CN109503657B - Synthesis method of 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester - Google Patents
Synthesis method of 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester Download PDFInfo
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- CN109503657B CN109503657B CN201811531121.3A CN201811531121A CN109503657B CN 109503657 B CN109503657 B CN 109503657B CN 201811531121 A CN201811531121 A CN 201811531121A CN 109503657 B CN109503657 B CN 109503657B
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- 238000001308 synthesis method Methods 0.000 title claims description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 42
- 239000002994 raw material Substances 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 alkyl imidazole iodide Chemical compound 0.000 claims description 35
- 238000003786 synthesis reaction Methods 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 239000002608 ionic liquid Substances 0.000 claims description 21
- RLZMYANQLOCZOB-UHFFFAOYSA-M tributyl(methyl)phosphanium;iodide Chemical compound [I-].CCCC[P+](C)(CCCC)CCCC RLZMYANQLOCZOB-UHFFFAOYSA-M 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
- LSMAIBOZUPTNBR-UHFFFAOYSA-N phosphanium;iodide Chemical group [PH4+].[I-] LSMAIBOZUPTNBR-UHFFFAOYSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 235000021466 carotenoid Nutrition 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001747 carotenoids Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- UGJYMKZYSUMAKJ-YSMVHXPUSA-N Neurosporaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC=C(/C)C(=O)O UGJYMKZYSUMAKJ-YSMVHXPUSA-N 0.000 claims description 3
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 claims description 3
- XREPTGNZZKNFQZ-UHFFFAOYSA-M 1-butyl-3-methylimidazolium iodide Chemical compound [I-].CCCCN1C=C[N+](C)=C1 XREPTGNZZKNFQZ-UHFFFAOYSA-M 0.000 claims description 2
- IKQCDTXBZKMPBB-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;iodide Chemical compound [I-].CCN1C=C[N+](C)=C1 IKQCDTXBZKMPBB-UHFFFAOYSA-M 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- SXQCPXKZTFJHQI-UHFFFAOYSA-N 2-hydroxy-2-methylbut-3-enoic acid Chemical compound C=CC(O)(C)C(O)=O SXQCPXKZTFJHQI-UHFFFAOYSA-N 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 1
- 239000002699 waste material Substances 0.000 abstract description 8
- 239000000047 product Substances 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000007858 starting material Substances 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 11
- 239000006227 byproduct Substances 0.000 description 11
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 150000008282 halocarbons Chemical class 0.000 description 9
- UNSIKXJBHRTIOD-UHFFFAOYSA-N ethyl 2-hydroxy-2-methylbut-3-enoate Chemical compound CCOC(=O)C(C)(O)C=C UNSIKXJBHRTIOD-UHFFFAOYSA-N 0.000 description 8
- GRFXGVMQYVLZJJ-UHFFFAOYSA-N methyl 2-hydroxy-2-methylbut-3-enoate Chemical compound COC(=O)C(C)(O)C=C GRFXGVMQYVLZJJ-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000001577 simple distillation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 5
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000005826 halohydrocarbons Chemical class 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229940117360 ethyl pyruvate Drugs 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KLFPUNSMDACYOK-UHFFFAOYSA-N 1-butyl-3-methyl-1,2-dihydroimidazol-1-ium;iodide Chemical compound [I-].CCCC[NH+]1CN(C)C=C1 KLFPUNSMDACYOK-UHFFFAOYSA-N 0.000 description 1
- COELWDHEVBNFLF-UHFFFAOYSA-N 1-ethyl-3-methyl-2H-imidazole hydroiodide Chemical compound I.CCN1CN(C)C=C1 COELWDHEVBNFLF-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ATFVTAOSZBVGHC-UHFFFAOYSA-N Glycolaldehyde dimer Chemical compound OC1COC(O)CO1 ATFVTAOSZBVGHC-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- UAYWVJHJZHQCIE-UHFFFAOYSA-L Zinc iodide Inorganic materials I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000004808 allyl alcohols Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N hydroxymethylethylene Natural products OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 150000003751 zinc Chemical class 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
- C07F9/4015—Esters of acyclic unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)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
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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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
The invention discloses a method for synthesizing 4-dialkoxyphosphonyl-2-methyl-2-butenoic acid alkyl ester. The invention mixes 2-methyl-2-hydroxy-3-alkyl crotonate (I) with trialkyl phosphite under the condition of gas protection and catalyst existence, and heats and reacts to prepare 4-dialkoxyphosphonyl-2-methyl-2-alkyl crotonate. The method has the advantages of easily available raw materials, low price, few reaction steps, high yield, less waste discharge, easy treatment and easy realization of industrialization.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for synthesizing 4-dialkoxyphosphonyl-2-methyl-2-butenoic acid alkyl ester.
Background
4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester (structure shown in formula II':
) Is an important organic synthesis intermediate, and the main application of the compound is to synthesize the conjugated polyene carboxylic acid and the derivatives thereof through Horner-Wadsworth-Emmons reaction, in particular to the synthesis of beta-apo-8 '-carotenoic acid ethyl ester and beta-apo-4' -carotenoic acid ethyl ester in the carotenoid field.
Due to the importance of compound (II '), its synthesis has been studied since the 60's of the 20 th century. For the synthesis of this compound, many methods are reported in the literature, but the preparation of this compound with a phosphono structure requires the preparation of the corresponding halohydrocarbon, followed by the Michaelis-Arbuzov reaction. The following are representative four synthetic methods in the prior art:
(1) US4937308 reports a synthesis process starting from ethyl 2-vinyl propionate, in particular: performing addition reaction on the 2-vinyl ethyl propionate and halogen, and removing one molecule of hydrogen halide under an alkaline condition to obtain 2-methyl-4-halogen-2-ethyl crotonate; and finally, carrying out Michaelis-Arbuzov reaction on the triethyl phosphite to obtain a target product. The reaction scheme is as follows:
(2) US5717128 reports a synthesis method using ethyl 2-methyl-2-hydroxy-3-butenoate as an intermediate. Specifically, the method comprises the following steps: carrying out isomerization and halogenation reaction on the 2-methyl-2-hydroxy-3-ethyl crotonate and phosphorus trihalide to obtain 2-methyl-4-halogen-2-ethyl crotonate; then, the triethyl phosphite is reacted with the catalyst to obtain a target product. The reaction scheme is as follows:
(3) CN104513164 reports a synthesis method using ethyl pyruvate as a raw material. Specifically, the method comprises the following steps: reacting ethyl pyruvate with a chloroethylene Grignard reagent to obtain 2-methyl-2-hydroxy-3-ethyl crotonate; then, reacting with hydrogen halide to obtain 2-methyl-4-halogen-2-ethyl crotonate; and finally, reacting with triethyl phosphite to obtain a target product. The reaction scheme is as follows:
(4) CN103113404 reports a synthetic method using 2-dihydrocarbyloxyphosphonoacetaldehyde as a raw material. Specifically, the method comprises the following steps: 2-dialkoxyphosphonyl acetaldehyde reacts with 2-triphenylphosphine ylide alkyl propionate to obtain a target product.
The synthetic route in this process appears to be free of halocarbons and Michaelis-Arbuzov reactions. In fact, the starting material 2-dihydrocarbyloxyphosphonoacetaldehyde of this route is synthesized by the Michaelis-Arbuzov reaction using a haloacetaldehyde and the corresponding phosphite. The synthetic route can be referred to as follows:
it follows that in the existing processes, the Michaelis-Arbuzov reaction is the step that the synthesis of compound (II) must go through. The classical Michaelis-Arbuzov reaction presents some insurmountable problems: (1) the halogenated hydrocarbon must be prepared firstly, the preparation process inevitably generates more wastes, such as the byproduct inorganic salt and phosphorous acid in the above route, and the halogen atom is finally discharged as the byproduct in the form of the halogenated hydrocarbon, which is not an indispensable part of the product; (2) the Michaelis-Arbuzov reaction is accompanied by the formation of a molecule of low boiling halohydrocarbon which can also undergo side reactions with the phosphite feedstock, continuously consuming the phosphite feedstock and producing another phosphonate by-product. As a result, environmentally unfriendly waste is generated, and the consumption of phosphite raw materials is increased, thereby increasing the synthesis cost of the product.
In response to the problems of the Michaelis-Arbuzov reaction itself, a number of reactions have been carried outAnd (5) improving the research. One important direction is to use alcohol compounds as starting materials and react them directly with phosphites to give the corresponding phosphonate products (without the need for halogenated hydrocarbons). However, most of the methods reported in the literature, such as J.org.chem.2011,76, 2875-2879 and org.Lett.,2011,13,1270-1273, require the use of an excess amount of activator (such as ZnBr)2，ZnI2Etc.), which also generate one molecule of halogenated hydrocarbon, generate a large amount of environmentally unfriendly waste (such as zinc salts, phosphonate by-products, etc.), and also increase the consumption of phosphite raw materials. Therefore, these methods do not fundamentally solve the problems.
The documents Green chem, 2018,20, 3408-one 3413 and patent CN106543221 report a method for synthesizing phosphonate by directly reacting alcohol compounds as raw materials with phosphite ester by using iodide salt as a catalyst. The method can obtain satisfactory effect only by using 2 mol% of the iodized salt, and no halohydrocarbon is generated, thereby well solving the problems of the Michaelis-Arbuzov reaction. However, in the synthesis of compound (II) by this method, it is necessary to use alkyl 4-hydroxy-2-methyl-2-butenoate (III) (structure shown below)
) As a starting material. At present, the compound (III) is synthesized by few methods, mainly by taking glycolaldehyde dimer as a raw material and carrying out Wittig reaction with 2-triphenylphosphine ylide alkyl propionate (such as WO2006039685, US2008221377, Angew. chem. int. Ed.,2018,57, 7240-. The hydrocarbyl 2-triphenylphosphine ylide propionate is typically prepared by reacting a hydrocarbyl 2-halopropionate with triphenylphosphine (Angew. chem. int. Ed.,2018,57, 7240-. It can be seen that the reaction also requires the use of halogenated hydrocarbons as raw materials, and triphenylphosphine oxide and inorganic salts produced by the reaction need to be disposed of as waste. Therefore, this method does not fundamentally solve the problem of synthesizing the compound (II)
As described above, in the synthesis methods of the compound (II) reported in the literature, halogenated hydrocarbons are required to be synthesized by Michaelis-Arbuzov reaction using halogenated hydrocarbons as raw materials, and this method inevitably generates one molecule of halogenated hydrocarbons and requires a large amount of waste disposal. The literature has already provided a method for efficiently synthesizing phosphonate ester by using an alcohol compound as a raw material and an iodonium salt as a catalyst. However, the problem of the Michaelis-Arbuzov reaction itself is solved, and the problem of the synthesis of the alcohol compound (III) is also brought.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the invention is to provide a method for synthesizing 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester, which has the advantages of few synthesis steps, high yield, less waste discharge, easy treatment and easy realization of industrialization.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
a method for synthesizing 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester comprises the following steps: under the conditions of gas protection and catalyst existence, 2-methyl-2-hydroxy-3-butenoic acid alkyl ester reacts with trialkyl phosphite to obtain 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester.
Compared with the prior art, the invention has the beneficial effects that:
(1) in the invention, quaternary phosphonium iodide salt or iodide salt ionic liquid is used as a catalyst, and the isomerization and phosphine esterification reaction of tertiary allyl alcohol are realized simultaneously.
(2) In the invention, the synthesis process of the raw material alcohol compound is mature, cheap and easy to obtain, and is beneficial to realizing industrial production.
(3) The invention does not need to use transition metal and ligand, the byproduct is alcohol, the waste discharge amount is less, the treatment is easy, and the influence on the environment is small.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In view of the problems of long reaction flow, multiple steps, difficult avoidance of halide byproduct generation/raw material application and the like existing in the synthesis of the existing 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester compound, the invention particularly provides a method for preparing the 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester compound by using 2-methyl-2-hydroxy-3-butenoic acid alkyl ester and trihydrocarbyl phosphite as raw materials and catalyzing by quaternary phosphonium iodide salt or iodide salt ionic liquid.
The synthetic route of the method is as follows:
the technical report of the prior literature indicates that the synthetic method of the 2-methyl-2-hydroxy-3-butenoic acid alkyl ester (I) is mature and has low cost, thus being more suitable for being used as a raw material. The compound of the formula (I) is used as a raw material in the invention, and the preparation cost of the product can be effectively reduced.
Meanwhile, as can be seen from the preparation reaction process of the invention, the byproduct for synthesizing the compound (II) by using the compound (I) as a raw material is only small molecular alcohol, so that the preparation method is green, environment-friendly and low in pollution, and has very important significance.
Specifically, in the above reaction of the present invention, the alkyl 2-methyl-2-hydroxy-3-butenoate is used
And trihydrocarbyl phosphites
The raw materials are reacted in the presence of catalyst (at least one of quaternary phosphonium iodide or iodide ionic liquid) to obtain the product 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester
And byproduct alcohol (R)2OH)。
Wherein the raw material is 2-methyl-2-hydroxy-3-butenoic acid alkyl ester
In, R1Is substituted or unsubstituted C1-C20Straight or branched alkyl of (2), C2-C20Linear or branched alkenyl of, C2-C20Straight-chain or branched alkynyl of, C3-C7Cycloalkyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any one of heteroaryl;
preferably, R1Is substituted or unsubstituted C1-C6Straight or branched alkyl of (2), C2-C6Linear or branched alkenyl of, C2-C6Straight-chain or branched alkynyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any of heteroaryl groups.
At the same time, the starting material trihydrocarbyl phosphite
In (1), substituted or unsubstituted C1-C20Straight or branched alkyl of (2), C2-C20Linear or branched alkenyl of, C2-C20Straight-chain or branched alkynyl of, C3-C7Cycloalkyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any one of heteroaryl;
preferably, R2Is substituted or unsubstituted C1-C6Straight or branched alkyl of (2), C2-C6Linear or branched alkenyl of, C2-C6Straight-chain or branched alkynyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any one of heteroaryl;
wherein, in the trihydrocarbyl phosphite, R is different2May each independently optionally be the same or different; preferably, in the starting trihydrocarbyl phosphite, three R' s2Are all the same.
As in the above two starting materials, the term "substituted" in the definition of the respective starting compounds means that one or more substitutable hydrogen atoms in a given structure are substituted with a particular substituent, that a substituted group may have one substituent at each substitutable position of the group, and that when more than one position in a given formula can be substituted with one or more substituents of a particular group, then the substituents may be substituted at each position, identically or differently.
Preferably, the substituents as described above are preferably C1-C20More preferably C1-C6Linear or branched alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, octyl, etc.).
Meanwhile, in the present invention, the following are recited in the definition of each raw material compound: "C1-C6Straight-chain or branched alkyl "means a straight-chain or branched saturated alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, octyl, etc.; "C2-C6Straight-chain or branched alkenyl "means a straight-chain or branched unsaturated alkenyl group having 2 to 6 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, octenyl and the like; "C2-C6Straight-chain or branched alkynyl denotes straight-chain or branched unsaturated alkynyl having 2 to 6 carbon atoms, e.g. ethynyl, propynyl, butynyl, isobutynyl, pentynylAlkynyl, octynyl and the like; "C3-C7Cycloalkyl "denotes cyclic alkyl containing only two elements from 3 to 7 carbon atoms containing carbon and hydrogen, such as cyclopropyl, 2-methylcyclopropyl, cyclopentyl, etc.; "C5-C12Aryl "represents a cyclic group having aromatic character having 5 to 12 carbon atoms, such as benzene ring, etc.; "C5-C12Heteroaryl "denotes a cyclic group having aromaticity containing 5 to 12 carbon atoms and 1 or more heteroatoms including, but not limited to, oxygen atom (O), sulfur atom (S), nitrogen atom (N), such as pyrrolidinyl, pyridylalkyl, etc.
The raw material, which is a 2-methyl-2-hydroxy-3-butenoic acid alkyl ester, having any of the structures described above
(I) And trihydrocarbyl phosphites
Under the condition of protective gas and catalysis of a catalyst, the product 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester is obtained
And byproduct alcohol (R)2OH)。
In the product and by-product compounds, R1、R2The definitions are the same as in the starting compounds; preferably, in the product and by-product, each R is2Are all the same; more preferably, in the present invention, the product, alkyl 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoate is: 4-Dimethoxyphosphonyl-2-methyl-2-butenoic acid methyl ester (corresponding to R in the starting materials and products)1、R2Both methyl), 4-diethoxyphosphonyl-2-methyl-2-butenoic acid methyl ester (corresponding to R in the starting materials and the product)1Is methyl, R2Is ethyl), 4-diisopropoxyphosphonyl-2-methyl-2-butenoic acid methyl ester (corresponding to R in the starting materials and products)1Is methyl, R2Is isopropyl), 4-dimethoxyphosphono-2-methyl-2-butenoic acid ethyl ester (corresponding to R in the starting materials and products)1Is ethyl, R2Is methyl), 4-diethoxyPhosphono-2-methyl-2-butenoic acid ethyl ester (corresponding to R in the starting materials and products)1、R2Both are ethyl), or 4-diisopropoxyphosphonyl-2-methyl-2-butenoic acid ethyl ester (corresponding to R in the starting materials and products)1Is ethyl, R2Is isopropyl).
In some embodiments of the invention, as in the above reaction, the shielding gas used is nitrogen or an inert gas; preferably nitrogen.
In some embodiments of the invention, the starting trihydrocarbyl phosphite is reacted as above
With 2-methyl-2-hydroxy-3-butenoic acid alkyl ester
The molar ratio of (0.8-3) to (1), such as 1:1,1.2:1,1.4:1,1.5:1,2:1,2.2:1, 2.5:1, etc.; preferably (1-1.4): 1.
in some embodiments of the present invention, as in the above reaction, the catalyst used is at least one of quaternary phosphonium iodide or iodide ionic liquids;
wherein the quaternary phosphonium iodide salt comprises: at least one of tributyl methyl phosphonium iodide or methyl triphenyl phosphonium iodide; preferably, the quaternary phosphonium iodide salt comprises tributyl methyl phosphonium iodide;
the iodide ionic liquid comprises: at least one of imidazole/alkyl imidazole iodide ionic liquid, pyridine/alkyl pyridine iodide ionic liquid, piperidine/alkyl piperidine iodide ionic liquid, or morpholine/alkyl morpholine iodide ionic liquid; preferably, the iodide ionic liquid comprises: at least one of imidazole/alkyl imidazole iodide ionic liquids; more preferably, the iodide ionic liquid comprises at least one of 1-butyl-3-methylimidazole iodide salt or 1-ethyl-3-methylimidazole iodide salt.
In some embodiments of the invention, the catalyst is reacted with 2-methyl-2-hydroxy-3-butenoic acid alkyl ester as above
The molar ratio of (0.0001-1): 1, for example, 0.001: 1,0.005:1,0.1: 1, 0.5:1, etc.; preferably (0.001-0.1): 1.
in some embodiments of the present invention, the above reaction may be carried out in a solvent system (i.e., the reaction is carried out by dispersing the starting materials in a solvent), or may be carried out under non-solvent conditions; preferably, the reaction as above is carried out under non-solvent conditions;
wherein, when the reaction is carried out in a solvent system, the solvent used is an inert solvent such as hexane, carbon tetrachloride, dichloroethane, etc.
In some embodiments of the present invention, in the above reaction, the reaction temperature is 70 to 150 ℃ and the reaction time is 1 to 60 hours; preferably, the reaction temperature is 100-130 ℃, and the reaction time is 8-30 h.
Furthermore, the 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester prepared by the method can also be used as a raw material and further used for preparing carotenoid compounds such as beta-apo-8 '-carotenoic acid ethyl ester or beta-apo-4' -carotenoic acid ethyl ester and the like.
In the following specific examples, starting materials methyl 2-methyl-2-hydroxy-3-butenoate and ethyl 2-methyl-2-hydroxy-3-butenoate can be synthesized according to the method provided in US 4596889.
EXAMPLE 14 Synthesis of methyl-dimethoxyphosphono-2-methyl-2-butenoate
To a 1000ml three-necked flask, methyl 2-methyl-2-hydroxy-3-butenoate (260.28g, 2mol), trimethyl phosphite (272.98g, 2.2mol) and tributylmethylphosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirrer and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 110 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 12h, the 2-methyl-2-hydroxy-3-butenoic acid methyl ester was completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 407.13g of product with the purity of 98.2 percent and the yield of 90.0 percent. The reaction route is as follows:
the nuclear magnetism and mass spectrum detection results of the product 4-dimethoxyphosphono-2-methyl-2-butenoic acid methyl ester are as follows:
1H NMR(600MHz,CDCl3)δ6.72-6.76(m,1H),3.75(d,J＝11.2Hz,6H),3.73(s,3H),2.77(dd,J＝23.8,8.0Hz,2H),1.88(d,J＝4.5Hz,3H).
13C NMR(150MHz,CDCl3)167.21(d,J＝3.1Hz),130.71(d,J＝10.2Hz),129.46(d,J＝11.5Hz),52.39(d,J＝7.0Hz),51.37,26.01(d,J＝139.4Hz),12.6(d,J＝3.1Hz).
ESI-MS:223.5(M+H)+,221.7(M-H)-.
examples 2 to 14
The procedure of example 1 was repeated to fix the amount of methyl 2-methyl-2-hydroxy-3-butenoate, and to change the reaction temperature, the amount of trimethyl phosphite, and the kind and amount of catalyst, to obtain the results shown in Table 1 below.
TABLE 1 results of examples 2 to 14
| Examples | Temperature/. degree.C | P(OMe)3Amount of (A) to be used | The type and amount of catalyst | Yield/% |
| 2 | 100 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (0.69g,0.002mol) | 85.3 |
| 3 | 120 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (0.69g,0.002mol) | 90.5 |
| 4 | 130 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (0.69g,0.002mol) | 88.4 |
| 5 | 110 | 297.79g,2.4mol | Tributyl methyl phosphonium iodide (0.69g,0.002mol) | 91.8 |
| 6 | 110 | 248.15g,2.0mol | Tributyl methyl phosphonium iodide (0.69g,0.002mol) | 84.2 |
| 7 | 110 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (0.17g,0.0005mol) | 80.7 |
| 8 | 110 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (0.34g,0.001mol) | 88.4 |
| 9 | 110 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (1.36g,0.004mol) | 92.1 |
| 10 | 110 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (2.72g,0.008mol) | 92.7 |
| 11 | 110 | 272.98g,2.2mol | Tributyl methyl phosphonium iodide (5.44g,0.016mol) | 93.1 |
| 12 | 110 | 272.98g,2.2mol | Methyltriphenylphosphonium iodide (0.81g,0.002mol) | 81.4 |
| 13 | 110 | 272.98g,2.2mol | 1-butyl-3-methylimidazolium iodide (0.53g,0.002mol) | 91.3 |
| 14 | 110 | 272.98g,2.2mol | 1-Ethyl-3-methylimidazolium iodide (0.48g,0.002mol) | 92.7 |
EXAMPLE 154 Synthesis of methyl diethoxyphosphonyl-2-methyl-2-butenoate
To a 1000ml three-necked flask, methyl 2-methyl-2-hydroxy-3-butenoate (260.28g, 2mol), triethyl phosphite (365.55g, 2.2mol) and tributyl methyl phosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirring and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 120 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 8h, the 2-methyl-2-hydroxy-3-butenoic acid methyl ester is completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 469.42g of product with the purity of 98.5 percent and the yield of 92.4 percent. The reaction route is as follows:
the nuclear magnetism and mass spectrum detection data of the product 4-diethoxyphosphonyl-2-methyl-2-butenoic acid methyl ester are as follows:
1H NMR(600MHz,CDCl3)δ6.73-6.78(m,1H),4.08-4.15(m,4H),3.74(s,3H),2.74(dd,J＝23.2,8.1Hz,2H),1.89(d,J＝4.2Hz,3H),1.25-1.38(m,6H).
13C NMR(150MHz,CDCl3)168.11(d,J＝3.2Hz),131.71(d,J＝13.2Hz),130.46(d,J＝11.2Hz),62.42(d,J＝6.7Hz),52.39,27.71(d,J＝138.4Hz),16.78(d,J＝6.0Hz),12.74(d,J＝2.8Hz).
ESI-MS:251.6(M+H)+,249.7(M-H)-.
example Synthesis of 164-Diisopropoxyphosphono-2-methyl-2-butenoic acid methyl ester
To a 1000ml three-necked flask, methyl 2-methyl-2-hydroxy-3-butenoate (260.28g, 2mol), triisopropyl phosphite (458.13g, 2.2mol) and tributylmethylphosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirrer and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 120 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 10h, the 2-methyl-2-hydroxy-3-butenoic acid methyl ester was completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 528.64g of product with the purity of 98.0 percent and the yield of 93.1 percent. The reaction route is as follows:
the nuclear magnetism and mass spectrum detection data of the product 4-diisopropoxyphosphonyl-2-methyl-2-butenoic acid methyl ester are as follows:
1H NMR(600MHz,CDCl3)δ6.63-6.68(m,1H),4.22-4.28(m,2H),3.72(s,3H),2.94(dd,J＝23.3,8.5Hz,2H),1.86(d,J＝4.7Hz,3H),1.37(d,J＝6.2Hz,6H)，1.27(d,J＝6.1Hz,6H).
13C NMR(150MHz,CDCl3)167.61(d,J＝3.4Hz),131.21(d,J＝13.5Hz),129.86(d,J＝12.2Hz),83.44(d,J＝6.9Hz),52.12,27.73(d,J＝128.4Hz),17.98(d,J＝6.0Hz),17.28(d,J＝6.3Hz),12.91(d,J＝3.1Hz).
ESI-MS:279.5(M+H)+,277.3(M-H)-.
example 174 Synthesis of Ethyl-dimethoxyphosphono-2-methyl-2-butenoate
To a 1000ml three-necked flask, ethyl 2-methyl-2-hydroxy-3-butenoate (288.34g, 2mol), trimethyl phosphite (272.98g, 2.2mol) and tributylmethylphosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirrer and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 110 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 12h, the ethyl 2-methyl-2-hydroxy-3-butenoate was completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 427.18g of product, the purity is 98.5%, and the yield is 89.1%. The reaction route is as follows:
the nuclear magnetic and mass spectrum detection data of the product 4-dimethoxyphosphono-2-methyl-2-ethyl crotonate are as follows:
1H NMR(600MHz,CDCl3)δ6.65-6.70(m,1H),4.10(q,J＝7.7Hz,2H),3.64(d,J＝10.7Hz,6H),2.98(dd,J＝23.1,8.8Hz,2H),1.85(d,J＝4.1Hz,3H),1.20(t,J＝7.4Hz,3H).
13C NMR(150MHz,CDCl3)167.35(d,J＝3.2Hz),131.43(d,J＝13.2Hz),130.01(d,J＝12.0Hz),61.27,52.58(d,J＝7.2Hz),29.14(d,J＝138.4Hz),17.10(d,J＝6.1Hz),12.51.
ESI-MS:237.5(M+H)+,235.4(M-H)-.
example 184 Synthesis of Ethyl diethoxyphosphonyl-2-methyl-2-butenoate
To a 1000ml three-necked flask, ethyl 2-methyl-2-hydroxy-3-butenoate (288.34g, 2mol), triethyl phosphite (365.55g, 2.2mol) and tributyl methyl phosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirring and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 120 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 12h, the ethyl 2-methyl-2-hydroxy-3-butenoate was completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 510.85g of product with the purity of 98.3 percent and the yield of 95.0 percent. The reaction route is as follows:
the nuclear magnetic and mass spectrum detection data of the product 4-diethoxyphosphonyl-2-methyl-2-butenoic acid ethyl ester are as follows:
1H NMR(600MHz,CDCl3)δ6.75-6.79(m,1H),4.21(q,J＝7.4Hz,2H),4.10-4.17(m,4H),2.76(dd,J＝23.2,7.8Hz,2H),1.90(d,J＝4.2Hz,3H),1.24-1.41(m,9H).
13C NMR(150MHz,CDCl3)167.38(d,J＝2.0Hz),131.90(d,J＝13.5Hz),130.07(d,J＝12.0Hz),62.20(d,J＝7.5Hz),60.77,27.58(d,J＝138.0Hz),16.43(d,J＝6.0Hz),14.23,12.60(d,J＝1.5Hz).
ESI-MS:265.8(M+H)+,263.5(M-H)-。
example 194 Synthesis of ethyl diisopropoxyphosphonyl-2-methyl-2-butenoate
To a 1000ml three-necked flask, ethyl 2-methyl-2-hydroxy-3-butenoate (288.34g, 2mol), triisopropyl phosphite (458.13g, 2.2mol), and tributylmethylphosphonium iodide (0.69g,0.002mol) were charged under a nitrogen atmosphere, and a mechanical stirrer and a simple distillation apparatus were installed. The stirring was started at 600r/min and heated to 120 ℃. During the reaction, the low boiling point material is continuously distilled and collected. Meanwhile, samples were taken every 1h for gas chromatography. After 12h, the ethyl 2-methyl-2-hydroxy-3-butenoate was completely converted. After the reaction is finished, the product is rectified, separated and purified to obtain 545.12g of product with the purity of 98.1 percent and the yield of 91.8 percent. The reaction route is as follows:
the nuclear magnetic and mass spectrum detection data of the product 4-diisopropoxyphosphonyl-2-methyl-2-ethyl crotonate are as follows:
1H NMR(600MHz,CDCl3)δ6.70-6.77(m,1H),4.27-4.35(m,2H),4.20(q,J＝7.5Hz,2H),2.82(dd,J＝23.6,8.2Hz,2H),1.87(d,J＝4.6Hz,3H),1.38(d,J＝6.3Hz,6H)，1.26(d,J＝6.5Hz,6H)，1.25(t,J＝7.9Hz,3H)；
13C NMR(150MHz,CDCl3)166.98(d,J＝2.4Hz),131.76(d,J＝13.2Hz),130.32(d,J＝12.3Hz),83.05(d,J＝6.3Hz),61.11,27.67(d,J＝138.9Hz),16.94(d,J＝6.5Hz),17.73(d,J＝6.8Hz),17.19(d,J＝6.5Hz),14.52.
ESI-MS:293.4(M+H)+,292.5(M-H)-。
while particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (16)
1. A method for synthesizing alkyl 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoate, which comprises the following steps:
under the conditions of protective atmosphere and catalyst existence, 2-methyl-2-hydroxy-3-butenoic acid alkyl ester reacts with trialkyl phosphite to obtain 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester;
the catalyst is at least one of quaternary phosphonium iodide or iodide ionic liquid;
the iodide ionic liquid is at least one of imidazole or alkyl imidazole iodide ionic liquid, pyridine or alkyl pyridine iodide ionic liquid, piperidine or alkyl piperidine iodide ionic liquid, or morpholine or alkyl morpholine iodide ionic liquid;
the molar ratio of the catalyst to the 2-methyl-2-hydroxy-3-butenoic acid alkyl ester is 0.001-0.1: 1.
2. The method of claim 1, wherein the alkyl 2-methyl-2-hydroxy-3-butenoate has the following structure (I);
in the formula (I), R1Is substituted or notSubstituted C1-C20Straight or branched alkyl of (2), C2-C20Linear or branched alkenyl of, C2-C20Straight-chain or branched alkynyl of, C3-C7Cycloalkyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any of heteroaryl groups.
3. The process of claim 2, wherein in formula (I), R is1Is substituted or unsubstituted C1-C6Straight or branched alkyl of (2), C2-C6Linear or branched alkenyl of, C2-C6Straight-chain or branched alkynyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any of heteroaryl groups.
4. A synthesis process according to claim 1, characterized in that the trihydrocarbyl phosphite is of the structure:
wherein R is2Is substituted or unsubstituted C1-C20Straight or branched alkyl of (2), C2-C20Linear or branched alkenyl of, C2-C20Straight-chain or branched alkynyl of, C3-C7Cycloalkyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any one of heteroaryl;
wherein the content of the first and second substances,R2independently optionally the same or different.
5. The method of synthesis of claim 4, wherein R is2Is substituted or unsubstituted C1-C6Straight or branched alkyl of (2), C2-C6Linear or branched alkenyl of, C2-C6Straight-chain or branched alkynyl of, C5-C12Aryl radical, C5-C12Heteroaryl, (C)1-C4Alkylene) -C5-C12Aryl, or (C)1-C4Alkylene) -C5-C12Any of heteroaryl groups.
6. The method of claim 1, wherein the quaternary phosphonium iodide salt is at least one of tributyl methyl phosphonium iodide or methyltriphenyl phosphonium iodide.
7. The method of claim 6, wherein the quaternary phosphonium iodide salt is tributyl methyl phosphonium iodide.
8. The method of claim 7, wherein the iodide ionic liquid is at least one of an imidazole or an alkyl imidazole iodide ionic liquid.
9. The synthesis method of claim 8, wherein the iodide ionic liquid is at least one of 1-butyl-3-methylimidazolium iodide or 1-ethyl-3-methylimidazolium iodide.
10. The method of claim 1, wherein the molar ratio of trihydrocarbyl phosphite to 2-methyl-2-hydroxy-3-butenoate is 0.8 to 3: 1.
11. The method of claim 10, wherein the molar ratio of trihydrocarbyl phosphite to 2-methyl-2-hydroxy-3-butenoate is 1-1.4: 1.
12. The synthesis method according to claim 1, wherein the reaction temperature is 70-150 ℃;
and/or the reaction time is 1-60 h.
13. The synthesis method according to claim 12, wherein the reaction temperature is 100-130 ℃;
and/or the presence of a gas in the gas,
the reaction time is 8-30 h.
14. The synthesis process according to claim 1, wherein the reaction is carried out in the absence of a solvent or an inert solvent.
15. The method of claim 14, wherein the reaction is carried out in the absence of a solvent.
16. A method for synthesizing carotenoid, characterized in that, in the method, 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester is firstly obtained according to the method of any one of claims 1 to 15, and then the carotenoid is obtained by using the 4-dihydrocarbyloxyphosphono-2-methyl-2-butenoic acid alkyl ester as raw material;
the carotenoid is beta-apo-8 '-carotenoic acid ethyl ester or beta-apo-4' -carotenoic acid ethyl ester.
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