CN111825546A - Synthesis method of piparidic acid - Google Patents
Synthesis method of piparidic acid Download PDFInfo
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- CN111825546A CN111825546A CN202010665264.4A CN202010665264A CN111825546A CN 111825546 A CN111825546 A CN 111825546A CN 202010665264 A CN202010665264 A CN 202010665264A CN 111825546 A CN111825546 A CN 111825546A
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- 239000002253 acid Substances 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- CNBFRBXEGGRSPL-UHFFFAOYSA-N 1,4-dibromopentane Chemical compound CC(Br)CCCBr CNBFRBXEGGRSPL-UHFFFAOYSA-N 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 150000007521 triprotic acids Chemical class 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 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 2
- 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 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims 2
- 229960004436 budesonide Drugs 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 15
- BXAHEDXQMMDMIQ-UHFFFAOYSA-N 7-bromo-2,2-dimethylheptanenitrile Chemical compound N#CC(C)(C)CCCCCBr BXAHEDXQMMDMIQ-UHFFFAOYSA-N 0.000 abstract description 4
- JQBOGCZVQIAXST-UHFFFAOYSA-N 8-hydroxy-2,2,14,14-tetramethylpentadecanedinitrile Chemical compound OC(CCCCCC(C#N)(C)C)CCCCCC(C#N)(C)C JQBOGCZVQIAXST-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 230000020477 pH reduction Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- -1 carboxylic acid compound Chemical class 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108010028554 LDL Cholesterol Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- IFWUSSSMHBKQAQ-UHFFFAOYSA-N methyl 7-bromo-2,2-dimethylheptanoate Chemical compound COC(=O)C(C)(C)CCCCCBr IFWUSSSMHBKQAQ-UHFFFAOYSA-N 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 102000004317 Lyases Human genes 0.000 description 2
- 108090000856 Lyases Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000007211 cardiovascular event Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- NHVXRVOYVVPVDU-UHFFFAOYSA-N 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid Chemical compound OC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(O)=O NHVXRVOYVVPVDU-UHFFFAOYSA-N 0.000 description 1
- BBBNHHFFABZOEK-UHFFFAOYSA-N 6-bromo-2,2-dimethylhexanenitrile Chemical compound N#CC(C)(C)CCCCBr BBBNHHFFABZOEK-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 206010008092 Cerebral artery thrombosis Diseases 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 229950002974 bempedoic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- LDURYVDWYUCWGK-UHFFFAOYSA-N diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate Chemical compound CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC LDURYVDWYUCWGK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- SYRIIFZUZOIRNU-UHFFFAOYSA-N ethyl 7-bromo-2,2-dimethylheptanoate Chemical compound CCOC(=O)C(C)(C)CCCCCBr SYRIIFZUZOIRNU-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- 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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of piparidic acid, which comprises the following steps: isobutyronitrile (ester) is used as a starting material and reacts with 2, 5-dibromopentane under the catalysis of alkali to generate 7-bromo-2, 2-dimethylheptanonitrile (ester), then the 7-bromo-2, 2-dimethylheptanonitrile (ester) and magnesium form a Grignard reagent, the Grignard reagent reacts with formate to generate 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedinitrile (ester), and finally the bipedane acid is obtained by alkali hydrolysis and acidification. The invention has short synthesis route, easily obtained raw materials, low cost, high reaction yield and high purity in each step, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of piparidic acid.
Background
Dyslipidemia is one of the important risk factors of cardiovascular diseases, and the rise of low-density lipoprotein cholesterol (LDL-C) is closely related to cardiovascular events such as acute myocardial infarction, cerebral arterial thrombosis and the like. The statins can effectively reduce the level of LDL-C and reduce the occurrence of ischemic cardiovascular events, and are the main drugs for the current lipid-regulating treatment. However, statins still have limitations in terms of safety, with the risk of dose-related muscle side effects, mainly manifested as rhabdomyolysis. The beteparic acid (Bempedoic acid) is a long-chain carboxylic acid compound with a structural formula
The oral small-molecule adenosine triphosphate-citrate lyase (ACL) inhibitor is an oral small-molecule inhibitor of ATP (adenosine triphosphate) -citrate lyase), can reduce the biosynthesis of cholesterol by up-regulating an LDL receptor, reduces the level of LDL-C, and can be used for treating dyslipidemia and reducing the risk of other cardiovascular diseases. Compared with the existing statins widely used clinically, the bemidic acid has the advantages of better tolerance and can be used for treating the LDL-C which cannot be controlled by the existing method when being combined with the statins.
At present, the synthesis of the bipedac acid mainly comprises the following routes:
the synthetic route is that of original research company published in patent WO2004067489, as follows:
in the route, ethyl isobutyrate and 1, 5-dibromopentane are used as initial raw materials and are condensed by LDA at low temperature to obtain ethyl 7-bromo-2, 2-dimethylheptanoate; the compound and p-methyl benzenesulfonyl methyl isonitrile are reacted under the action of strong alkali to obtain an addition product intermediate; then hydrolyzing under acidic condition to obtain 8-oxo-2, 2,14, 14-tetramethyl pentadecanedioic acid diethyl ester; then carrying out alkalization hydrolysis in an ethanol system, and then carrying out acidification to obtain 8-oxo-2, 2,14, 14-tetramethylpentadecanedioic acid; finally, sodium borohydride is used for reduction and acidification to obtain the product of the pimelic acid. The use of p-toluenesulfonylmethyl isonitrile in the second step of the route is more toxic; a large amount of sodium borohydride is used in the last step, a large amount of hydrogen is generated in the post-treatment process, and the material flushing danger is easy to occur. In addition, the reaction steps in the route are multiple, the yield of each step of reaction is low, and the reaction conditions are harsh, so the route is not easy for industrial production.
The second synthetic route is a synthetic route disclosed in chinese patent CN111170855A, and is as follows:
in the route, isobutyrate is taken as a starting material and is subjected to alkylation reaction with 1, 4-dihalogenated alkane to obtain a compound 1; condensing the compound 1 with acetone dicarboxylic acid diester to obtain a compound 2; then, carrying out alkaline hydrolysis on the compound 2 in an ethanol system and then acidifying to obtain a compound 3; finally, sodium borohydride is used for reduction to obtain the bipartite acid. In the first step of the route, because the hydrogen activity in isobutyrate is low and the reaction conditions are harsh, ultralow temperature reaction is required, and the yield is low; the second condensation reaction results in a low yield in this step due to selectivity and polysubstitution problems. Therefore, the route has the problems of low total yield, harsh reaction conditions and the like.
The third synthetic route is a synthetic route disclosed in chinese patent CN111285760A, and is shown as follows:
the method comprises the steps of taking 2-bromo-2, 2-dimethyl methyl propionate as a starting material, reacting with pinacol borate to prepare aliphatic borate, carrying out Suzuki-like coupling reaction with 1, 9-dibromononanone under the catalysis of noble metal to obtain a coupling product, and finally hydrolyzing with sodium borohydride to obtain the besidiric acid. In the route, no commercial products exist in both 1, 9-dibromononanone and 2-bromo-2, 2-dimethyl methyl propionate, and the two raw materials are synthesized under harsh reaction conditions and low yield; in the route, noble metals are used in the first step and the second step, so that the reaction cost is high; since the 1, 9-dibromononanone in the second step is non-unsaturated bromide and the boric acid is aliphatic, the Suzuki coupling reaction hardly occurs, because the Suzuki coupling reaction is only performed between arylboronic acid or boronic ester and arylbromide (Tetrahedron Lett.1979,36,3437-3440.), obviously, the structure of the reaction substrate does not meet the conditions, so the coupling reaction is difficult to perform or the yield is low.
In conclusion, the prior art method of the beradix has the problems that reaction raw materials are difficult to obtain, the cost is high, or the toxicity of the used raw materials is high; the reaction conditions are harsh or the reaction selectivity is not good, so that the reaction yield is low; the designed reaction is difficult to perform due to the mechanism. Therefore, a new synthesis process route of the besmead acid is urgently needed to be found, the raw materials are easy to obtain, the reaction conditions are mild, the reaction yield is high, and the method is suitable for industrialized production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel method for synthesizing the piparidic acid, which has the advantages of short steps, easily obtained raw materials, mild reaction conditions, high yield and high purity, and is suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows.
A synthesis method of pimelic acid comprises the following steps:
(1) reacting a compound shown in a formula (I) with 2, 5-dibromopentane under the catalysis of alkali to obtain a compound shown in a formula (II);
(2) forming a Grignard reagent by the compound of the formula (II) and magnesium, and reacting with HCOOR to obtain a compound of a formula (III);
(3) the compound of formula (III) is hydrolyzed with alkali and acidified to give the triprotic acid. The synthetic route is as follows:
wherein X in the compounds of formula (I), formula (II) and formula (III) is-CN or-COOR 1, R1 is C1-C6 chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, isopentyl, etc., preferably methyl, ethyl, n-propyl.
Wherein R in HCOOR is selected from alkyl, cycloalkyl, alkenyl and substituted phenyl, preferably alkyl, more preferably methyl.
The alkyl group as referred to herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, and the like.
The alkenyl group in the present invention refers to a straight chain or branched group having a double bond at the end and 2 to 6 carbon atoms, and includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
The cycloalkyl group as referred to herein means a saturated monocyclic cyclic hydrocarbon substituent having 3 to 6 carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The substituted phenyl refers to single substitution at any position or more than two substitutions at any position on a benzene ring. The substituent is selected from hydrogen, halogen, nitro, cyano and C1-4 alkyl.
The base in the step (1) is at least one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (HMDSLi), sodium bis (trimethylsilyl) amide (HMDSNa) and potassium bis (trimethylsilyl) amide (HMDSK), and is preferably sodium hydride.
The molar ratio of the alkali to the compound of the formula (I) in the step (1) is 1-5: 1, preferably 2-4: 1.
The solvent used in the reaction in the step (1) is one or a combination of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and 1, 4-dioxane, and preferably the solvent used in the reaction is tetrahydrofuran.
The reaction temperature in the step (1) is-78 ℃ to 10 ℃. Preferably, the reaction temperature is from-20 ℃ to 10 ℃.
The molar ratio of the Grignard reagent to the formate in the step (2) is 2.0-4.0: 1, preferably, the molar ratio of the Grignard reagent to the formate is 2-2.5: 1.
the temperature for preparing the Grignard reagent in the step (2) is reflux reaction, and the temperature for dripping the formic ether is-50 to 0 ℃, preferably-10 to 0 ℃.
The compound of formula (III) can be hydrolyzed with or without purification to yield the triprotic acid. Preferably, the compound of formula (iii) is capable of undergoing hydrolysis without purification to yield the betadiric acid.
The alkali hydrolyzed in the step (3) can be any one or combination of sodium hydroxide, potassium hydroxide and ammonia water, and is preferably sodium hydroxide. The solvent is an alcohol solvent, and is any one or combination of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.
The reaction temperature in the step (3) is 50-100 ℃, and preferably 60-90 ℃.
The acid in the step (3) is a base capable of neutralizing the reaction, such as hydrochloric acid and sulfuric acid, and the pH value in the reaction is controlled to be 1-2.
Further, the method also comprises the steps of post-treatment such as filtration, concentration and the like.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a new synthesis method of piparidic acid;
(2) the method has the advantages of short reaction steps, high yield and high purity of each step, and is suitable for industrial production;
(3) all the raw materials are easy to obtain, and the cost is low;
(4) the invention does not use toxic and dangerous raw materials, and the reaction is safer.
Detailed Description
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts () are given in units of 10-6 (ppm). NMR was measured using a Brucker AVANCE-400 NMR spectrometer using deuterated chloroform (CDCl3) as the solvent and Tetramethylsilane (TMS) as the internal standard.
MS was measured using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: FINNIGAN LCQAdvantage MAX).
Example 1
The first step is as follows: preparation of 7-bromo-2, 2-dimethylheptanonitrile
Under the protection of nitrogen, 50g (0.72mol,1.0eq) of isobutyronitrile and 300mL of tetrahydrofuran are added into a 1000mL four-neck flask, the temperature of a reaction system is slowly reduced to-20 ℃, 86.8g (2.17mol,3.0eq) of sodium hydride is added in batches, the temperature of the reaction system is controlled not to exceed-10 ℃, after the dropwise addition is finished, the stirring reaction is continued for 1 hour at-20 ℃, 166g (0.72mol,1.0eq) of 1, 5-dibromopentane is slowly added dropwise, the reaction temperature is controlled not to exceed-10 ℃ when the dropwise addition is finished, the reaction temperature is slowly increased to room temperature after the dropwise addition is finished, the stirring reaction is carried out overnight, and the conversion of raw materials is completely detected by GC. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (500mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 173g of a brown oil. The oily matter is distilled under reduced pressure at high temperature to obtain 152g of light yellow liquid 7-bromine-2, 2-dimethylhexanenitrile, the yield is 96.3 percent, and the GC purity is 98.9 percent.
MS m/z 217((M+H)+
Second step preparation of 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedinitrile
Under the protection of nitrogen, 12.36g (0.509mol,1.02eq) of activated magnesium powder and 300mL of anhydrous tetrahydrofuran are sequentially added into a 1000mL round-bottom flask, 0.1g of iodine simple substance is added, the temperature of a reaction system is raised to 40 ℃, 109g (0.50mol,1.0eq) of 7-bromo-2, 2-dimethylheptanonitrile is transferred into a constant-pressure dropping funnel, slowly dripping a little of 7-bromo-2, 2-dimethylheptanitrile under the protection of nitrogen, continuously and slowly dripping the rest part of 6-bromo-2, 2-dimethylhexanenitrile after violent reflux is found, and carrying out reflux reaction for 3 hours after the dripping is finished, the temperature of the reaction system is reduced to-10 ℃, 15.0g (0.25mol,0.5eq) of ethyl formate is slowly dropped, the temperature of the reaction system is controlled not to exceed 0 ℃, the temperature of the reaction system is raised to room temperature after dropping, and the reaction is carried out overnight (12 hours). The raw material was less than 0.5% by GC assay, extracted with saturated ammonium chloride, extracted with ethyl acetate (500 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 131g of 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedinitrile was obtained as a brown oil with a yield of 85.2%. The GC purity was 96.8%, impure and used directly in the next reaction.
The third step is the preparation of 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid
200mL of ethanol, 123g of 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedinitrile (0.4mol, 1.0eq) and 400mL of 3N sodium hydroxide solution are added into a 1000mL round bottom flask, the temperature value of a reaction system is increased, the reflux reaction is carried out overnight, the residual of the raw materials is less than 0.5 percent through GC detection, the ethanol is concentrated and removed, 1000mL of deionized water is added into the solution, the solution is extracted for 2 times by dichloromethane (200mL multiplied by 2), then the pH value of a water layer is adjusted to 1-2 by 3N hydrochloric acid, the stirring reaction is continued for half an hour, and 126g of white solid 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid is obtained through filtration and deionized water washing, the yield is 91.2 percent, and the purity is 99..
MS m/z 345((M+H)+
1H NMR(400MHz,CDCl3):(ppm):7.42(s,3H),3.59(s,1H),1.65-1.00(m,20H),1.18(s,12H)。
Example 2
First step preparation of methyl 7-bromo-2, 2-dimethylheptanoate
Under the protection of nitrogen, 74g (0.72mol,1.0eq) of methyl isobutyrate and 300mL of tetrahydrofuran are added into a 1000mL four-neck flask, the temperature of a reaction system is slowly reduced to-20 ℃, 86.8g (2.17mol,3.0eq) of sodium hydride is added in batches, the temperature of the reaction system is controlled not to exceed-10 ℃, after the dropwise addition is finished, the reaction is continuously stirred at-20 ℃ for 1 hour, 166g (0.72mol,1.0eq) of 1, 5-dibromopentane is slowly added dropwise, the reaction temperature is controlled not to exceed-10 ℃ when the dropwise addition is finished, the reaction temperature is slowly increased to room temperature after the dropwise addition is finished, the stirring reaction is carried out overnight (12 hours), and the raw materials are completely converted through GC detection. The reaction solution was quenched with saturated ammonium chloride, extracted with 500mL x 3 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 143g of a brown oil were obtained. The oily matter is distilled under reduced pressure at high temperature to obtain light yellow liquid methyl 7-bromo-2, 2-dimethylheptanoate 131g, the yield is 71.3 percent, and the GC purity is 99.2 percent.
MS m/z 251.0716(M+H)+
Second step methyl 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedicarboxylate
Under the protection of nitrogen, 12.36g (0.509mol,1.02eq) of activated magnesium powder and 300mL of anhydrous tetrahydrofuran are sequentially added into a 1000mL round-bottom flask, 0.1g of iodine simple substance is added, the temperature of a reaction system is raised to 40 ℃, 118g of 7-bromo-2, 2-dimethylheptanoic acid methyl ester is transferred into a constant-pressure dropping funnel, slowly dripping a little of 7-bromo-2, 2-dimethyl methyl heptanoate under the protection of nitrogen, continuously and slowly dripping the rest part of 7-bromo-2, 2-dimethyl methyl heptanoate after violent reflux is found, carrying out reflux reaction for 3 hours after the dripping is finished, reducing the temperature of the reaction system to-10 ℃, slowly adding 18.0g (0.25mol,0.5eq) of ethyl formate dropwise, controlling the temperature of the reaction system not to exceed 0 ℃, raising the temperature of the reaction system to room temperature after dropwise addition, and reacting overnight. The raw material was less than 0.5% by GC assay, extracted with saturated ammonium chloride, extracted with ethyl acetate (500 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. 135g of methyl 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedicarboxylate as a brown oil was obtained in a yield of 88.2%. The GC purity was 97.2%, impure and used directly in the next reaction.
The third step is 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid
Adding 130g (0.35mol, 1.0eq) of methyl 8-hydroxy-2, 2,14, 14-tetramethylpentadecane dicarboxylate and 400mL of 3N sodium hydroxide solution into a 1000mL round-bottom flask, raising the temperature value of a reaction system, refluxing for reaction overnight, detecting that the raw material residue is less than 0.5 percent by GC, concentrating to remove ethanol, adding 1000mL of deionized water, extracting for 2 times by 200mL of dichloromethane by 2, adjusting the pH of a water layer to 1-2 by using 3N hydrochloric acid, continuing stirring for half an hour for reaction, filtering, washing by using deionized water to obtain 107g of white solid 8-hydroxy-2, 2,14, 14-tetramethylpentadecane dicarboxylate, the yield is 89.3 percent, and the purity is 99.4 percent,
MS m/z 345.2641((M+H)+
1H NMR(400MHz,CDCl3):(ppm):7.42(s,3H),3.59(s,1H),1.65-1.00(m,20H),1.18(s,12H)。
examples 3 to 5
The same conditions as in example 1, except that the base in the first step was replaced with the following components, the experimental results are shown in table 1:
TABLE 1
| Examples | Alkali | Yield of the first reaction (%) | Purity of the first reaction (%) |
| Example 3 | Potassium tert-butoxide | 85.1 | 98.4 |
| Example 4 | Lithium diisopropylamide | 94.6 | 99.1 |
| Example 5 | Lithium bis (trimethylsilyl) amide | 90.8 | 98.5 |
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the invention is not limited to the embodiments described above, which are described in the specification only to illustrate the principles of the invention. The invention also includes various insubstantial changes and modifications within the spirit of the invention, as claimed by those skilled in the art.
Claims (10)
1. A synthesis method of pimelic acid comprises the following steps:
(1) reacting a compound shown in a formula (I) with 2, 5-dibromopentane under the catalysis of alkali to obtain a compound shown in a formula (II);
(2) forming a Grignard reagent by the compound of the formula (II) and magnesium, and reacting with HCOOR to obtain a compound of a formula (III);
(3) hydrolyzing and acidifying the compound of the formula (III) by alkali to obtain the triprotic acid;
wherein the structural formulas of the compound of the formula (I), the compound of the formula (II) and the compound of the formula (III) are as follows:
wherein X in the compounds of the formula (I), the formula (II) and the formula (III) is-CN or-COOR 1, and R1 is C1-C6 chain alkyl; wherein R in HCOOR is selected from alkyl, cycloalkyl, alkenyl and substituted phenyl.
2. Process for the synthesis of budesonide according to claim 1, wherein R in HCOOR is an alkyl group, preferably methyl.
3. The method for synthesizing pipadiric acid according to claim 1, wherein the base in the step (1) is at least one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (HMDSLi), sodium bis (trimethylsilyl) amide (HMDSNa), and potassium bis (trimethylsilyl) amide (HMDSK), and preferably is sodium hydride.
4. The synthesis method of biparidic acid according to claim 1, characterized in that the molar ratio of the base to the compound of formula (i) in step (1) is 1-5: 1, preferably 2-4: 1.
5. The synthesis method of pimelic acid according to claim 1, wherein the solvent used in the step (1) is one or a combination of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and 1, 4-dioxane, preferably the solvent used in the reaction is tetrahydrofuran.
6. The process for the synthesis of bipidelic acid according to claim 1, characterized in that the reaction temperature in step (1) is-78 ℃ to 10 ℃, more preferably-20 ℃ to 10 ℃.
7. The method for synthesizing bipidenoic acid according to claim 1, wherein the molar ratio of grignard reagent to formate in step (2) is 2.0-4.0: 1, preferably, the molar ratio of the Grignard reagent to the formate is 2-2.5: 1.
8. the synthesis method of budesonide acid according to claim 1, wherein the base in step (3) is any one or a combination of sodium hydroxide, potassium hydroxide and ammonia water, preferably sodium hydroxide.
9. The method for synthesizing pipidic acid according to claim 1, wherein the solvent in the step (3) is an alcohol solvent. Wherein the alcohol solvent is any one or combination of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.
10. The synthesis method of biparidic acid according to claim 1, characterized in that the temperature for preparing the middle Grignard reagent in step (2) is reflux reaction, and the temperature for dripping formic ester is-50 to 0 ℃, preferably-10 to 0 ℃; the reaction temperature in the step (3) is 50-100 ℃, and preferably 60-90 ℃.
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| CN112521282A (en) * | 2020-12-02 | 2021-03-19 | 苏州汉德创宏生化科技有限公司 | Bepaidic acid intermediate and synthesis method thereof |
| CN113233975A (en) * | 2021-04-07 | 2021-08-10 | 海化生命(厦门)科技有限公司 | Preparation method of biparidic acid |
| CN114907204A (en) * | 2021-02-07 | 2022-08-16 | 苏州特瑞药业股份有限公司 | Synthesis method of piparidic acid |
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| CN112521282A (en) * | 2020-12-02 | 2021-03-19 | 苏州汉德创宏生化科技有限公司 | Bepaidic acid intermediate and synthesis method thereof |
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| CN115504914A (en) * | 2021-06-23 | 2022-12-23 | 武汉武药科技有限公司 | Preparation method of piparidic acid intermediate |
| CN115504914B (en) * | 2021-06-23 | 2024-05-07 | 武汉武药科技有限公司 | Preparation method of bevacizidine acid intermediate |
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