CN114456065A - Synthesis method of carinic acid diester compound and carinic acid derivative - Google Patents
Synthesis method of carinic acid diester compound and carinic acid derivative Download PDFInfo
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- CN114456065A CN114456065A CN202111593446.6A CN202111593446A CN114456065A CN 114456065 A CN114456065 A CN 114456065A CN 202111593446 A CN202111593446 A CN 202111593446A CN 114456065 A CN114456065 A CN 114456065A
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- Prior art keywords
- acid
- caronic
- caronic acid
- reacting
- acid derivative
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- -1 diester compound Chemical class 0.000 title claims abstract description 51
- 238000001308 synthesis method Methods 0.000 title claims abstract description 23
- 239000002253 acid Substances 0.000 title claims description 13
- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical class CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 claims abstract description 72
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 42
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 21
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 14
- YYPNJNDODFVZLE-UHFFFAOYSA-N 3-methylbut-2-enoic acid Chemical class CC(C)=CC(O)=O YYPNJNDODFVZLE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- CXCXTEMZMJZMJX-UHFFFAOYSA-M (2-methoxy-2-oxoethyl)-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC(=O)OC)C1=CC=CC=C1 CXCXTEMZMJZMJX-UHFFFAOYSA-M 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 19
- 229940011051 isopropyl acetate Drugs 0.000 claims description 19
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052698 phosphorus Inorganic materials 0.000 claims description 14
- 239000011574 phosphorus Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 150000005690 diesters Chemical class 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- FZIBCCGGICGWBP-UHFFFAOYSA-N methyl 3-methylbut-2-enoate Chemical compound COC(=O)C=C(C)C FZIBCCGGICGWBP-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- SOGXBRHOWDEKQB-UHFFFAOYSA-N benzyl 2-chloroacetate Chemical compound ClCC(=O)OCC1=CC=CC=C1 SOGXBRHOWDEKQB-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 3
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 3
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims description 3
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- NEMOJKROKMMQBQ-UHFFFAOYSA-N dimethyl 2-bromopropanedioate Chemical compound COC(=O)C(Br)C(=O)OC NEMOJKROKMMQBQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- GSJFXBNYJCXDGI-UHFFFAOYSA-N methyl 2-hydroxyacetate Chemical compound COC(=O)CO GSJFXBNYJCXDGI-UHFFFAOYSA-N 0.000 claims description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 claims 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 claims 1
- 229950006874 kainic acid Drugs 0.000 claims 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004494 ethyl ester group Chemical group 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 239000012071 phase Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- JHLHKCWPDVKWNS-UHFFFAOYSA-N 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid Chemical compound CC1=NOC(C=2C(=CC=CC=2)C(O)=O)=N1 JHLHKCWPDVKWNS-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 101710118538 Protease Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- UTXVCHVLDOLVPC-UHFFFAOYSA-N ethyl 3-methylbut-2-enoate Chemical compound CCOC(=O)C=C(C)C UTXVCHVLDOLVPC-UHFFFAOYSA-N 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- PXIMQGSMXJFQOF-UHFFFAOYSA-N triphenyl(propan-2-yl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C)C)C1=CC=CC=C1 PXIMQGSMXJFQOF-UHFFFAOYSA-N 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
-
- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention relates to a synthesis method of a caronic acid diester compound and a caronic acid derivative, belonging to the technical field of organic synthesis, wherein the synthesis method of caronic acid dimethyl ester comprises the following steps: 1) reacting alpha-haloacetate with triphenylphosphine to prepare a phosphine ylide intermediate; 2) reacting the phosphine ylide intermediate obtained in the step 1) with a 3, 3-dimethylacrylic acid derivative to obtain a caronic acid diester compound; the caronic acid derivative is obtained by reacting the caronic acid diester compound with tetrabutylammonium bromide. The invention utilizes cheap alpha-haloacetic ester such as ethyl methyl bromoacetate, methyl chloroacetate and the like to react with triphenylphosphine to prepare phosphine ylide, and further reacts with cheap 3, 3-dimethylacrylic acid derivatives such as: reacting 3, 3-dimethyl methyl acrylate and ethyl ester to obtain a caronic acid diester compound, and further preparing the caronic acid derivative by using the caronic acid diester compound as a raw material. 1. The raw materials are easy to obtain, cheap and available in large quantity, 2, the reaction path is short, 3, dangerous reaction is not involved, and the production safety coefficient is high.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a caronic acid diester compound and a caronic acid derivative.
Background
Compound (I)
And the protecting group derivative is a key intermediate for synthesizing Hepatitis C (HCV) therapeutic drugs, namely the Boceprevir and 2019 coronavirus disease (COVID-19) therapeutic drug PF-07321332.
PF-07321332 is an oral compound developed autonomously by pfizer to inhibit the replication of new coronaviruses in humans. In vitro experiments prove that PF-07321332 can specifically inhibit 3CL endoprotease, thereby inhibiting virus replication in human body. The oral medicament Paxlovid can effectively reduce severe and death events for new coronary patients with mild and moderate symptoms but without hospitalization, and the protection efficiency reaches 89%.
The caronic acid, caronic anhydride and derivatives are key raw materials for synthesizing the compound. The compounds are generally obtained by the following route:
the diesters of caronic acid include various alcohol-substituted diester compounds such as:
the caronic acid and the derivatives thereof comprise caronic acid, caronic acid monoester, caronic anhydride, caronic imide and the like, such as:
existing synthetic route
Generally obtained by oxidation and ring closure of chrysanthemate compounds. The method is difficult to obtain, high in cost and much in dangerous waste.
Or the method of inserting isopropyl group into sulfur ylide has the defect that a large amount of malodorous and virulent dimethyl sulfide is used, so that the method has potential huge environmental hazard risks.
Disclosure of Invention
The invention aims to overcome the technical defects and provide a synthesis method of a caronic acid diester compound and a caronic acid derivative, which utilizes cheap alpha-haloacetate such as ethyl methyl bromoacetate, methyl chloroacetate and the like to react with triphenylphosphine to prepare phosphine ylide, and further reacts with cheap 3, 3-dimethylacrylic acid derivatives such as: reacting 3, 3-dimethyl methyl acrylate and ethyl ester to obtain a caronic acid diester compound, and further preparing the caronic acid derivative by using the caronic acid diester compound as a raw material.
The reaction scheme is as follows (which is only one example and does not limit the scope of the invention)
The technical scheme of the invention is as follows:
a synthesis method of a carinic acid diester compound is obtained by reacting a phosphine ylide intermediate with a 3, 3-dimethylacrylic acid derivative, and the synthesis route is as follows:
the phosphine ylide intermediate can be prepared by the preparation method in the prior art, and can also be isopropyl triphenylphosphine ylide sold in the market, which is not limited here.
Further, the 3, 3-dimethylacrylic acid derivative comprises one or more of 3, 3-dimethylacrylic acid methyl ester, 3-dimethylacrylic acid ethyl ester, tert-butyl ester compounds and benzyl ester compounds.
Further, the synthesis method of the diester caronate compound comprises the following steps:
1) reacting alpha-haloacetate with triphenylphosphine to prepare a phosphine ylide intermediate;
2) reacting the phosphine ylide intermediate obtained in the step 1) with a 3, 3-dimethylacrylic acid derivative to obtain a caronic acid diester compound;
the synthetic route is as follows:
further, the alpha-halogenated acetate is one or more of methyl chloroacetate, ethyl chloroacetate, tert-butyl chloroacetate, benzyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, tert-butyl bromoacetate, methyl hydroxyacetate, methanesulfonate, p-toluenesulfonate, easily decarboxylated dimethyl chloropropionate and dimethyl bromomalonate.
Further, the air conditioner is provided with a fan,
the step 1) is to prepare (methoxycarbonylmethyl) triphenyl phosphonium halide by taking alpha-haloacetate and triphenylphosphine as raw materials; then (methoxycarbonylmethyl) triphenyl phosphonium chloride reacts with alkali to obtain phosphine ylide intermediate.
In the above synthesis method, the preparation method of the phosphorus ylide intermediate may be a preparation method disclosed in the prior art, and is not limited herein, and as a preferred embodiment, the preparation method of the phosphorus ylide intermediate includes the following steps:
A. preparation of (methoxycarbonylmethyl) triphenylphosphonium halide: preparing (methoxycarbonylmethyl) triphenyl phosphonium halide by using alpha-haloacetate and triphenylphosphine as raw materials;
B. preparation of phosphorus ylide intermediate: reacting isopropyl triphenyl phosphonium halide with alkali to obtain a phosphorus ylide intermediate;
further, the selection of the base is not limited, and as a preferred technical scheme, the base is one or more of LiHMDS, NaHMDS, KHMDS, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, LDA, butyl lithium, phenyl lithium, methylsulfinyl carbanion, sodium amide, lithium diisopropylamide, sodium carbonate, sodium ethoxide, potassium tert-butoxide and sodium hydride.
Further, in the above-mentioned case,
the step A is as follows:
dropwise adding the alpha-haloacetate solution into the triphenylphosphine solution at the temperature of-20-150 ℃, and reacting for more than 3 hours to obtain a (methoxycarbonylmethyl) triphenyl phosphonium chloride solution;
the reaction temperature is not limited, and in the prior art, the selectable temperatures can be, preferably-20 to 150 ℃, and the temperatures in the range are acceptable, such as-20 ℃, 15 ℃, 10 ℃, 5 ℃, 0 ℃, 5 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 140 ℃, 150 ℃ and the like.
The reaction time is not limited, and may be 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, and the like, or may be longer.
Further, filtering, washing and drying can be carried out to obtain (methoxycarbonylmethyl) triphenyl phosphonium chloride powder;
further, the solvent of the alpha-haloacetate solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, tertiary butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl tertiary butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane and petroleum ether.
Further, the reaction time is more than 6 h;
further, the reaction time was 12 h.
Further, in the above-mentioned case,
the step B) is as follows:
preparation of phosphorus ylide intermediate:
dropwise adding alkali liquor into the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution at the temperature of-15-150 ℃; reacting for more than 0.5h to obtain a phosphorus ylide intermediate;
the reaction temperature is not limited, and in the prior art, any temperature can be selected, preferably-15 to 150 ℃, and the temperatures in this range are acceptable, for example, -15 ℃, 10 ℃, 5 ℃, 0 ℃, 5 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃ and the like.
The reaction time is not limited, but may be longer than 0.5h, 0.6h, 0.7h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, and the like.
Further, the solvent of the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, tertiary butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl tertiary butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane and petroleum ether.
Further, the reaction time was 1 h.
The patent also discloses a synthetic method of the caronic acid derivative, which comprises the following steps:
the caronic acid diester compound obtained by the method is used as a raw material to prepare the caronic acid derivative. The preparation method is a preparation method in the prior art, and as a preferable technical scheme, the synthesis method of the caronic acid derivative comprises the following steps:
the preparation method comprises the following steps of reacting the prepared caronic acid diester compound with tetrabutylammonium bromide (for the selection of the substance, a substance commonly used by a person skilled in the art in the prior art, such as tetrabutylammonium hydroxide or benzyltriethylammonium chloride, without limitation) under an alkaline condition, wherein the reaction temperature is 20-90 ℃, the reaction time is more than 0.5h, cooling and separating liquid, retaining the aqueous phase, adjusting the pH of the aqueous phase to 2-3, filtering, washing with water to obtain caronic acid (part I), extracting the filtrate with isopropyl acetate (for the selection of the extracting agent, a substance commonly used by a person skilled in the art, such as ethyl acetate, methyl tert-butyl ether and toluene, without limitation), drying, concentrating and crystallizing to obtain caronic acid (part II), and combining and metering two parts of caronic acid to obtain the product caronic acid.
Wherein the content of the first and second substances,
tetrabutylammonium bromide can also be replaced by tetrabutylammonium hydroxide or benzyltriethylammonium chloride;
isopropyl acetate may also be replaced by ethyl acetate, methyl tert-butyl ether, toluene;
further, hydrochloric acid is adopted to adjust the pH value, further, the hydrochloric acid is 35% hydrochloric acid,
further, the synthesis method of the caronic acid derivative comprises the following steps:
adding purified water into the caronic acid derivative prepared by the method at the temperature of 0-30 ℃, adding tetrabutyl ammonium bromide, adding alkali liquor, reacting for more than 0.5h at the temperature of 20-90 ℃, cooling, separating liquid, retaining a water phase, adjusting the pH of the water phase to 2-3 by hydrochloric acid, filtering, washing to obtain caronic acid (part I), extracting filtrate by isopropyl acetate, drying, concentrating and crystallizing to obtain caronic acid (part II), and combining and metering the two parts of caronic acid to obtain the caronic acid product.
Further, the synthesis method of the caronic acid derivative comprises the following steps:
purified water (800g) and tetrabutylammonium bromide (2g) are added to the caronic acid derivative prepared by the method at the temperature of 20-30 ℃, and a 30% sodium hydroxide solution (295g, 2.97mol) is dropwise added. After the addition, the temperature was raised to 80 ℃ to react for 1.5 hours. And cooling and separating. And (3) retaining the water phase, adjusting the pH of the water phase to 2-3 by using 35% hydrochloric acid, filtering, washing and drying to obtain the caronic acid (part I). The filtrate is extracted by isopropyl acetate (800g), concentrated and crystallized after being dried to obtain the caronic acid (part II), and the two parts of the caronic acid are combined and measured to obtain the product caronic acid.
The invention discloses a synthesis method of a carinic acid diester compound and a carinic acid derivative, which utilizes cheap alpha-haloacetic ester such as ethyl methyl bromoacetate, methyl chloroacetate and the like to react with triphenylphosphine to prepare phosphine ylide, and further reacts with cheap 3, 3-dimethylacrylic acid derivatives such as: reacting 3, 3-dimethyl methyl acrylate and ethyl ester to obtain a caronic acid diester compound, and further preparing the caronic acid derivative by using the caronic acid diester compound as a raw material. 1. The raw materials are easy to obtain, cheap and available in large quantity, 2, the reaction path is short, 3, dangerous reaction is not involved, and the production safety coefficient is high.
Drawings
FIG. 1 shows KLS HNMR 400MHz DMSO-d of caronic acid in example
FIG. 2 shows dimethyl carbazinate KLSZ HNMR 400MHz CDCl3 in example
Detailed Description
The present invention is further illustrated by the following specific examples, it should be noted that, for those skilled in the art, variations and modifications can be made without departing from the principle of the present invention, and these should also be construed as falling within the scope of the present invention.
A synthesis method of a carinic acid diester compound is obtained by reacting a phosphine ylide intermediate with a 3, 3-dimethylacrylic acid derivative, and the synthesis route is as follows:
in some embodiments, the 3, 3-dimethylacrylic acid derivative comprises one or more of methyl 3, 3-dimethylacrylate, ethyl 3, 3-dimethylacrylate, tert-butyl ester compounds and benzyl ester compounds.
A synthesis method of a carinic acid diester compound comprises the following steps:
1) reacting alpha-haloacetate with triphenylphosphine to prepare a phosphine ylide intermediate; in some embodiments, the α -haloacetate is one or more of methyl chloroacetate, ethyl chloroacetate, t-butyl chloroacetate, benzyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, t-butyl bromoacetate. 2) Reacting the phosphine ylide intermediate obtained in the step 1) with a 3, 3-dimethylacrylic acid derivative to obtain a caronic acid diester compound;
the synthetic route is as follows:
in some embodiments, step 1) is to prepare a (methoxycarbonylmethyl) triphenyl phosphonium halide starting from an α -haloacetate and triphenylphosphine; then (methoxycarbonylmethyl) triphenyl phosphonium chloride reacts with alkali to obtain phosphine ylide intermediate.
In the above synthesis method, the preparation method of the phosphine ylide intermediate may be a preparation method disclosed in the prior art, and is not limited herein, and as a preferred technical solution, in some embodiments, the preparation method of the phosphine ylide intermediate includes the following steps:
A. preparation of (methoxycarbonylmethyl) triphenylphosphonium halide: preparing (methoxycarbonylmethyl) triphenyl phosphonium halide by using alpha-haloacetate and triphenylphosphine as raw materials;
B. preparation of phosphorus ylide intermediate: reacting isopropyl triphenyl phosphonium halide with alkali to obtain a phosphorus ylide intermediate;
the base is not limited in its choice, and as a preferred embodiment, the base is one or more of LiHMDS, NaHMDS, KHMDS, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, LDA, butyllithium, phenyllithium, methylsulfinylcarbanion, sodium amide, lithium diisopropylamide, sodium carbonate, sodium ethoxide, potassium tert-butoxide, and sodium hydride.
In some embodiments, the step a is: dropwise adding the alpha-haloacetate solution into the triphenylphosphine solution at the temperature of-20-150 ℃, and reacting for more than 3 hours to obtain a (methoxycarbonylmethyl) triphenyl phosphonium chloride solution; in some embodiments, the solvent of the α -haloacetate solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, t-butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl t-butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane, petroleum ether.
In some embodiments, the (methoxycarbonylmethyl) triphenyl phosphonium chloride powder can be obtained by filtering, washing and drying;
the step B) is as follows:
preparation of phosphorus ylide intermediate:
dropwise adding alkali liquor into the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution at the temperature of-15-150 ℃; reacting for more than 0.5h to obtain a phosphorus ylide intermediate; in some embodiments, the solvent of the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, tert-butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl tert-butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane, petroleum ether.
A synthetic method of a caronic acid derivative comprises the following steps:
the caronic acid diester compound obtained by the method is used for preparing the caronic acid derivative. The preparation method is a preparation method in the prior art, and as a preferred technical scheme, in some embodiments, the synthesis method of the caronic acid derivative comprises the following steps:
the caronic acid diester compound prepared by the method reacts with tetrabutylammonium bromide under the alkaline condition, the reaction temperature is 20-90 ℃, the reaction time is more than 0.5h, the solution is cooled and separated, the water phase is reserved, the pH value of the water phase is adjusted to 2-3, the filtering and the washing are carried out to obtain caronic acid (part I), the filtrate is extracted by isopropyl acetate, the caronic acid (part II) is obtained by drying, concentrating and crystallizing, and the two parts of caronic acid are combined and measured to obtain the product caronic acid. In some embodiments, the pH is adjusted with hydrochloric acid, which is 35% hydrochloric acid,
in some embodiments, tetrabutylammonium bromide may also be replaced with tetrabutylammonium hydroxide or benzyltriethylammonium chloride;
in some embodiments, isopropyl acetate may also be replaced with ethyl acetate, methyl tert-butyl ether, toluene;
in some embodiments, the synthesis method of the caronic acid derivative is:
adding purified water into the caronic acid derivative prepared by the method at the temperature of 0-30 ℃, adding tetrabutyl ammonium bromide, adding alkali liquor, reacting for more than 0.5h at the temperature of 20-90 ℃, cooling, separating liquid, retaining a water phase, adjusting the pH of the water phase to 2-3 by hydrochloric acid, filtering, washing to obtain caronic acid (part I), extracting filtrate by isopropyl acetate, drying, concentrating and crystallizing to obtain caronic acid (part II), and combining and metering the two parts of caronic acid to obtain the caronic acid product.
In other embodiments, the synthesis method of the caronic acid derivative comprises:
purified water (800g) and tetrabutylammonium bromide (2g) are added to the caronic acid derivative prepared by the method at the temperature of 20-30 ℃, and a 30% sodium hydroxide solution (295g, 2.97mol) is dropwise added. After the addition, the temperature was raised to 80 ℃ to react for 1.5 hours. And cooling and separating. And (3) retaining the water phase, adjusting the pH of the water phase to 2-3 by using 35% hydrochloric acid, filtering, washing and drying to obtain the caronic acid (part I). The filtrate is extracted by isopropyl acetate (800g), concentrated and crystallized after being dried to obtain the caronic acid (part II), and the two parts of the caronic acid are combined and measured to obtain the product caronic acid.
Example 1:
preparation of (methoxycarbonylmethyl) triphenylphosphonium chloride
Toluene (2L) and triphenylphosphine (1.93kg 7.37mol) were added to a 5L reaction flask in this order. Stirring was started and methyl 2-chloroacetate (0.8kg 7.37mol) was added dropwise at 30 ℃. After the addition, the temperature is raised to 110 ℃ for reflux reaction for 12 hours. After completion, the mixture was cooled to 20 ℃ and filtered. The filter cake was washed with cold toluene and dried to give (methoxycarbonylmethyl) triphenyl phosphonium chloride as a solid powder (2.38kg yield 87%).
Preparation of ylide intermediates
A5L reaction flask was charged with anhydrous tetrahydrofuran (1000ml), and (methoxycarbonylmethyl) triphenylphosphonium chloride (300g809mmol), under nitrogen protection, and 20% potassium tert-butoxide/tetrahydrofuran solution (463g 825mmol) was added dropwise at 30 ℃. The addition was completed in about 1 hour. Heating to 60 ℃ for reaction for 1 hour, and obtaining a ylide intermediate suspension after the reaction is finished, wherein the obtained turbid solution is used for later use.
Preparation of Carbonic acid dimethyl ester
Methyl 3, 3-dimethacrylate (92.3g809mmol) was added dropwise to a 5L reaction flask containing the ylide suspension from the previous step at 0 ℃ over about 1 hour. After the addition, the temperature was raised to reflux and the reaction was carried out for 5 hours. After confirming complete conversion, the solvent was concentrated under reduced pressure. Dichloromethane (800g) was added, purified water (800g) was stirred for separation, the organic phase was dried over sodium sulfate and the concentrate. Using petroleum ether: silica gel column chromatography with an eluent in the ratio of ethyl acetate 20:1 to 10:1 gave dimethyl carbazonate (143.1g yield 95%). HNMR 400MHz, CDCl3:δ3.57(s, 6H; OCH3),1.79(s, 2H; CH),1.29(s, 3H; CH3),1.11(s, 3H; CH3) ppm. See in particular fig. 2.
Example 2:
preparation of Caronic acid
Toluene (2L) and triphenylphosphine (1.93kg 7.37mol) were added to a 5L reaction flask in this order. Stirring was started and methyl 2-chloroacetate (0.8kg 7.37mol) was added dropwise at 30 ℃. After the addition, the temperature is raised to 110 ℃ for reflux reaction for 12 hours. After completion, the mixture was cooled to 20 ℃ and filtered. The filter cake was washed with cold toluene and dried to give (methoxycarbonylmethyl) triphenyl phosphonium chloride as a solid powder (2.38kg yield 87%).
Toluene (2000ml), and (methoxycarbonylmethyl) triphenylphosphonium chloride (500g, 1.35mol) were charged in a 5L reaction flask, and under nitrogen protection, a 30% potassium tert-butoxide/methanol solution (248g, 1.38mol) was added dropwise at 30 ℃. The addition was completed in about 1 hour. The temperature was raised to 70 ℃ to react for 1 hour. After the reaction is finished, the temperature is reduced to 20 ℃. Methyl 3, 3-dimethacrylate (153.9g, 1.35mol) was added dropwise to the reaction system with stirring, and the addition was completed in about 1 hour. After the addition, the temperature was raised to 80 ℃ and the reaction was carried out for 5 hours.
After the conversion is finished, the temperature is reduced to 20-30 ℃, purified water (800g) and tetrabutylammonium bromide (2g) are added, and 30% sodium hydroxide solution (295g and 2.97mol) is dropwise added. After the addition, the temperature was raised to 80 ℃ to react for 1.5 hours. And cooling and separating. And (3) retaining the water phase, adjusting the pH of the water phase to 2-3 by using 35% hydrochloric acid, filtering, washing and drying to obtain the caronic acid (part I). The filtrate was extracted with isopropyl acetate (800g), dried and concentrated to give caronic acid (part II) which was metered in two portions (196g, 92% yield). HNMR 400MHz, DMSO-d:. delta. 12.10(s, 2H; COOH),1.84(s, 2H; CH),1.30(s, 3H; CH3),1.13(s, 3H; CH3) ppm. See figure 1 for details.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Variations or modifications in other variations may occur to those skilled in the art based upon the foregoing description. Not all embodiments need be illustrated or described herein. And obvious variations or modifications of this embodiment may be made without departing from the spirit or scope of the invention.
Claims (10)
1. A synthesis method of a carinic acid diester compound is characterized in that the compound is obtained by reacting a phosphine ylide intermediate with a 3, 3-dimethylacrylic acid derivative, and the synthesis route is as follows:
2. the method for synthesizing a diester caronate compound according to claim 1,
the 3, 3-dimethylacrylic acid derivative comprises one or more of 3, 3-dimethylacrylic acid methyl ester, 3-dimethylacrylic acid ethyl ester, tert-butyl ester compounds and benzyl ester compounds.
3. The synthesis method of the diester caronate compound according to claim 1 or 2, characterized by comprising the following steps:
1) reacting alpha-haloacetate with triphenylphosphine to prepare a phosphine ylide intermediate;
2) reacting the phosphine ylide intermediate obtained in the step 1) with a 3, 3-dimethylacrylic acid derivative to obtain a caronic acid diester compound;
the synthetic route is as follows:
4. the method for synthesizing a diester caronate compound according to claim 3,
the alpha-halogenated acetate is one or more of methyl chloroacetate, ethyl chloroacetate, tert-butyl chloroacetate, benzyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, tert-butyl bromoacetate, methyl hydroxyacetate, methanesulfonate, p-toluenesulfonate, dimethyl chloropropionate easy to decarboxylate and dimethyl bromomalonate.
5. The method for synthesizing a diester caronate compound according to claim 3,
the step 1) is to prepare (methoxycarbonylmethyl) triphenyl phosphonium halide by taking alpha-haloacetate and triphenylphosphine as raw materials; then (methoxycarbonylmethyl) triphenyl phosphonium chloride reacts with alkali to obtain phosphine ylide intermediate.
6. The method for synthesizing a diester of kainic acid according to any one of claims 3-5, wherein,
the preparation method of the phosphine ylide intermediate comprises the following steps:
A. preparation of (methoxycarbonylmethyl) triphenylphosphonium halide: preparing (methoxycarbonylmethyl) triphenyl phosphonium halide by using alpha-haloacetate and triphenylphosphine as raw materials;
B. preparation of phosphorus ylide intermediate: reacting isopropyl triphenyl phosphonium halide with alkali to obtain a phosphorus ylide intermediate;
7. the method for synthesizing a diester caronate compound according to claim 6,
the alkali is one or more of LiHMDS, NaHMDS, KHMDS, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, LDA, butyl lithium, phenyl lithium, methylsulfinyl carbanion, sodium amide, lithium diisopropylamide, sodium carbonate, sodium ethoxide, potassium tert-butoxide and sodium hydride.
8. The method for synthesizing a diester caronate compound according to claim 6,
the step A is as follows:
dropwise adding the alpha-haloacetate solution into the triphenylphosphine solution at the temperature of-20-150 ℃, and reacting for more than 3 hours to obtain a (methoxycarbonylmethyl) triphenyl phosphonium chloride solution;
further, filtering, washing and drying can be carried out to obtain (methoxycarbonylmethyl) triphenyl phosphonium chloride powder;
further, the solvent of the alpha-haloacetate solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, tertiary butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl tertiary butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane and petroleum ether;
further, the reaction time is more than 6 h;
further, the reaction time is 12 h;
the step B) is as follows:
preparation of phosphorus ylide intermediate:
dropwise adding alkali liquor into the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution at the temperature of-15-150 ℃; reacting for more than 0.5h to obtain a phosphorus ylide intermediate;
further, the solvent of the (methoxycarbonylmethyl) triphenyl phosphonium chloride solution is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, toluene, xylene, ethanol, tertiary butanol, methanol, DMSO, DMF, n-butanol, ethylene glycol dimethyl ether, methyl cyclopentyl ether, methyl tertiary butyl ether, isopropyl acetate, dichloromethane, n-hexane, n-heptane and petroleum ether;
further, the reaction time was 1 h.
9. A synthetic method of a caronic acid derivative is characterized by comprising the following steps:
preparing the caronic acid derivative by using the caronic acid diester compound obtained in any one of claims 1-8 as a raw material.
10. The method for synthesizing a caronic acid derivative according to claim 9, wherein the method comprises the following steps:
reacting the carinic acid diester compound obtained in any one of claims 1-8 with tetrabutylammonium bromide under an alkaline condition, wherein the reaction temperature is 20-90 ℃, the reaction time is more than 0.5h, cooling and separating liquid, retaining a water phase, adjusting the pH value of the water phase to 2-3, filtering, washing to obtain carinic acid (part I), extracting filtrate with isopropyl acetate, drying, concentrating and crystallizing to obtain the carinic acid (part II); combining and metering the two parts of the caronic acid to obtain a product caronic acid;
wherein the content of the first and second substances,
tetrabutylammonium bromide can also be replaced by tetrabutylammonium hydroxide or benzyltriethylammonium chloride;
isopropyl acetate may also be replaced by ethyl acetate, methyl tert-butyl ether, toluene;
further, hydrochloric acid is adopted to adjust the pH value, further, the hydrochloric acid is 35% hydrochloric acid,
further, the synthesis method of the caronic acid derivative comprises the following steps:
adding purified water, tetrabutylammonium bromide and alkali liquor into the caronic acid derivative prepared by the method at the temperature of 0-30 ℃, reacting for more than 0.5h at the temperature of 20-90 ℃, cooling, separating liquid, retaining a water phase, adjusting the pH of the water phase to 2-3 by hydrochloric acid, filtering, washing to obtain caronic acid (part I), extracting filtrate by isopropyl acetate, drying, concentrating and crystallizing to obtain caronic acid (part II), and combining and metering the two parts of caronic acid to obtain a product caronic acid;
further, the synthesis method of the caronic acid derivative comprises the following steps:
purified water (800g) and tetrabutylammonium bromide (2g) are added to the caronic acid derivative prepared by the method at the temperature of 20-30 ℃, and a 30% sodium hydroxide solution (295g, 2.97mol) is dropwise added. After the addition, heating to 80 ℃ for reaction for 1.5 hours, cooling, separating liquid, retaining a water phase, adjusting the pH of the water phase to 2-3 by using 35% hydrochloric acid, filtering, washing with water, and drying to obtain the caronic acid (part I); the filtrate is extracted by isopropyl acetate (800g), concentrated and crystallized after being dried to obtain the caronic acid (part II), and the two parts of the caronic acid are combined and measured to obtain the product caronic acid.
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| GB1596030A (en) * | 1976-12-30 | 1981-08-19 | Roussel Uclaf | Esters of formyl cyclopropane carboxylic acids |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115477576A (en) * | 2022-08-04 | 2022-12-16 | 杭州国瑞生物科技有限公司 | Preparation method of caronic acid |
| CN115477576B (en) * | 2022-08-04 | 2024-02-09 | 杭州国瑞生物科技有限公司 | Preparation method of Carlongic acid |
| CN115417767A (en) * | 2022-09-13 | 2022-12-02 | 江苏南大光电材料股份有限公司 | Preparation method of caronic anhydride and intermediate thereof |
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