CN105503945A - Method for preparing 2-phosphonic acid ester base-1, 3-dicarbonyl derivative - Google Patents
Method for preparing 2-phosphonic acid ester base-1, 3-dicarbonyl derivative Download PDFInfo
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- CN105503945A CN105503945A CN201510927543.2A CN201510927543A CN105503945A CN 105503945 A CN105503945 A CN 105503945A CN 201510927543 A CN201510927543 A CN 201510927543A CN 105503945 A CN105503945 A CN 105503945A
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- Prior art keywords
- phenyl
- propanedione
- dicarbonyl derivatives
- phosphonate group
- oxopropanoate
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Links
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 159
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 238000004440 column chromatography Methods 0.000 claims description 32
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 24
- -1 3-(4-aminomethyl phenyl)-3-oxopropanoate Chemical compound 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 10
- 229910052802 copper Inorganic materials 0.000 claims description 10
- NZZIMKJIVMHWJC-UHFFFAOYSA-N dibenzoylmethane Chemical compound C=1C=CC=CC=1C(=O)CC(=O)C1=CC=CC=C1 NZZIMKJIVMHWJC-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- UDRCONFHWYGWFI-UHFFFAOYSA-N ethyl 3-oxopentanoate Chemical compound CCOC(=O)CC(=O)CC UDRCONFHWYGWFI-UHFFFAOYSA-N 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 4
- HXUIDZOMTRMIOE-UHFFFAOYSA-N 3-oxo-3-phenylpropionic acid Chemical compound OC(=O)CC(=O)C1=CC=CC=C1 HXUIDZOMTRMIOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- HOVMFCOUXZBNBX-UHFFFAOYSA-N 1,3-bis(4-bromophenyl)propane-1,3-dione Chemical compound C1=CC(Br)=CC=C1C(=O)CC(=O)C1=CC=C(Br)C=C1 HOVMFCOUXZBNBX-UHFFFAOYSA-N 0.000 claims description 3
- FCRMMLQWCOHDJC-UHFFFAOYSA-N 1-(3-bromophenyl)-3-phenylpropane-1,3-dione Chemical compound BrC1=CC=CC(C(=O)CC(=O)C=2C=CC=CC=2)=C1 FCRMMLQWCOHDJC-UHFFFAOYSA-N 0.000 claims description 3
- IDQRBGOEWUVZGM-UHFFFAOYSA-N 1-(4-bromophenyl)-3-phenylpropane-1,3-dione Chemical compound C1=CC(Br)=CC=C1C(=O)CC(=O)C1=CC=CC=C1 IDQRBGOEWUVZGM-UHFFFAOYSA-N 0.000 claims description 3
- TYNRJXSHXIDFKH-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-phenylpropane-1,3-dione Chemical compound C1=CC(Cl)=CC=C1C(=O)CC(=O)C1=CC=CC=C1 TYNRJXSHXIDFKH-UHFFFAOYSA-N 0.000 claims description 3
- BQYYHUYOFMQQDR-UHFFFAOYSA-N 3-(2-bromophenyl)-3-oxopropanoic acid Chemical compound OC(=O)CC(=O)C1=CC=CC=C1Br BQYYHUYOFMQQDR-UHFFFAOYSA-N 0.000 claims description 3
- XMWZFYHYFVNEGT-UHFFFAOYSA-N 3-(4-bromophenyl)-3-oxopropanoic acid Chemical compound OC(=O)CC(=O)C1=CC=C(Br)C=C1 XMWZFYHYFVNEGT-UHFFFAOYSA-N 0.000 claims description 3
- DFCMMQZTRVXXMX-UHFFFAOYSA-N NCC1=CC=C(C=C1)C(CC(=O)C1=CC=C(C=C1)CN)=O Chemical compound NCC1=CC=C(C=C1)C(CC(=O)C1=CC=C(C=C1)CN)=O DFCMMQZTRVXXMX-UHFFFAOYSA-N 0.000 claims description 3
- NHQNMDBGKTWRKX-UHFFFAOYSA-N NCC1=CC=C(C=C1)C(CC(=O)C1=CC=CC=C1)=O Chemical compound NCC1=CC=C(C=C1)C(CC(=O)C1=CC=CC=C1)=O NHQNMDBGKTWRKX-UHFFFAOYSA-N 0.000 claims description 3
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 3
- QASWQXKZQZCVST-UHFFFAOYSA-N propan-2-yl dihydrogen phosphite Chemical compound CC(C)OP(O)O QASWQXKZQZCVST-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 33
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000008301 phosphite esters Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 11
- 229960003328 benzoyl peroxide Drugs 0.000 description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 8
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 7
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 7
- 239000004342 Benzoyl peroxide Substances 0.000 description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YIVJZNGAASQVEM-UHFFFAOYSA-N Lauroyl peroxide Chemical compound CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC YIVJZNGAASQVEM-UHFFFAOYSA-N 0.000 description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 6
- 229940045803 cuprous chloride Drugs 0.000 description 6
- BSAIUMLZVGUGKX-BQYQJAHWSA-N (E)-non-2-enal Chemical compound CCCCCC\C=C\C=O BSAIUMLZVGUGKX-BQYQJAHWSA-N 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 229960003280 cupric chloride Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 1
- MUKYLHIZBOASDM-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid 2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound NC(=N)N(C)CC(O)=O.OCC(O)C(O)C(O)C(O)C(O)=O MUKYLHIZBOASDM-UHFFFAOYSA-N 0.000 description 1
- TUJWGDXCTRWVDC-UHFFFAOYSA-N 2-diethoxyphosphorylethyl acetate Chemical compound CCOP(=O)(OCC)CCOC(C)=O TUJWGDXCTRWVDC-UHFFFAOYSA-N 0.000 description 1
- UWDMKTDPDJCJOP-UHFFFAOYSA-N 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium-4-carboxylate Chemical compound CC1(C)CC(O)(C(O)=O)CC(C)(C)N1 UWDMKTDPDJCJOP-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 241000819233 Tribulus <sea snail> Species 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 108010042388 protease C Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940047183 tribulus Drugs 0.000 description 1
- 239000002699 waste material Substances 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
- C07F9/4059—Compounds containing the structure (RY)2P(=X)-(CH2)n-C(=O)-(CH2)m-Ar, (X, Y = O, S, Se; n>=1, m>=0)
-
- 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
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- 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
- C07F9/4018—Esters of cycloaliphatic acids
Landscapes
- 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)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing a 2-phosphonic acid ester base-1, 3-dicarbonyl derivative. A 1, 3-dicarbonyl derivative and trialkyl phosphite ester are used as starting materials, and a great variety of raw materials are easy to obtain. Varied types of products are obtained through the method, can be directly used, and can also be used for other further reactions. In addition, the reaction is performed in air, the condition is mild, the reaction time is short, the target product yield is high, pollution is small, the reaction operation and aftertreatment process is simple, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to the preparing technical field of organic compound, be specifically related to a kind of preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives.
Background technology
2-phosphonate group-1,3-Dicarbonyl derivatives is widely used in, in witting and Horner-Wardsworth-Emmons (HWE) reaction, reacting prepare various important α, beta-unsaturated carbonyl compound with aldehydes or ketones.As 4-hydroxyl-2 (E)-nonenal (4-hydroxy-2 (E)-nonenal (HNE)) and 4-oxo-2 (E)-nonenal (4-oxo-2 (E)-nonenal (ONE)), they are the products in organism inner lipid peroxidation process, have important biological activity, its structure is as follows:
Wherein HNE can suppress the activity of many biological enzymes effectively, as protease C (proteinkinaseC), adenylate cyclase (adenylatecyclase), glyceraldehyde-3-phosphate dehydrogenase (glyceraldehyde-3-phosphatedehydrogenase) etc.; Simultaneously can cell death inducing, change gene expression pattern etc.; In addition, its Ahl tribulus sea silent sickness (Alzheimer ' sdisease), Parkinson's disease (Parkinson ' sdisease) and cancer have substantial connection.ONE has stronger neurotoxicity, and simultaneously the reactivity of it and protein is stronger.
2-phosphonate group-1,3-Dicarbonyl derivatives is the key intermediate of synthesizing pyrazole ether phosphate derivatives, the people such as the latter has important biological activity, such as Miller disclose 4-phosphonate group pyrazoles ether derivant, and these compound growths to crops such as hybrid wheats have vital role; 2-phosphonate group-1,3-Dicarbonyl derivatives can also be used to synthesis thiazolinyl pyrazolone derivative, the people such as this compounds has important bacteriostatic activity, such as Janecki disclose a kind of thiazolinyl pyrazolone derivative, and this compounds can as potential cytotoxic agent.
The synthetic route of existing 2-phosphonate group-1,3-Dicarbonyl derivatives is as follows:
There is raw material and be difficult to obtain in above synthetic route, such as 2-diethoxy phosphoryl ethyl acetate is unconventional product, is difficult to obtain; Reaction conditions is strict, will use caproyl chloride in reaction, and this substance toxicity is large, runs into air and smolders, therefore will have strict personal protection measure in reaction, can not suck and maybe can not contact this material; Simultaneous reactions environment, solvent and reactant will keep dry; Pollute larger grade not enough; Therefore find that a kind of raw material sources are simple, to meet the preparation method that Green Chemistry requires, reaction conditions is gentle, universality is good necessary effectively to synthesize 2-phosphonate group-1,3-Dicarbonyl derivatives.
Summary of the invention
The object of this invention is to provide the method that one prepares 2-phosphonate group-1,3-Dicarbonyl derivatives, it has simple, the high yield of raw material sources, reaction conditions is gentle, universality is good, safe advantage.
To achieve the above object of the invention, the technical solution used in the present invention is: one prepares 2-phosphonate group-1, the method of 3-Dicarbonyl derivatives, comprise the following steps: by 1,3-Dicarbonyl derivatives, trialkyl phosphinate, organo-peroxide and copper catalyst add in solvent, in 70 ~ 120 DEG C of reactions, obtain 2-phosphonate group-1,3-Dicarbonyl derivatives;
Described 1,3-Dicarbonyl derivatives is as shown in following chemical structure of general formula:
Wherein R
1be selected from: the one in alkyl, aryl or alkoxyl group; R
2be selected from: the one in alkyl, aryl or alkoxyl group;
Described trialkyl phosphinate derivative is as shown in following chemical formula:
P (OR
3)
3; R
3for alkyl or aryl;
Described organo-peroxide is as shown in following chemical structure of general formula:
Wherein R
4be selected from: the one in hydrogen, the tertiary butyl and benzoyl; R
5be selected from: the one in hydrogen, the tertiary butyl and benzoyl;
The chemical formula of described copper catalyst is CuX
n, wherein X is selected from: the one in Cl, Br, I or trifluoromethanesulfonic acid base; N is 1 or 2;
Described solvent is selected from: the one in ethanol, acetonitrile, acetic acid, propionic acid, 1,2-ethylene dichloride, toluene, dimethyl formamide;
Described 2-phosphonate group-1,3-Dicarbonyl derivatives is as shown in following chemical structure of general formula:
。
In technique scheme, described 1,3-Dicarbonyl derivatives is selected from 1,3-diphenylpropane-1，3-dione, 1-(4-aminomethyl phenyl)-3-phenyl-1,3-propanedione, 1,3-bis-(4-aminomethyl phenyl)-1,3-propanedione, 1,3-bis-(4-p-methoxy-phenyl)-1,3-propanedione, 1-(4-chloro-phenyl-)-3-phenyl-1,3-propanedione, 1-(4-bromophenyl)-3-(4-p-methoxy-phenyl)-1,3-propanedione, 1,3-bis-(4-bromophenyl)-1,3-propanedione, 1-(4-bromophenyl)-3-phenyl-1,3-propanedione, 1-(4-p-methoxy-phenyl)-3-phenyl-1,3-propanedione, 1-(3-bromophenyl)-3-phenyl-1,3-propanedione, 2,2,6,6-tetramethyl--3,5-heptadione, 1-phenyl-1,3-diacetylmethane, 5,5-dimedone-1,3, 3-phenyl-3-oxopropanoate, 3-(4-bromophenyl)-3-oxopropanoate, 3-(4-p-methoxy-phenyl)-3-oxopropanoate, 3-(2-p-methoxy-phenyl)-3-oxopropanoate, 3-(2-bromophenyl)-3-oxopropanoate, 3-(4-aminomethyl phenyl)-3-oxopropanoate, 3-(4-chloro-phenyl-)-3-oxopropanoate, Propionylacetic acid ethyl ester, one in diethyl malonate, described trialkyl phosphite is selected from the one in trimethyl phosphite, triethyl phosphorite, tri isopropyl phosphorite, tributyl phosphorous acid ester, triphenyl phosphite.
In technique scheme, thin-layer chromatography (TLC) is utilized to follow the tracks of reaction until terminate completely.
In technique scheme, in molar ratio, 1,3-Dicarbonyl derivatives: trialkyl phosphinate: organo-peroxide: copper catalyst is 1: (1 ~ 8): (1 ~ 8): (0.05 ~ 0.2); Be preferably 1: 7: 7: 0.1.
In technique scheme, described reaction is carried out in atmosphere.Operation is simple and safe.
In preferred technical scheme, reaction terminates to carry out column chromatography for separation purification processes to product afterwards; Be eluent with petrol ether/ethyl acetate during column chromatography for separation purification processes.
Preparation method disclosed by the invention is simple, and universality is good, therefore the invention also discloses 2-phosphonate group-1, the 3-Dicarbonyl derivatives prepared according to above-mentioned preparation method.
The reaction process of technique scheme can be expressed as:
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages:
1. the present invention uses 1,3-Dicarbonyl derivatives and trialkyl phosphite to be initiator first, only under organic oxidizing agent and copper catalyst exist, in air, and efficient preparation 2-phosphonate group-1,3-Dicarbonyl derivatives; Raw material is easy to get, kind is many, and the product prepared can directly use, and can also be used for other further react as intermediate.
2. the present invention uses raw material simple, and without the need to the multiple reagents that prior art requires, cost is low, and avoids wastage of material; Particular avoid existing acyl chlorides as reactant, decrease environmental pollution; Only need a small amount of catalyzer efficiently can obtain product, not only simplify the purification process of product, reduce the generation of waste, and for industrial application, there is positive realistic meaning.
3. preparation method's reaction conditions disclosed by the invention is simple, without the need to the complicated atmosphere of prior art, in air, reaction efficiently can obtain product, aftertreatment is very simple, column chromatography, avoid the Hazard Factor that existing reaction process exists, be conducive to chemosynthesis safety in production, ensure the security of the lives and property.
4. in method disclosed by the invention, reaction is carried out in atmosphere, and reaction conditions is gentle, pollute little, the reaction times is short, is specially adapted to multiple 1,3-Dicarbonyl derivatives, the yield of target product is high, and operation and last handling process simply, are suitable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
The synthesis of embodiment one: 2-dimethyl phosphonate base-1,3-diphenylpropane-1，3-dione
With 1,3-diphenylpropane-1，3-dione, trimethyl phosphite as raw material, its reactions steps is as follows:
1,3-diphenylpropane-1，3-dione (0.224g is added in reaction flask, 1.0mmol), trimethyl phosphite (0.124g, 1.0mmol), cuprous chloride (0.010g, 0.1mmol), tertbutyl peroxide (0.09g, 1mmol), and ethanol (5 milliliters), 70 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 54%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.09 (d, J=7.4Hz, 4H), 7.71 (t, J=7.4Hz, 2H), 7.58 (t, J=7.7Hz, 4H), 7.17 (d, 1H), 3.71 (d, 6H).
Embodiment two: 2-dimethyl phosphonate base-1-(4-aminomethyl phenyl) synthesis of-3-phenyl-1,3-propanedione
With 1-(4-aminomethyl phenyl)-3-phenyl-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(4-aminomethyl phenyl is added in reaction flask)-3-phenyl-1,3-propanedione (0.238g, 1.0mmol), trimethyl phosphite (0.248g, 2.0mmol), cuprous chloride (0.010g, 0.1mmol), tertbutyl peroxide (0.18g, 2mmol) with acetonitrile (5 milliliters), 70 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 64%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.03 (dd, J=25.2,7.9Hz, 4H), 7.70 (s, 1H), 7.57 (d, J=7.7Hz, 2H), 7.38 (d, J=8.0Hz, 2H), 3.84 – 3.64 (m, 6H), 2.49 – 2.33 (m, 3H).
The synthesis of embodiment three: 2-dimethyl phosphonate base-1,3-bis-(4-aminomethyl phenyl)-1,3-propanedione
With 1,3-bis-(4-aminomethyl phenyl)-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1 is added in reaction flask, 3-bis-(4-aminomethyl phenyl)-1,3-propanedione (0.252g, 1.0mmol), trimethyl phosphite (0.372g, 3.0mmol), cupric chloride (0.013g, 0.1mmol), tertbutyl peroxide (0.27g, 3mmol) and acetic acid (5 milliliters), 70 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 90%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.05 (d, J=7.9Hz, 4H), 7.08 (d, J=7.9Hz, 4H), 6.98 (d, J=7.8Hz, 1H), 3.87 (s, 6H), 3.71 (d, J=11.2Hz, 6H).
The synthesis of embodiment four: 2-dimethyl phosphonate base-1,3-bis-(4-p-methoxy-phenyl)-1,3-propanedione
With 1,3-bis-(4-p-methoxy-phenyl)-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1 is added in reaction flask, 3-bis-(4-p-methoxy-phenyl)-1,3-propanedione (0.284g, 1.0mmol), trimethyl phosphite (0.496g, 4.0mmol), cupric chloride (0.013g, 0.1mmol), tertbutyl peroxide (0.36g, 4mmol) and propionic acid (5 milliliters), 80 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 86%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.97 (d, J=8.0Hz, 4H), 7.36 (d, J=7.9Hz, 4H), 7.05 (d, J=22.8Hz, 1H), 3.71 (d, J=11.3Hz, 6H), 2.39 (s, 6H).
Embodiment five: 2-dimethyl phosphonate base-1-(4-chloro-phenyl-) synthesis of-3-phenyl-1,3-propanedione
With 1-(4-chloro-phenyl-)-3-phenyl-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(4-chloro-phenyl-is added in reaction flask)-3-phenyl-1,3-propanedione (0.259g, 1.0mmol), trimethyl phosphite (0.620g, 5.0mmol), cupric bromide (0.022g, 0.1mmol), tertbutyl peroxide (0.45g, 5mmol) with 1,2-ethylene dichloride (5 milliliters), 70 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 82%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.15 – 7.97 (m, 4H), 7.76 – 7.64 (m, 3H), 7.58 (t, J=7.7Hz, 2H), 7.16 (d, J=23.3Hz, 1H), 3.72 (d, J=4.7Hz, 3H), 3.69 (d, J=4.8Hz, 3H).
Embodiment six: 2-dimethyl phosphonate base-1-(4-bromophenyl)-3-(4-p-methoxy-phenyl) synthesis of-1,3-propanedione
With 1-(4-bromophenyl)-3-(4-p-methoxy-phenyl)-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(4-bromophenyl is added in reaction flask)-3-(4-p-methoxy-phenyl)-1,3-propanedione (0.333g, 1.0mmol), trimethyl phosphite (0.744g, 6.0mmol), cupric bromide (0.022g, 0.1mmol), tertbutyl peroxide (0.54g, 6mmol) with toluene (5 milliliters), 90 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 80%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.05 (d, J=8.9Hz, 4H), 7.99 (d, J=8.7Hz, 2H), 7.80 (d, J=8.6Hz, 3H), 7.08 (dd, J=16.0,11.3Hz, 3H), 3.88 (s, 3H), 3.73 (d, J=5.0Hz, 3H), 3.70 (d, J=5.0Hz, 3H).
The synthesis of embodiment seven: 2-dimethyl phosphonate base-1,3-bis-(4-bromophenyl)-1,3-propanedione
With 1,3-bis-(4-bromophenyl)-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1 is added in reaction flask, 3-bis-(4-bromophenyl)-1,3-propanedione (0.382g, 1.0mmol), trimethyl phosphite (0.868g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), tertbutyl peroxide (0.63g, 7mmol) and toluene (5 milliliters), 100 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 81%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.99 (d, J=8.6Hz, 4H), 7.81 (d, J=8.6Hz, 4H), 7.14 (d, J=23.5Hz, 1H), 3.71 (d, J=11.3Hz, 6H).
Embodiment eight: 2-dimethyl phosphonate base-1-(4-bromophenyl) synthesis of-3-phenyl-1,3-propanedione
With 1-(4-bromophenyl)-3-phenyl-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(4-bromophenyl is added in reaction flask)-3-phenyl-1,3-propanedione (0.301g, 1.0mmol), trimethyl phosphite (0.992g, 8.0mmol), cuprous bromide (0.014g, 0.1mmol), tertbutyl peroxide (0.81g, 8mmol) with toluene (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 83%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.02 – 7.98 (m, 4H), 7.78 (d, J=8.6Hz, 2H), 7.68 (t, J=7.4Hz, 1H), 7.54 (t, J=7.7Hz, 2H), 7.11 (d, J=23.3Hz, 1H), 3.69 (d, J=5.0Hz, 3H), 3.66 (d, J=5.0Hz, 3H).
Embodiment nine: 2-dimethyl phosphonate base-1-(4-p-methoxy-phenyl) synthesis of-3-phenyl-1,3-propanedione
With 1-(4-p-methoxy-phenyl)-3-phenyl-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(4-p-methoxy-phenyl is added in reaction flask)-3-phenyl-1,3-propanedione (0.254g, 1.0mmol), trimethyl phosphite (0.868g, 7.0mmol), cuprous iodide (0.010g, 0.05mmol), tert-butyl-benzoyl superoxide (1.362g, 7mmol) with dimethyl formamide (5 milliliters), 120 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 77%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.07 – 8.02 (m, 4H), 7.66 (t, J=7.4Hz, 1H), 7.53 (t, J=7.7Hz, 2H), 7.07 – 7.02 (m, J=8.8Hz, 3H), 3.85 (s, 3H), 3.69 (d, J=11.3Hz, 6H).
Embodiment ten: 2-dimethyl phosphonate base-1-(3-bromophenyl) synthesis of-3-phenyl-1,3-propanedione
With 1-(3-bromophenyl)-3-phenyl-1,3-propanedione, trimethyl phosphite as raw material, its reactions steps is as follows:
1-(3-bromophenyl is added in reaction flask)-3-phenyl-1,3-propanedione (0.301g, 1.0mmol), trimethyl phosphite (0.868g, 7.0mmol), cuprous iodide (0.019g, 0.1mmol), tert-butyl-benzoyl superoxide (1.362g, 7mmol) with dimethyl formamide (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 82%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.23 (t, J=1.7Hz, 1H), 8.03 (d, J=8.0Hz, 3H), 7.92 – 7.81 (m, 1H), 7.68 (t, J=7.4Hz, 1H), 7.57 – 7.50 (m, 3H), 7.15 (d, J=23.4Hz, 1H), 3.69 (d, J=3.4Hz, 3H), 3.66 (d, J=3.4Hz, 3H).
The synthesis of embodiment 11: 4-dimethyl phosphonate base-2,2,6,6-tetramethyl--3,5-heptadione
With 2,2,6,6-tetramethyl--3,5-heptadione, trimethyl phosphite as raw material, its reactions steps is as follows:
2 are added in reaction flask, 2,6,6-tetramethyl--3,5-heptadione (0.184g, 1mmol), trimethyl phosphite (0.868g, 7.0mmol), cupric iodide (0.064g, 0.2mmol), tert-butyl-benzoyl superoxide (1.362g, 7mmol) and dimethyl formamide (5 milliliters), 100 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 85%).The analytical data of product is as follows:
1hNMR (400MHz, CDCl
3): δ 6.19 – 6.17 (m, 1H), 3.69 (d, J=3.4Hz, 3H), 3.66 (d, J=3.4Hz, 3H), 1.18 – 1.15 (m, 9H), 1.15 – 1.12 (m, 9H).
The synthesis of embodiment 12: 2-dimethyl phosphonate base-1-phenyl-1,3-diacetylmethane
With 1-phenyl-1,3-diacetylmethane, trimethyl phosphite as raw material, its reactions steps is as follows:
1-phenyl-1 is added in reaction flask, 3-diacetylmethane (0.176g, 1.0mmol), trimethyl phosphite (0.868g, 7.0mmol), cupric iodide (0.032g, 0.1mmol), tert-butyl-benzoyl superoxide (1.362g, 7mmol) with dimethyl formamide (5 milliliters), 90 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 68%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.07 – 7.95 (m, 2H), 7.69 (t, J=7.4Hz, 1H), 7.56 (t, J=7.7Hz, 2H), 6.17 (d, J=23.3Hz, 1H), 3.71 (dd, J=11.3,1.7Hz, 6H), 2.75 (qd, J=7.2,2.8Hz, 2H), 0.92 (t, J=7.2Hz, 3H).
The synthesis of embodiment 13: 2-dimethyl phosphonate base-5,5-dimedone-1,3
With 5,5-dimedone-1,3, trimethyl phosphite as raw material, its reactions steps is as follows:
5 are added in reaction flask, 5-dimedone-1,3(0.140g, 1mmol), trimethyl phosphite (0.868g, 7.0mmol), the cuprous (0.021g of trifluoromethanesulfonic acid, 0.1mmol), ditertiary butyl peroxide (1.022g, 7mmol) and dimethyl formamide (5 milliliters), 80 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 69%).The analytical data of product is as follows:
1hNMR (400MHz, CDCl
3): δ 5.89 (s, 1H), 3.69 (d, J=3.4Hz, 3H), 3.66 (d, J=3.4Hz, 3H), 2.45 (s, 2H), 2.25 (s, 2H), 1.10 (s, 6H).
The synthesis of embodiment 14: 2-diethyl phosphonate base-1,3-diphenylpropane-1，3-dione
With 1,3-diphenylpropane-1，3-dione, triethyl phosphorite as raw material, its reactions steps is as follows:
1 is added in reaction flask, 3-phenylbenzene-1,3-propanedione (0.224g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), the cuprous (0.021g of trifluoromethanesulfonic acid, 0.1mmol), ditertiary butyl peroxide (1.022g, 7mmol) and toluene (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 72%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.07 (d, J=7.3Hz, 4H), 7.67 (t, J=7.4Hz, 2H), 7.54 (t, J=7.7Hz, 4H), 7.08 (d, J=23.2Hz, 1H), 4.23 – 3.92 (m, 4H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of embodiment 15: 2-di-isopropyl phosphonate group-1,3-diphenylpropane-1，3-dione
With 1,3-diphenylpropane-1，3-dione, tri isopropyl phosphorite as raw material, its reactions steps is as follows:
1 is added in reaction flask, 3-phenylbenzene-1,3-propanedione (0.224g, 1.0mmol), triisopropyl base phosphorous acid ester (1.456g, 7.0mmol), copper trifluoromethanesulfcomposite (0.036g, 0.1mmol), ditertiary butyl peroxide (1.022g, 7mmol) and toluene (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 63%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO) δ 8.09 (d, J=7.4Hz, 4H), 7.69 (t, J=7.4Hz, 2H), 7.56 (t, J=7.7Hz, 4H), 7.02 (d, J=23.3Hz, 1H), 3.85 – 3.05 (m, 2H), 1.14 (dd, J=5.9,4.8Hz, 12H).
The synthesis of embodiment 16: 2-di-n-butyl phosphonate group-1,3-diphenylpropane-1，3-dione
With 1,3-diphenylpropane-1，3-dione, three normal-butyl phosphorous acid esters as raw material, its reactions steps is as follows:
1,3-diphenylpropane-1，3-dione (0.224g is added in reaction flask, 1.0mmol), three normal-butyl phosphorous acid esters (1.862g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with toluene (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 65%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO) δ 8.09 (d, J=7.4Hz, 4H), 7.69 (t, J=7.4Hz, 2H), 7.56 (t, J=7.7Hz, 4H), 7.02 (d, J=23.3Hz, 1H), 3.44 – 3.37 (m, 2H), 3.35 – 3.27 (m, 2H), 1.66 (m, 4H), 1.37 (m, 4H), 0.99 (m, 6H).
The synthesis of embodiment 17: 2-diethyl phosphonate base-3-phenyl-3-oxopropanoate
Using 3-phenyl-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-phenyl-3-oxopropanoate (0.192g is added in reaction flask, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), copper trifluoromethanesulfcomposite (0.036g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with toluene (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 73%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.03 (d, J=7.4Hz, 2H), 7.69 (t, J=7.4Hz, 1H), 7.55 (t, J=7.7Hz, 2H), 5.84 (d, J=23.1Hz, 1H), 4.40 – 3.85 (m, 6H), 1.34 – 0.99 (m, 9H).
Embodiment 18: 2-diethyl phosphonate base-3-(4 – bromophenyl) synthesis of-3-oxopropanoate
Using 3-(4-bromophenyl)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(4-bromophenyl is added in reaction flask)-3-oxopropanoate (0.269g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cupric chloride (0.013g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with dimethyl formamide (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 73%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.99 (d, J=8.7Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 5.88 (d, J=23.3Hz, 1H), 4.29 – 3.88 (m, 6H), 1.22 – 1.16 (m, 9H).
Embodiment 19: 2-diethyl phosphonate base-3-(4 – p-methoxy-phenyl) synthesis of-3-oxopropanoate
Using 3-(4-p-methoxy-phenyl)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(4-p-methoxy-phenyl is added in reaction flask)-3-oxopropanoate (0.222g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cupric chloride (0.013g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with dimethyl formamide (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 70%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.57 (dd, J=384.1,8.9Hz, 2H), 7.09 (d, J=8.9Hz, 2H), 5.77 (d, J=22.8Hz, 1H), 4.15 – 3.89 (m, 6H), 3.89 (s, 3H), 1.34 – 0.90 (m, 9H).
Embodiment 20: 2-diethyl phosphonate base-3-(2 – p-methoxy-phenyl) synthesis of-3-oxopropanoate
Using 3-(2-p-methoxy-phenyl)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(2-p-methoxy-phenyl is added in reaction flask)-3-oxopropanoate (0.222g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous chloride (0.010g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 72%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.89 – 7.56 (m, 2H), 7.22 (d, J=8.2Hz, 1H), 7.17 – 7.05 (m, 1H), 5.36 (d, J=22.4Hz, 1H), 4.28 – 4.01 (m, 6H), 3.90 (s, 3H), 1.28 – 1.16 (m, 9H).
Embodiment 21: 2-diethyl phosphonate base-3-(2 – bromophenyl) synthesis of-3-oxopropanoate
Using 3-(2-bromophenyl)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(2-bromophenyl is added in reaction flask)-3-oxopropanoate (0.269g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous chloride (0.010g, 0.1mmol), benzoyl peroxide (1.694g, 7.0mmol) with dimethyl formamide (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 79%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 13.85 (s, 1H), 7.70 (d, J=7.9Hz, 1H), 7.55 – 7.44 (m, 1H), 7.42 – 7.38 (m, 2H), 4.51 – 4.07 (m, 4H), 3.88 (q, J=7.1Hz, 2H), 1.33 (t, J=7.0Hz, 6H), 0.89 (t, J=7.1Hz, 4=3H).
Embodiment 22: 2-diethyl phosphonate base-3-(4 – aminomethyl phenyl) synthesis of-3-oxopropanoate
Using 3-(4-aminomethyl phenyl)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(4-aminomethyl phenyl is added in reaction flask)-3-oxopropanoate (0.206g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous chloride (0.010g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with dimethyl formamide (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 73%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 7.92 (d, J=8.3Hz, 2H), 7.35 (d, J=8.1Hz, 2H), 5.76 (d, J=22.9Hz, 1H), 4.51 – 3.84 (m, 6H), 2.38 (s, 3H), 1.19 – 1.12 (m, 9H).
Embodiment 23: 2-diethyl phosphonate base-3-(4 – chloro-phenyl-) synthesis of-3-oxopropanoate
Using 3-(4-chloro-phenyl-)-3-oxopropanoate, triethyl phosphorite as raw material, its reactions steps is as follows:
3-(4-chloro-phenyl-is added in reaction flask)-3-oxopropanoate (0.226g, 1.0mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous chloride (0.010g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 71%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6): δ 8.05 (d, J=8.7Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 5.86 (d, J=23.3Hz, 1H), 4.70 – 3.88 (m, 6H), 1.19 – 1.13 (m, 9H).
The synthesis of embodiment 24: 2-diethyl phosphonate base Propionylacetic acid ethyl ester
Using Propionylacetic acid ethyl ester, triethyl phosphorite as raw material, its reactions steps is as follows:
propionylacetic acid ethyl ester (0.144g is added in reaction flask, 1mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 93%).The analytical data of product is as follows:
1hNMR (400MHz, CDCl
3): δ 5.55 (t, J=0.9,1H), 4.23 – 3.92 (m, 6H), 2.34 (qd, J=7.4Hz, 0.9Hz, 2H), 1.25 (t, J=7.1Hz, 3H), 1.12 (t, J=7.4Hz, 3H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of embodiment 25: 2-diethyl phosphonate propylmalonic acid diethyl ester
Using diethyl malonate, triethyl phosphorite as raw material, its reactions steps is as follows:
diethyl malonate (0.160g is added in reaction flask, 1mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 93%).The analytical data of product is as follows:
1hNMR (400MHz, CDCl
3): δ 5.16 (s, 1H), 4.23 – 3.92 (m, 8H), 1.12 (t, J=7.4Hz, 6H), 1.08 (t, J=7.0Hz, 6H).
The synthesis of embodiment 26: 2-diphenylphosphine perester radical-1,3-diphenylpropane-1，3-dione
With 1,3-diphenylpropane-1，3-dione, triphenyl phosphite as raw material, its reactions steps is as follows:
1,3-diphenylpropane-1，3-dione (0.224g is added in reaction flask, 1.0mmol), triphenyl phosphite (2.282g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 68%).The analytical data of product is as follows:
1hNMR (400MHz, DMSO-d
6) δ 8.00 – 7.50 (m, 10H), 7.45 – 7.10 (m, 10H), 7.02 (d, J=23.3Hz, 1H).
The synthesis of embodiment 27: 2-diethyl phosphonate base hexanoyl ethyl acetate
Using hexanoyl ethyl acetate, triethyl phosphorite as raw material, its reactions steps is as follows:
hexanoyl ethyl acetate (0.186g is added in reaction flask, 1mmol), triethyl phosphorite (1.162g, 7.0mmol), cuprous bromide (0.014g, 0.1mmol), lauroyl peroxide (2.80g, 7.0mmol) with acetic acid (5 milliliters), 110 DEG C of reactions;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=4:1), obtains target product (productive rate 88%).The analytical data of product is as follows:
1hNMR (400MHz, CDCl
3): δ 5.86 (d, J=23.3Hz, 1H), 4.23 – 3.92 (m, 6H), 2.34 (t, J=6.0Hz, 2H), 1.60 – 1.20 (m, 6H), 1.12 (t, J=7.4Hz, 3H), 1.08 (t, J=7.0Hz, 6H), 0.90 (t, J=6.0Hz, 3H).
Claims (10)
1. prepare 2-phosphonate group-1 for one kind, the method of 3-Dicarbonyl derivatives, it is characterized in that, comprise the following steps: by 1,3-Dicarbonyl derivatives, trialkyl phosphinate, organo-peroxide and copper catalyst add in solvent, in 70 ~ 120 DEG C of reactions, obtain 2-phosphonate group-1,3-Dicarbonyl derivatives;
Described 1,3-Dicarbonyl derivatives is as shown in following chemical structure of general formula:
Wherein R
1be selected from: the one in alkyl, aryl or alkoxyl group; R
2be selected from: the one in alkyl, aryl or alkoxyl group;
The chemical formula of described trialkyl phosphinate derivative is: P (OR
3)
3; R
3for alkyl or aryl;
Described organo-peroxide is as shown in following chemical structure of general formula:
Wherein R
4be selected from: the one in hydrogen, the tertiary butyl and benzoyl; R
5be selected from: the one in hydrogen, the tertiary butyl and benzoyl;
The chemical formula of described copper catalyst is CuX
n, wherein X is selected from: the one in Cl, Br, I or trifluoromethanesulfonic acid base; N is 1 or 2;
Described solvent is selected from: the one in ethanol, acetonitrile, acetic acid, propionic acid, 1,2-ethylene dichloride, toluene, dimethyl formamide;
Described 2-phosphonate group-1,3-Dicarbonyl derivatives is as shown in following chemical structure of general formula:
。
2. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 1, is characterized in that: described 1,3-Dicarbonyl derivatives is selected from 1,3-diphenylpropane-1，3-dione, 1-(4-aminomethyl phenyl)-3-phenyl-1,3-propanedione, 1,3-bis-(4-aminomethyl phenyl)-1,3-propanedione, 1,3-bis-(4-p-methoxy-phenyl)-1,3-propanedione, 1-(4-chloro-phenyl-)-3-phenyl-1,3-propanedione, 1-(4-bromophenyl)-3-(4-p-methoxy-phenyl)-1,3-propanedione, 1,3-bis-(4-bromophenyl)-1,3-propanedione, 1-(4-bromophenyl)-3-phenyl-1,3-propanedione, 1-(4-p-methoxy-phenyl)-3-phenyl-1,3-propanedione, 1-(3-bromophenyl)-3-phenyl-1,3-propanedione, 2,2,6,6-tetramethyl--3,5-heptadione, 1-phenyl-1,3-diacetylmethane, 5,5-dimedone-1,3, 3-phenyl-3-oxopropanoate, 3-(4-bromophenyl)-3-oxopropanoate, 3-(4-p-methoxy-phenyl)-3-oxopropanoate, 3-(2-p-methoxy-phenyl)-3-oxopropanoate, 3-(2-bromophenyl)-3-oxopropanoate, 3-(4-aminomethyl phenyl)-3-oxopropanoate, 3-(4-chloro-phenyl-)-3-oxopropanoate, Propionylacetic acid ethyl ester, one in diethyl malonate.
3. 2-phosphonate group-1 according to claim 1, the preparation method of 3-Dicarbonyl derivatives, is characterized in that: described trialkyl phosphite is selected from the one in trimethyl phosphite, triethyl phosphorite, tri isopropyl phosphorite, tributyl phosphorous acid ester, triphenyl phosphite.
4. 2-phosphonate group-1 according to claim 1, the preparation method of 3-Dicarbonyl derivatives, it is characterized in that: in molar ratio, 1,3-Dicarbonyl derivatives: trialkyl phosphinate: organo-peroxide: copper catalyst is 1: (1 ~ 8): (1 ~ 8): (0.05 ~ 0.2).
5. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 4, is characterized in that: in molar ratio, 1,3-Dicarbonyl derivatives: trialkyl phosphinate: organo-peroxide: copper catalyst is 1: 7: 7: 0.1.
6. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 1, is characterized in that: utilize thin-layer chromatography to follow the tracks of reaction until terminate completely.
7. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 1, is characterized in that: described reaction is carried out in atmosphere.
8. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 1, is characterized in that: reaction terminates to carry out column chromatography for separation purification processes to product afterwards.
9. the preparation method of 2-phosphonate group-1,3-Dicarbonyl derivatives according to claim 8, is characterized in that: be eluent with petrol ether/ethyl acetate during described column chromatography for separation purification processes.
10. 2-phosphonate group-1, the 3-Dicarbonyl derivatives prepared of the preparation method of any one 2-phosphonate group-1,3-Dicarbonyl derivatives according to claims 1 to 9.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110218229A (en) * | 2017-09-08 | 2019-09-10 | 江苏强盛功能化学股份有限公司 | A kind of β-sulfydryl azepine phosphorus heterocycle analog derivative and preparation method thereof |
| CN110256496A (en) * | 2017-09-08 | 2019-09-20 | 江苏强盛功能化学股份有限公司 | A kind of β-thioindole ketones derivant and preparation method thereof |
| CN110272450A (en) * | 2017-09-08 | 2019-09-24 | 江苏强盛功能化学股份有限公司 | Double phosphono analog derivatives of a kind of β-thiocarbonyl group and preparation method thereof |
| CN110218229B (en) * | 2017-09-08 | 2021-08-17 | 江苏强盛功能化学股份有限公司 | Beta-mercapto azaphospho heterocyclic derivative and preparation method thereof |
| CN110256496B (en) * | 2017-09-08 | 2021-08-17 | 江苏强盛功能化学股份有限公司 | Beta-thioindolone derivative and preparation method thereof |
| CN110272450B (en) * | 2017-09-08 | 2021-08-17 | 江苏强盛功能化学股份有限公司 | Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof |
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