min, then room temperature reaction 15h, react complete.Reaction solution is extracted with ethyl acetate 2-3 time, discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction 2-3 time.Merge lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, obtain intermediate 1;
2mmol diethyl phosphite and 2mmol p-Fluorobenzenecarboxaldehyde are added in 50ml three-necked bottle, fully mixes, then 1.5mmol triethylamine is dropwise added in mixed solution.After 10min, raised temperature, at 80 DEG C of stirring reaction 1.5h.Again at stirring at room temperature reaction 24h.React complete, decompression removing triethylamine, with ether: sherwood oil=1:1 recrystallization, obtains intermediate 2.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add HBTU (4.1mmol) again, with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip DIPEA (4.1mmol, anhydrous methylene chloride 15mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 12h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:1) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (1mmoL) and Acetyl Chloride 98Min. (1mmoL) successively, maintain this temperature, react about 3h.Then by intermediate 3 (0.5mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 10h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography (chloroform: methyl alcohol=7:1) separation and purification, vacuum-drying, obtain compound (Ic), productive rate 52.3%.
=-36.5°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.08～1.12(m,6H,CH
3),1.87(s,2H,NH
2),2.88～3.11(m,2H,CH
2Ar),3.84～3.95(m,4H,OCH
2),4.60(s,1H,NCH),6.01(dd,1H,J=8HzPCH),6.90～7.33(m,9H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
The preparation of embodiment 4:O, O'-diethyl-α-(4-fluorophenyl)-α-(D-2-amino-benzene propionyloxy) methylphosphonate (Id).
10mmolD-phenylalanine is dissolved in 50mL tetrahydrofuran (THF), about ice-water bath to 0 DEG C, adds triethylamine 20mmol.Then by 12mmol (Boc)
2o slowly instills to above-mentioned solution.About 0 DEG C, reaction 40min, then room temperature reaction 15h, react complete.Reaction solution is extracted with ethyl acetate 2-3 time, discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction 2-3 time.Merge lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, obtain intermediate 1;
2mmol diethyl phosphite and 2mmol p-Fluorobenzenecarboxaldehyde are added in 50ml three-necked bottle, fully mixes, then 1.5mmol triethylamine is dropwise added in mixed solution.After 10min, raised temperature, at 80 DEG C of stirring reaction 1.5h.Again at stirring at room temperature reaction 24h.React complete, decompression removing triethylamine, with ether: sherwood oil=1:1 recrystallization, obtains intermediate 2.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add EDCI (4.1mmol) again, with anhydrous methylene chloride (15mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip DMAP (4.1mmol, anhydrous methylene chloride 15mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 12h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:1) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (1mmoL) and Acetyl Chloride 98Min. (1mmoL) successively, maintain this temperature, react about 3h.Then by intermediate 3 (0.5mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 10h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography (chloroform: methyl alcohol=9:1) separation and purification, vacuum-drying, obtain compound (Id), productive rate 49.7%.
=+35.0°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.08～1.10(m,6H,CH
3),1.87(s,2H,NH
2),288～3.12(m,2H,CH
2Ar),3.86～4.03(m,4H,OCH
2),4.61(s,1H,NCH),6.03(dd,1H,J=12HzPCH),6.92～7.36(m,9H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
The preparation of embodiment 5:O, O'-diethyl-α-(4-fluorophenyl)-α-(L-2-Pyrrolidine methanoyl) methylphosphonate (Ie).
The preparation of intermediate 1 and intermediate 2 is with embodiment 4 method.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add EDCI (4.5mmol) again, with anhydrous methylene chloride (20mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip DMAP (4.5mmol, anhydrous methylene chloride 20mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 12h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:2) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (1mmoL) and Acetyl Chloride 98Min. (1mmoL) successively, maintain this temperature, reaction 2h.Then by intermediate 3 (0.8mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 10h under ice-water bath, concentrating under reduced pressure, obtains thick liquid, column chromatography (chloroform: methyl alcohol=8:1) separation and purification, vacuum-drying, obtain compound (Ie), m.p.85-87 DEG C, productive rate 44.1%.
=-47.6°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.06～1.13(m,6H,CH
3),1.79～1.81(m,2H,CH
2),1.96(s,1H,NH),2.14(s,1H,CCH
2),2.43(s,1H,CCH
2),3.27～3.43(m,2H,NCH
2),3.88～4.03(m,2H,NCH
2),4.23～4.36(m,H,CH
2CO),6.35(dd,1H,J=12HzPCH),6.94～7.48(m,4H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
The preparation of embodiment 6:O, O'-diethyl-α-(4-fluorophenyl)-α-(D-2-Pyrrolidine methanoyl) methylphosphonate (If).
The preparation of intermediate 1 and intermediate 2 is with embodiment 4 method.
Get intermediate 1 (4mmoL) and intermediate 2 (4mmol), join in 50mL there-necked flask, add EDCI (4.2mmol) again, with anhydrous methylene chloride (20mL) for solvent, stirring and dissolving, under cryosel bath (-5 ~ 0 DEG C), slowly drip DMAP (4.2mmol, anhydrous methylene chloride 20mL dissolve) with constant pressure funnel, 30min dropwises, room temperature reaction 12h, filter, removing insolubles, concentrated solvent, column chromatography (ethyl acetate: sherwood oil=1:1) separation and purification, obtains intermediate 3.
In reaction flask, add anhydrous ethyl acetate (4mL), fully stir under cryosel bath (-5 ~ 0 DEG C), add methyl alcohol (1mmoL) and Acetyl Chloride 98Min. (1mmoL) successively, maintain this temperature, reaction 2h.Then by intermediate 3 (0.6mmoL, dissolve with 5mL anhydrous ethyl acetate), slowly add in reaction system, TLC follows the tracks of, stirring reaction 10h under ice-water bath, concentrating under reduced pressure, obtains thick liquid, column chromatography (chloroform: methyl alcohol=10:1) separation and purification, vacuum-drying, obtain compound (If), m.p.66-68 DEG C, productive rate 45.8%.
=+48.9°(c=0.01g/mL,methanol).
1HNMR(400MHz,CDCl
3),δ:1.04～1.19(m,6H,CH
3),1.71～1.82(m,2H,CH
2),1.96(s,1H,NH),2.12(s,1H,CCH
2),2.48(s,1H,CCH
2),3.24～3.47(m,2H,NCH
2),3.89～4.03(m,2H,NCH
2),4.23～4.34(m,H,CH
2CO),6.34(dd,1H,J=8HzPCH),6.97～7.48(m,4H,Ar-H);
13CNMR(100MHz,CDCl
3),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。
Anti-tumor activity is tested:
Adopting mtt assay, take cis-platinum as contrast, and measure target compound to the inhibited proliferation of tumour cell A-549, SGC-7901 and EC-109, two-point method (ReedandMuench method) calculates its IC
50value, the anti-tumor activity data of above-mentioned each group of embodiment target compound are as following table:
As can be seen from the above table, such compound on tumor cell A-549, SGC-7901, EC-109 has potential inhibited proliferation.Part of compounds presents remarkable anti-tumor activity, and medicine cis-platinum is close with contrasting.Can be used as the research of antitumor lead compound.
Meanwhile, the L configuration of same structure target compound (I) comparatively D amino acids derivative have remarkable anti-tumor activity.
The above; be only the present invention's preferably embodiment; but protection scope of the present invention is not limited thereto; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to according to technical scheme of the present invention and inventive concept thereof and replace or change, all should be encompassed within protection scope of the present invention.
Claims (3)
1., containing a preparation method for the phosphate derivatives of amino acid fragment, its characteristic reaction formula is as follows:
Reaction conditions a.NaOH, b.Et
3n, c.EDCI and DMAP, d.CH
3oH and CH
3cOCl; Wherein, R is the alkyl of 1-5 carbon or the alkoxyl group of 1-5 atom, R
1for H or the alkyl of halogen or a nitro 1-3 carbon or the alkoxyl group of 1-3 atom, R
2for the alkyl of H or 1-5 carbon or phenmethyl or indoles-2-methyl or methylol or thiopurine methyltransferase or para hydroxybenzene methyl or carbamoyl methyl or carbamoylethyl or CH
2cH
2cH
2or HOCH (CH
3), with R
2the carbon atom be directly connected is R or S configuration.
2. preparation method according to claim 1, is characterized in that: preparation process is:
1) prepare intermediate 1: be dissolved in by amino acid in tetrahydrofuran (THF), ice-water bath, add sodium bicarbonate or the triethylamine of 1-3 times of amount of amino acid, then add (Boc) of 1-2 times amount
2o, ice-water bath reaction 30-60min, then room temperature reaction 15-20h, reaction solution is extracted with ethyl acetate, and discards upper strata, with acid for adjusting pH, then uses dichloromethane extraction, merges lower floor's organic phase, with anhydrous sodium sulfate drying, concentrated solvent, to obtain final product;
2) intermediate 2 is prepared: add in three-necked bottle by phosphorous acid ester and aromatic aldehyde (1:1.5 mol ratio feeds intake), then add the triethylamine of 1-2 times amount, 40-80 DEG C of reaction 1.5h, then at room temperature reaction 24h, removing triethylamine, recrystallization, to obtain final product;
3) intermediate 3 is prepared: get intermediate 1 and intermediate 2(1:1 mol ratio feeds intake), add in reaction flask, cryosel bath adds the condensing agent (DCC/DMAP, EDCI/DMAP or HBTU/DIPEA) of 1 times amount, take methylene dichloride as solvent, dissolve condensing agent, room temperature reaction 10-12h, removing insolubles, concentrated solvent, column chromatography separation and purification, to obtain final product;
4) target compound (I) is prepared: get reaction flask, add ethyl acetate as solvent, add the methyl alcohol of 1 times amount and the Acetyl Chloride 98Min. of 1 times amount successively, reaction 3-5h, then the intermediate 3 of 0.5-1 times amount is dissolved in ethyl acetate, add reaction flask, react 8-10h under ice-water bath, concentrating under reduced pressure, obtain thick liquid, column chromatography separation and purification, vacuum-drying, obtains target compound (I).
3. the application of phosphate derivatives as antitumor lead compound containing amino acid fragment that according to claim 1 or 2 prepared by preparation method.
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| CN108250253A (en) * | 2018-03-15 | 2018-07-06 | 遵义医学院 | A kind of preparation method and antitumor application thereof of phosphonate ester glycosides derivatives |
| CN110964060A (en) * | 2019-12-25 | 2020-04-07 | 宁波大学 | Preparation method of bis- (α -hydroxy phosphate) |
| CN111171114A (en) * | 2020-01-17 | 2020-05-19 | 遵义医科大学 | Phosphonate dipeptide compound and application thereof |
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| CN1515586A (en) * | 2003-01-08 | 2004-07-28 | 清华大学 | Diisopropoxyphosphorylated dipeptide methyl ester, its preparation and application |
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| CN1515586A (en) * | 2003-01-08 | 2004-07-28 | 清华大学 | Diisopropoxyphosphorylated dipeptide methyl ester, its preparation and application |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108250253A (en) * | 2018-03-15 | 2018-07-06 | 遵义医学院 | A kind of preparation method and antitumor application thereof of phosphonate ester glycosides derivatives |
| CN108250253B (en) * | 2018-03-15 | 2020-04-14 | 遵义医学院 | Preparation method and anti-tumor application of phosphonate glucoside derivative |
| CN110964060A (en) * | 2019-12-25 | 2020-04-07 | 宁波大学 | Preparation method of bis- (α -hydroxy phosphate) |
| CN111171114A (en) * | 2020-01-17 | 2020-05-19 | 遵义医科大学 | Phosphonate dipeptide compound and application thereof |
| CN111171114B (en) * | 2020-01-17 | 2022-08-12 | 遵义医科大学 | Phosphonate dipeptide compound and application thereof |
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