WO2020073209A1 - 一种三氟甲基烯基膦酸酯及其制备方法 - Google Patents
一种三氟甲基烯基膦酸酯及其制备方法 Download PDFInfo
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- WO2020073209A1 WO2020073209A1 PCT/CN2018/109541 CN2018109541W WO2020073209A1 WO 2020073209 A1 WO2020073209 A1 WO 2020073209A1 CN 2018109541 W CN2018109541 W CN 2018109541W WO 2020073209 A1 WO2020073209 A1 WO 2020073209A1
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- Prior art keywords
- derivative
- reaction
- phosphonate
- trifluoromethyl
- trifluoromethylalkenyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 150000002497 iodine compounds Chemical class 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 150000000475 acetylene derivatives Chemical class 0.000 claims abstract description 19
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 16
- 239000011574 phosphorus Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 18
- 238000004809 thin layer chromatography Methods 0.000 claims description 18
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 11
- 125000004185 ester group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- -1 trifluoromethyl alkenyl phosphonate derivative Chemical class 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- RVDOYUFNRDGYGU-UHFFFAOYSA-N 1-bromo-2-ethynylbenzene Chemical group BrC1=CC=CC=C1C#C RVDOYUFNRDGYGU-UHFFFAOYSA-N 0.000 claims description 4
- LTLVZQZDXQWLHU-UHFFFAOYSA-N 1-bromo-4-ethynylbenzene Chemical group BrC1=CC=C(C#C)C=C1 LTLVZQZDXQWLHU-UHFFFAOYSA-N 0.000 claims description 4
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 claims description 4
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 claims description 4
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 claims description 4
- GAZZTEJDUGESGQ-UHFFFAOYSA-N 1-ethynyl-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(C#C)C=C1 GAZZTEJDUGESGQ-UHFFFAOYSA-N 0.000 claims description 4
- LWISLHRIEATKTM-UHFFFAOYSA-N 2-Ethynylthiophene Chemical compound C#CC1=CC=CS1 LWISLHRIEATKTM-UHFFFAOYSA-N 0.000 claims description 4
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 claims description 4
- LAGNMUUUMQJXBF-UHFFFAOYSA-N 4-ethynylbenzonitrile Chemical group C#CC1=CC=C(C#N)C=C1 LAGNMUUUMQJXBF-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- JPGRSTBIEYGVNO-UHFFFAOYSA-N methyl 4-ethynylbenzoate Chemical group COC(=O)C1=CC=C(C#C)C=C1 JPGRSTBIEYGVNO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- PTRUTZFCVFUTMW-UHFFFAOYSA-N 1-ethynyl-3-fluorobenzene Chemical group FC1=CC=CC(C#C)=C1 PTRUTZFCVFUTMW-UHFFFAOYSA-N 0.000 claims description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims 1
- LNDJVIYUJOJFSO-UHFFFAOYSA-N cyanoacetylene Chemical group C#CC#N LNDJVIYUJOJFSO-UHFFFAOYSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- DREPONDJUKIQLX-UHFFFAOYSA-N 1-[ethenyl(ethoxy)phosphoryl]oxyethane Chemical compound CCOP(=O)(C=C)OCC DREPONDJUKIQLX-UHFFFAOYSA-N 0.000 description 11
- YZNFAKUUGQFZOK-UHFFFAOYSA-N 4,4,4-trifluorobut-2-ynenitrile Chemical group FC(F)(F)C#CC#N YZNFAKUUGQFZOK-UHFFFAOYSA-N 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- XHEOXSQMBWJOKP-UHFFFAOYSA-N O=C1O[I](C(F)(F)F)c2c1cccc2 Chemical compound O=C1O[I](C(F)(F)F)c2c1cccc2 XHEOXSQMBWJOKP-UHFFFAOYSA-N 0.000 description 2
- 108090000783 Renin Proteins 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 description 2
- CQCXMYUCNSJSKG-UHFFFAOYSA-N 1-dimethoxyphosphorylethene Chemical compound COP(=O)(OC)C=C CQCXMYUCNSJSKG-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- CNPMOHGYTDYJAE-UHFFFAOYSA-N 2-cyanoethenylphosphonic acid Chemical class OP(O)(=O)C=CC#N CNPMOHGYTDYJAE-UHFFFAOYSA-N 0.000 description 1
- LIVGOYMLLAOTQV-UHFFFAOYSA-N 2-diethoxyphosphoryl-4,4,4-trifluoro-3-(trifluoromethyl)but-2-enenitrile Chemical compound C(C)OP(OCC)(=O)C(=C(C(F)(F)F)C(F)(F)F)C#N LIVGOYMLLAOTQV-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- GZLMFCWSEKVVGO-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-5-methylhexanoate Chemical compound CC(C)CC(N)C(O)C(O)=O GZLMFCWSEKVVGO-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QILPCLKCJQYLQA-UHFFFAOYSA-N C(C)OP(OCC)(=O)C(=CC(F)(F)F)C1=CC=CC=C1 Chemical compound C(C)OP(OCC)(=O)C(=CC(F)(F)F)C1=CC=CC=C1 QILPCLKCJQYLQA-UHFFFAOYSA-N 0.000 description 1
- RDMBVSWDJJPVKH-UHFFFAOYSA-N C(CCC)OP(OCCCC)(=O)C(=CC(F)(F)F)C1=CC=CC=C1 Chemical compound C(CCC)OP(OCCCC)(=O)C(=CC(F)(F)F)C1=CC=CC=C1 RDMBVSWDJJPVKH-UHFFFAOYSA-N 0.000 description 1
- MDSUKZSLOATHMH-IUCAKERBSA-N Leu-Val Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C([O-])=O MDSUKZSLOATHMH-IUCAKERBSA-N 0.000 description 1
- MDSUKZSLOATHMH-UHFFFAOYSA-N N-L-leucyl-L-valine Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(O)=O MDSUKZSLOATHMH-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000000280 densification Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect 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
-
- 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
- C07F9/4015—Esters of acyclic unsaturated acids
Definitions
- the invention belongs to the technical field of preparation of organic compounds, and in particular relates to a preparation method of trifluoromethylalkenyl phosphonate derivatives.
- Organic phosphonates have strong biological activity and are widely used as insecticides, renin and protease inhibitors.
- Reference 1 Shidlovskii A, F, Peregudov A, S, Averkiev B, B, et Al, Three-component, densification of trifluoromethyl-substituted cyanovinylphosphonates, arylamines, and ketones, cytotoxicity, activity, of products, thus, obtained, Russian, 144 Reference 2: Dellaria Jr J, F, Maki R G, Stein H H, et al, New inhibitors of Renin that container novel, phosphorostatine Leu-Val replacements, Journal of medical chemistry, 1990, 33, 534.
- the object of the present invention is to provide a method for preparing trifluoromethyl alkenyl phosphonate derivatives, which has the advantages of short steps, mild reaction conditions, high yield and good universality, and can be synthesized in one step from the raw materials product.
- a preparation method of trifluoromethylalkenyl phosphonate derivative includes the following steps: dissolving acetylene derivative, iodine compound and phosphorus reagent in a solvent, and reacting at room temperature to 100 ° C to obtain trifluoromethylene Phosphonate derivatives;
- the acetylene derivative is represented by the following general chemical structure formula:
- R 1 is selected from one of aryl, cyano or ester groups
- R 2 is selected from one of hydrogen, cyano or ester groups
- the iodine compound is shown in the following chemical structural formula:
- the phosphorus reagent is shown by the following general structure formula:
- R 4 is selected from one of methyl, ethyl, isopropyl or butyl.
- the aryl group is shown by the following general chemical structure formula:
- R 3 is selected from one of alkyl, alkoxy, halogen, nitro, trifluoromethyl and ester groups; the corresponding acetylene derivative is aryl alkyne, as shown in the following general chemical structure formula:
- the solvent is selected from one of acetone, ethyl acetate, toluene, and N, N-dimethylformamide.
- the acetylene derivative is selected from: phenylacetylene, 4-methylphenylacetylene, 4-methoxyphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4 -Nitrophenylacetylene, 4-methoxycarbonylphenylacetylene, 4-cyanophenylacetylene, 1-trifluoromethyl-2-cyanoacetylene, 2-ethynylthiophene, 2-bromophenylacetylene, 3-fluoro One of phenylacetylene; the phosphorus reagent is selected from the group consisting of trimethyl phosphite, triethyl phosphite, and tri-n-butyl phosphite.
- reaction is followed by thin layer chromatography (TLC) until it is completely completed.
- TLC thin layer chromatography
- the molar ratio: acetylene derivative: iodine compound: phosphorus reagent is 1: 1.5: (3-7).
- the product is subjected to column chromatography separation and purification after the reaction.
- the invention also discloses the application of acetylene derivatives, iodine compounds and phosphorus reagents as raw materials in the preparation of trifluoromethylalkenyl phosphonate derivatives.
- the preparation is carried out in the presence of a solvent.
- the acetylene derivative, iodine compound, and phosphorus reagent are dissolved in a solvent, and reacted at room temperature to 100 ° C to obtain a trifluoromethylalkenyl phosphonate derivative;
- the acetylene derivative is represented by the following general chemical structure formula:
- R 1 is selected from one of aryl, cyano or ester groups
- R 2 is selected from one of hydrogen, cyano or ester groups
- the iodine compound is shown in the following chemical structural formula:
- the phosphorus reagent is shown by the following general structure formula:
- R 4 is selected from one of methyl, ethyl, isopropyl or butyl;
- the solvent is selected from one of acetone, ethyl acetate, toluene, and N, N-dimethylformamide.
- the present invention has the following advantages compared with the prior art:
- the present invention uses an acetylene derivative as a starting material, and the raw materials are easily available and there are many types; the products obtained by the method of the present invention are of various types, which can be used directly or used in other further reactions.
- the present invention has mild reaction conditions, simple reaction operation and post-treatment process, high yield, especially no catalyst, and is suitable for large-scale production.
- Phenylacetylene (20.4mg, 0.2mmol), iodine compound (94.8mg, 0.3mmol), triethyl phosphite (99.4mg, 0.6mmol) were dissolved in 1mL acetone, the mixture was at 60 °C reaction;
- Phenylacetylene (20.4 mg, 0.2 mmol), iodine compound (94.8 mg, 0.3 mmol), trimethyl phosphite (99.2 mg, 0.8 mmol) were dissolved in 1 mL of acetone. The mixture reacts at 50 ° C;
- Phenylacetylene (20.4 mg, 0.2 mmol), iodine compound (94.8 mg, 0.3 mmol), tri-n-butyl phosphite (300 mg, 1.2 mmol) were dissolved in 1 mL of acetone. The mixture reacts at 30 ° C;
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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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种三氟甲基烯基膦酸酯衍生物及其制备方法,包括以下步骤:将乙炔衍生物、碘化合物、磷试剂溶于溶剂中,于室温~100℃下反应,获得三氟甲基烯基膦酸酯衍生物。本发明使用乙炔衍生物为起始物,原料易得、种类很多;利用本发明的方法得到的产物类型多样,既可以直接使用、又可以用于其他进一步的反应;同时,本发明公开的方法步骤短、反应条件温和、反应操作和后处理过程简单、产率高,适合于规模化生产。
Description
本发明属于有机化合物的制备技术领域,具体涉及一种三氟甲基烯基膦酸酯衍生物的制备方法。
有机膦酸酯具有很强的生物活性,作为杀虫剂、肾素和蛋白酶抑制剂等得到了广泛的应用。(参考文献1:Shidlovskii A F,Peregudov A S,Averkiev B B,et al,Three-component condensation of trifluoromethyl-substituted cyanovinylphosphonates,arylamines,and ketones and cytotoxic activity of products thus obtained,Russian Chemical Bulletin,2010,59,144.参考文献2:Dellaria Jr J F,Maki R G,Stein H H,et al,New inhibitors of renin that contain novel phosphostatine Leu-Val replacements,Journal of medicinal chemistry,1990,33,534.参考文献3Wester R T,Chambers R J,Green M D,et al,Preparation of a novel series of phosphonate norstatine renin inhibitors,Bioorganic & Medicinal Chemistry Letters,1994,4,2005.参考文献4Arai T,Bougauchi M,Sasai H,et al,Catalytic asymmetric synthesis ofα-hydroxy phosphonates using the Al-Li-BINOL complex,The Journal of organic chemistry,1996,61,2926.)。在有机膦酸酯分子中引入三氟甲基后其活性会进一步提高,三氟甲基烯基膦酸酯含有多种重要的官能团,具有各种潜在的生理活性,此外,可以作为重要的原料应用于各种化学合成中,但是现有制备方法存在原料难得、步骤多、反应条件苛刻、需要用到剧毒品氯化亚砜和溴等问题。
发明内容
本发明的目的是提供一种制备三氟甲基烯基膦酸酯衍生物的方法,其具有步骤短、反应条件温和、产率高、普适性好的优点,从原料出发一步即可合成产物。
为达到上述发明目的,本发明采用的技术方案是:
一种三氟甲基烯基膦酸酯衍生物的制备方法,包括以下步骤:将乙炔衍生物、碘化合物、磷试剂溶于溶剂中,于室温~100℃下反应,获得三氟甲基烯基膦酸酯衍生物;
所述乙炔衍生物如下列化学结构通式所示:
其中R
1选自芳基、氰基或酯基中的一种;R
2选自氢、氰基或酯基中的一种;
所述碘化合物如下列化学结构式所示:
所述磷试剂如下列结构通式所示:
P(OR
4)
3
其中R
4选自:甲基、乙基、异丙基或丁基中的一种。
优选的,所述芳基如下列化学结构通式所示:
其中R
3选自:烷基、烷氧基、卤素、硝基、三氟甲基、酯基中的一种;对应的乙炔衍生物为芳基炔烃,如下列化学结构通式所示:
本发明所述三氟甲基烯基膦酸酯衍生物如下列结构通式所示:
本发明中,所述溶剂选自:丙酮、乙酸乙酯、甲苯、N,N-二甲基甲酰胺中的一种。
上述技术方案中,所述乙炔衍生物选自:苯乙炔、4-甲基苯乙炔、4-甲氧基苯乙炔、4-氟苯乙炔、4-氯苯乙炔、4-溴苯乙炔、4-硝基苯乙炔、4-甲氧基羰基苯乙炔、4-氰基苯乙炔、1-三氟甲基-2-氰基乙炔、2-乙炔基噻吩、2-溴苯乙炔、3-氟苯乙炔中的一种;所述磷试剂选自:亚磷酸三甲酯、亚磷酸三乙酯、亚磷酸三正丁酯中的一种。
上述技术方案中,利用薄层层析色谱(TLC)跟踪反应直至完全结束。
上述技术方案中,按摩尔比:乙炔衍生物∶碘化合物∶磷试剂为1∶1.5∶(3~7)。
上述技术方案中,反应结束后对产物进行柱层析分离提纯处理。
本发明还公开了乙炔衍生物、碘化合物、磷试剂作为原料在制备三氟甲基烯基膦酸酯衍生物中的应用,优选的,所述制备在溶剂存在下进行。
上述技术方案中,将乙炔衍生物、碘化合物、磷试剂溶于溶剂中,于室温~100℃下反应,获得三氟甲基烯基膦酸酯衍生物;
所述乙炔衍生物如下列化学结构通式所示:
其中R
1选自芳基、氰基或酯基中的一种;R
2选自氢、氰基或酯基中的一种;
所述碘化合物如下列化学结构式所示:
所述磷试剂如下列结构通式所示:
P(OR
4)
3
其中R
4选自:甲基、乙基、异丙基或丁基中的一种;
所述溶剂选自:丙酮、乙酸乙酯、甲苯、N,N-二甲基甲酰胺中的一种。
上述技术方案的反应过程可表示为:
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:
1.本发明使用乙炔衍生物为起始物,原料易得、种类很多;利用本发明的方法得到的产物类型多样,既可以直接使用、又可以用于其他进一步的反应。
2.本发明反应条件温和、反应操作和后处理过程简单,产率高,尤其是不需要催化剂,适合于规模生产。
下面结合实施例对本发明作进一步描述:
实施例中,所述碘化合物如下列化学结构式所示:
实施例一:(1-苯基-2-三氟甲基)乙烯基膦酸二乙酯的合成
以苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入苯乙炔(20.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(99.4mg,0.6mmol)溶于1mL丙酮中,混合物于60℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率93%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.54–7.36(m,3H),7.30(dd,J=6.7,2.8Hz,2H),6.81(dq,J=23.0,7.7Hz,1H),4.27–4.01(m,4H),1.41–1.24(m,6H);HRMS(ESI-TOF)m/z:(M+Na)计算值331.0687,实测值331.0691。
实施例二:(1-(4-甲苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-甲基苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-甲基苯乙炔(23.2mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(132.8mg,0.8mmol)溶于1mL丙酮中,混合物于50℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率87%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.17(q,J=8.2Hz,3H),6.74(dq,J=23.0,7.7Hz,1H),4.18–3.95(m,4H),2.37(s,3H),1.28(t,J=7.1Hz,6H).HRMS(ESI-TOF)m/z:(M+Na)计算值345.0843,实测值345.0857。
实施例三:(1-(4-甲氧基苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-甲氧基苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-甲氧基苯乙炔(26.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(166mg,1.0mmol)溶于1mL乙酸乙酯中,混合物于40℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率83%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.20(dd,J=8.7,1.9Hz,2H),6.90(t,J=5.5Hz,2H),6.70(dq,J=23.0,7.8Hz,1H),4.12–4.02(m,4H),3.81(s,3H),1.27(t,J=7.1Hz,6H).HRMS(ESI-TOF)m/z:(M+H)计算值339.0973,实测值339.0984。
实施例四:(1-(4-氟苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-氟苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-氟苯乙炔(24mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(199.2mg,1.2mmol)溶于1mL乙酸乙酯中。混合物于室温反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率75%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.32–7.20(m,2H),7.07(dd,J=15.4,7.0Hz,2H),6.75(dq,J=22.8,7.6Hz,1H),4.23–3.99(m,4H),1.28(t,J=12.3,6.0Hz,6H).HRMS(ESI-TOF)m/z:(M+Na)计算值349.0593,实测值349.0600。
实施例五:(1-(4-氯苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-氯苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-氯苯乙炔(27.2mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(232mg,1.4mmol)溶于1mL乙酸乙酯中。混合物于70℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率77%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.37–7.33(m,2H),7.24–7.15(m,2H),6.75(dq,J=22.9,7.6Hz,1H),4.13–4.04(m,4H),1.31–1.25(m,6H).HRMS(ESI-TOF)m/z:(M+H)计算值343.0478,实测值343.0485。
实施例六:(1-(4-溴苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-溴苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-溴苯乙炔(36.2mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(99.4mg,0.6mmol)溶于1mL甲苯中。混合物于100℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率81%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.50(d,J=8.2Hz,2H),7.12(dd,J=8.5,1.9Hz,2H),6.74(dq,J=22.9,7.6Hz,1H),4.12–4.03(m,4H),1.27(t,J=7.1Hz,6H).HRMS(ESI-TOF)m/z:(M+Na)计算值408.9792,实测值8.9810。
实施例七:(1-(4-氰基苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-氰基苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-氰基苯乙炔(25.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(166mg,1.0mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于室温反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率88%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.67(t,J=7.2Hz,2H),7.37(dd,J=8.3,1.7Hz,2H),6.79(dq,J=22.8,7.5Hz,1H),4.16–4.07(m,4H),1.29(t,J=7.1Hz,6H).HRMS(ESI-TOF)m/z:(M+Na)计算值356.0639,实测值356.0645。
实施例八:(1-(4-硝基苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-硝基苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-硝基苯乙炔(29.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(166mg,1.0mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于90℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率82%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ8.28(d,J=8.3Hz,2H),7.46(dd,J=8.7,1.8Hz,2H),6.85(dq,J=22.7,7.5Hz,1H),4.21–4.07(m,4H),1.31(t,J=7.0Hz,6H);HRMS(ESI-TOF)m/z:(M+H)计算值354.0718,实测值354.0731。
实施例九:(1-(4-甲氧基羰基苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以4-甲氧基羰基苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入4-甲氧基羰基苯乙炔(32mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(199.2mg,1.2mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于80℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率81%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ8.07(d,J=8.1Hz,2H),7.35(dd,J=8.3,1.7Hz,2H),6.80(dq,J=22.9,7.6Hz,1H),4.17–4.03(m,4H),3.94(s,3H),1.29(t,J=7.1Hz,6H);HRMS(ESI-TOF)m/z:(M+H)计算值367.0922,实测值367.0935。
实施例十:(1-苯基-2-三氟甲基)乙烯基膦酸二甲酯的合成
以苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入苯乙炔(20.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷 酸三甲酯(99.2mg,0.8mmol)溶于1mL丙酮中。混合物于50℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率81%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.43–7.33(m,3H),7.26(dd,J=7.8,4.3Hz,2H),6.79(dq,J=23.0,7.6Hz,1H),3.74(d,J=11.1Hz,6H);HRMS(ESI-TOF)m/z:(M+Na)计算值303.0374,实测值303.0381。
实施例十一:(1-苯基-2-三氟甲基)乙烯基膦酸二丁酯的合成
以苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入苯乙炔(20.4mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三正丁酯(300mg,1.2mmol)溶于1mL丙酮中。混合物于30℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率71%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.45–7.33(m,3H),7.31–7.19(m,2H),6.76(dq,J=23.0,7.7Hz,1H),4.11–3.91(m,4H),1.66–1.51(m,4H),1.40–1.24(m,4H),0.88(t,J=7.4Hz,6H);HRMS(ESI-TOF)m/z:(M+H)计算值365.1493,实测值365.1505。
实施例十二:(1-氰基-2,2-二(三氟甲基)乙烯基膦酸二乙酯的合成
以1-三氟甲基-2-氰基乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入1-三氟甲基-2-氰基乙炔(23.6mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(99.4mg,0.6mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于60℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率77%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ4.54–4.30(m,4H),1.22(t,J=7.4Hz,6H);HRMS(ESI-TOF)m/z:(M+H)计算值326.0381,实测值326.0392。
实施例十三:(1-(噻吩-2-基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以2-乙炔基噻吩作为原料,其反应步骤如下:
(1)在反应瓶中加入2-乙炔基噻吩(21.6mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(99.4mg,0.6mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于室 温反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率84%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.50–7.40(m,1H),7.19(t,J=2.5Hz,1H),7.06(dd,J=6.5,2.2Hz,1H),6.79(dq,J=22.3,7.9Hz,1H),4.18–4.07(m,4H),1.30(t,J=7.1Hz,6H);HRMS(ESI-TOF)m/z:(M+Na)计算值337.0251,实测值337.0263。
实施例十四:(1-(2-溴苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以2-溴苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入2-溴苯乙炔(36mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(199.2mg,1.2mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于40℃反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率93%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.48–7.43(m,1H),7.36–7.29(m,2H),7.25–7.20(m,1H),6.88(dq,J=22.6,7.5Hz,1H),4.23–4.08(m,4H),1.33(t,J=10.6,7.0,0.4Hz,6H).HRMS(ESI-TOF)m/z:(M+H)计算值386.9973,实测值386.9984。
实施例十五:(1-(3-氟苯基)-2-三氟甲基)乙烯基膦酸二乙酯的合成
以3-氟苯乙炔作为原料,其反应步骤如下:
(1)在反应瓶中加入3-氟苯乙炔(24mg,0.2mmol),碘化合物(94.8mg,0.3mmol),亚磷酸三乙酯(199.2mg,1.2mmol)溶于1mL N,N-二甲基甲酰胺中。混合物于室温反应;
(2)TLC跟踪反应直到反应完全结束;
(3)反应结束后粗产物经硅胶柱层析(石油醚∶丙酮=1∶8)分离得到产物(产率8%),产物的分析数据如下:
1H NMR(400MHz,CDCl
3):δ7.34–7.19(m,2H),7.05(dd,J=15.4,7.0Hz,2H),6.74(dq,J=22.8,7.6Hz,1H),4.22–4.01(m,4H),1.27(t,J=12.3,6.0Hz,6H).HRMS(ESI-TOF)m/z:(M+Na)计算值349.0593,实测值349.0586。
Claims (10)
- 根据权利要求1所述三氟甲基烯基膦酸酯衍生物的制备方法,其特征在于,所述溶剂选自:丙酮、乙酸乙酯、甲苯、N,N-二甲基甲酰胺中的一种。
- 根据权利要求1所述三氟甲基烯基膦酸酯衍生物的制备方法,其特征在于,所述乙炔衍生物选自:苯乙炔、4-甲基苯乙炔、4-甲氧基苯乙炔、4-氟苯乙炔、4-氯苯乙炔、4-溴苯乙炔、4-硝基苯乙炔、4-甲氧基羰基苯乙炔、4-氰基苯乙炔、1-三氟甲基-2-氰基乙炔、2-乙炔基噻吩、2-溴苯乙炔、3-氟苯乙炔中的一种;所述磷试剂选自:亚磷酸三甲酯、亚磷酸三乙酯、亚磷酸三正丁酯中的一种。
- 根据权利要求1所述三氟甲基烯基膦酸酯衍生物的制备方法,其特征在于,利用薄层层析色谱跟踪反应直至完全结束。
- 根据权利要求1所述三氟甲基烯基膦酸酯衍生物的制备方法,其特征在于,按摩尔比:乙炔衍生物∶碘化合物∶磷试剂为1∶1.5∶(3~7)。
- 乙炔衍生物、碘化合物、磷试剂作为原料在制备三氟甲基烯基膦酸酯衍生物中的应用。
- 根据权利要求7所述的应用,其特征在于,在溶剂存在下,乙炔衍生物、碘化合物、磷试剂作为原料制备三氟甲基烯基膦酸酯衍生物。
- 根据权利要求8所述的应用,其特征在于,将乙炔衍生物、碘化合物、磷试剂溶于溶剂中,于室温~100℃下反应,获得三氟甲基烯基膦酸酯衍生物。
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MAJI, ARUN ET AL.: "Direct Synthesis of alpha- Trifluoromethyl Ketone from (Hetero)arylacetylene: Design, Intermediate Trapping, and Mechanistic Investigations", ORGANIC LETTERS, vol. 16, no. 17, 15 August 2014 (2014-08-15), pages 4524 - 4527, XP055702982 * |
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