CN113956204A - Synthesis method of anserine - Google Patents
Synthesis method of anserine Download PDFInfo
- Publication number
- CN113956204A CN113956204A CN202111055935.6A CN202111055935A CN113956204A CN 113956204 A CN113956204 A CN 113956204A CN 202111055935 A CN202111055935 A CN 202111055935A CN 113956204 A CN113956204 A CN 113956204A
- Authority
- CN
- China
- Prior art keywords
- compound
- anserine
- solvent
- molar ratio
- synthesizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108010085443 Anserine Proteins 0.000 title claims abstract description 28
- SLRNWACWRVGMKD-UHFFFAOYSA-N L-anserine Natural products CN1C=NC(CC(NC(=O)CCN)C(O)=O)=C1 SLRNWACWRVGMKD-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 241000210053 Potentilla elegans Species 0.000 title claims abstract description 28
- MYYIAHXIVFADCU-QMMMGPOBSA-N anserine Chemical compound CN1C=NC=C1C[C@H](NC(=O)CC[NH3+])C([O-])=O MYYIAHXIVFADCU-QMMMGPOBSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 19
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 10
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 20
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 20
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 16
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 229940126062 Compound A Drugs 0.000 claims description 14
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 239000012022 methylating agents Substances 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- -1 p-methoxybenzyl Chemical group 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000006315 carbonylation Effects 0.000 claims description 6
- 238000005810 carbonylation reaction Methods 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000004996 alkyl benzenes Chemical class 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical group CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-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
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 2
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical group ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 229940109239 creatinine Drugs 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 108010087806 Carnosine Proteins 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 3
- HIXYEIRACBUSON-FJXQXJEOSA-N (2s)-2-(3-aminopropanoylamino)-3-(1h-imidazol-5-yl)propanoic acid;hydrochloride Chemical compound Cl.NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 HIXYEIRACBUSON-FJXQXJEOSA-N 0.000 abstract 1
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 229940070763 carnosine hydrochloride Drugs 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 2
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 229940044199 carnosine Drugs 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- MMGJNINGVUMRFI-UHFFFAOYSA-N 15686-38-1 Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)C3)CCCCC2C3N1CC1CC1 MMGJNINGVUMRFI-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides 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
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 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
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthetic method of anserine, belonging to the technical field of chemical synthesis. The method takes creatinine benzene carnosine hydrochloride as raw material and comprises esterification protection, carbon acylation, methylation and deprotection of a group R1And deprotecting phthalic anhydride. The method has the advantages of cheap and easily available raw materials, good selectivity and high yield. Simple operation, stable process, easy control and convenient post-treatment. The reaction condition is mild, safe and environment-friendly. High product yield and high purity.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of anserine.
Background
Anserine is also called "N- (beta-aminopropionyl) -1' -methylhistidine", and its dried product has strong hygroscopicity. Is soluble in water and slightly soluble in methanol and ethanol. pK1＝2.64、pK2＝7.04、pK39.49. And 20% of H2SO4Heated together to hydrolyze to beta-alanine and 1' -methylhistidine. Is a component of the muscle tissue of birds, first found in goose muscle,so the name is. Anserine is a histidine dipeptide naturally existing in vertebrates, has obvious functions of reducing uric acid, resisting oxidation, resisting aging and the like, and is widely applied to the food industry. Therefore, the development of an industrialized preparation method of anserine to replace the traditional extraction process is imminent.
The preparation method of anserine is reported in the literature, and patent JP2005082571A reports a route 1:
the protecting group selected in the route is difficult to remove, the conditions are harsh, the production is not facilitated, and the chiral center is easy to racemize in the removing process.
Patent CN108727269A reports scheme 2:
although the route is simple, the compound 3 cannot be obtained in the system, and the reaction cannot be carried out by using MeI as a methylating agent in the attempt of the route.
Therefore, a synthesis route which has cheap and easily obtained raw materials and simple and convenient operation and is suitable for industrial production of anserine is urgently needed to be provided.
Disclosure of Invention
The embodiment of the invention provides a synthetic method of anserine, which has the following reaction equation:
the method comprises the following steps:
(1) compound A and alcohol R1And (3) carrying out esterification reaction on OH to obtain a compound B, wherein the structural formula of the compound A is as follows:
the structural formula of the compound B is as follows:
wherein R is1Is optionally substituted or unsubstituted C1-C10 aliphatic alkane, optionally substituted or unsubstituted C7-C17 alkylbenzene or optionally substituted or unsubstituted C7-C17 aromatic hydrocarbon, etc.
(2) Reacting the compound B with a carbonylation reagent in a solvent B under an alkaline condition to obtain a compound C, wherein the reaction temperature is 0-80 ℃ (preferably 20-50 ℃), and the molar ratio of the compound B to the carbonylation reagent to a base is 1: 1-10: 0.1-5 (preferably 1: 2-5: 1-3), the reaction time is 1-48h (preferably 2-24h), and the structural formula of the compound C is as follows:
wherein R is2Is optionally substituted or unsubstituted C1-C10 aliphatic alkane, optionally substituted or unsubstituted C7-C17 alkylbenzene or optionally substituted or unsubstituted C7-C17 aromatic hydrocarbon; accordingly, the carbonylation reagent should yield R2，R2Preferably tert-butyl, benzyl, Fmoc or the like.
(3) In a solvent C, reacting the compound C with a methylating agent under an alkaline condition to obtain a methylated intermediate, decarbonylating the methylated intermediate under an acidic condition to obtain a compound D, wherein the reaction temperature is-10-100 ℃ (preferably 20-60 ℃), and the molar ratio of the compound C, the methylating agent and a base is 1: 1-10: 0.5-10 (preferably 1: 2-6: 1-5), the reaction time is 1-48h (preferably 2-24h), and the structural formula of the compound D is as follows:
(4) compound D deputyProtecting group R1To obtain a compound E, wherein the structural formula of the compound E is as follows:
(5) removing the protecting group of phthalic anhydride by using the compound E to obtain a compound F, wherein the structural formula of the compound F is as follows:
preferably, R1Is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl, p-methoxyphenyl or p-methoxybenzyl, etc., more preferably R1Is methyl. R2Is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl, p-methoxyphenyl or p-methoxybenzyl, etc., more preferably R1Is tert-butyl or benzyl.
Specifically, in the step (1), in the solvent A, the compound A and alcohol are subjected to esterification reaction under the action of a catalyst to obtain the compound B, the reaction temperature is 0-70 ℃ (preferably 20-50 ℃), the reaction time is 1-48h (preferably 2-24h), and the molar ratio of the compound A, the alcohol and the catalyst is 1: 1-10: 0.01-2 (preferably 1: 2-4: 0.1-1.5). Wherein, the catalyst is selected from concentrated sulfuric acid, phosphoric acid or thionyl chloride, and the like, and thionyl chloride is preferred. Solvent a is selected from toluene, reactant alcohols or mixtures thereof, preferably reactant alcohols (e.g., methanol).
Wherein, in the step (2), the solvent B is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, butyl acetate, ethylene glycol dimethyl ether, acetone, butanone, THF, dioxane, DMF, water, dichloromethane or chloroform, etc., preferably a mixed solution of THF and water; the carbonylation reagent is selected from benzyl chloroformate, fluorenylmethyl chloroformate or di-tert-butyl dicarbonate, etc., preferably di-tert-butyl dicarbonate; the base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, trimethylamine, triethylamine, etc., preferably sodium bicarbonate.
Wherein, in the step (3), the solvent C is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, butyl acetate, ethylene glycol dimethyl ether, acetone, butanone, dioxane, tetrahydrofuran, DMF, dichloromethane or water, and preferably acetonitrile; the methylating agent is selected from methyl iodide, dimethyl sulfate or dimethyl carbonate, etc.; the base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or triethylamine, preferably triethylamine.
Preferably, in step (3), the methylating agent is dimethyl sulfate, the compound C reacts with the methylating agent to directly obtain the compound D, the reaction temperature is 20-60 ℃, and the molar ratio of the compound C to the methylating agent to the base is 1: 2-6: 1-5. Namely, in the step (3), the compound D can be obtained by one-step reaction.
Further, in the step (3), after the reaction is completed, the solvent is distilled off, extraction (for example, water and methylene chloride are added), aqueous phase is added with ammonia water to adjust pH to be more than 10, solid-liquid separation and drying of the compound D are carried out.
Specifically, in the step (4), in the solvent D, the compound D deprotects the group R under the action of a base1To obtain a compound E, wherein the reaction temperature is-10-100 ℃ (preferably 20-60 ℃), the reaction time is 1-48h (preferably 2-24h), and the molar ratio of the compound D to the alkali is 1: 1-10 (preferably 1: 2-6). Wherein, the solvent D is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, DMF, acetone, butanone, dichloromethane or water, and preferably acetonitrile; the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium bicarbonate or potassium carbonate, etc., preferably sodium hydroxide.
Specifically, in the step (5), in the solvent E, the compound E is subjected to deprotection under the action of a phthalic anhydride removing reagent to obtain the compound F, the reaction temperature is-10-100 ℃ (preferably 40-80 ℃), the reaction time is 1-48h (preferably 2-24h), and the molar ratio of the compound E to the phthalic anhydride removing reagent is 1: 1-50 (preferably 1: 5-20). Wherein, the solvent E is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, DMF, acetone, butanone, dichloromethane or water, and the like, preferably toluene; the phthalic anhydride removing reagent is selected from hydrazine hydrate, n-butylamine, n-pentylamine, isobutylamine or hexylamine, and is preferably n-butylamine.
Specifically, the method for synthesizing anserine provided by the invention comprises the following steps:
(1) dissolving the compound A in methanol, dropwise adding thionyl chloride at room temperature, and reacting at 20-50 ℃ after dropwise adding to obtain a compound B, wherein the molar ratio of the compound A to the methanol to the thionyl chloride is 1: 2-4: 0.1-1.5.
(2) Dissolving the compound B in water, dropwise adding sodium bicarbonate, dropwise adding a THF solution of di-tert-butyl dicarbonate after dropwise adding is finished, and reacting at 20-50 ℃ to obtain a compound C, wherein the molar ratio of the compound B to the di-tert-butyl dicarbonate to the sodium bicarbonate is 1: 2-5: 1-3.
(3) Dissolving a compound C and triethylamine in acetonitrile, dropwise adding dimethyl sulfate, reacting at 20-60 ℃ after dropwise adding, evaporating to remove a solvent after the reaction is finished, extracting, adding ammonia water into a water phase to adjust the pH value to be more than 10, carrying out solid-liquid separation and drying on a compound D, wherein the molar ratio of the compound C to the dimethyl sulfate to the triethylamine is 1: 2-6: 1-5.
(4) Dissolving a compound D in acetonitrile, dropwise adding a sodium hydroxide solution, and reacting at 20-60 ℃ after dropwise adding to obtain a compound E, wherein the molar ratio of the compound D to the sodium hydroxide is 1: 2-6.
(5) Dissolving the compound E and n-butylamine in toluene to obtain a compound F, wherein the reaction temperature is 40-80 ℃, and the molar ratio of the compound E to the n-butylamine is 1: 5-20.
The invention provides a synthetic method of anserine, which has the advantages of cheap and easily-obtained raw materials, good selectivity and high yield. Simple operation, stable process, easy control and convenient post-treatment. The reaction condition is mild, safe and environment-friendly. The product has high yield and high purity (more than 98 percent, and only one main byproduct, namely the n-butyl phthalide).
Drawings
FIG. 1 is a mass spectrum of Compound A of example 1;
FIG. 2 is a mass spectrum of compound D of example 3;
FIG. 3 is a mass spectrum of anserine in example 5;
fig. 4 is a partially enlarged view of fig. 3.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
EXAMPLE 1 preparation of creatinine carnosine methyl ester (B)
Creatinine hydrochloride (Compound A, 100g, 0.25mol) was dissolved in 500mL of methanol and SOCl was added dropwise at room temperature2(89.2g, 0.75mol) (tail gas absorption required to be added). In the dripping process, heat and gas are released, and the dripping is slowly carried out, so that the safety is kept. After the dropwise addition, slowly heating to 50 ℃ for reaction for 3h, monitoring the completion of the reaction of the raw materials by hplc, and evaporating the solvent (methanol and SOCl)2) Then obtaining a solid crude product, pulping, washing and drying by using methanol to obtain a product, namely, phthalic anhydride carnosine methyl ester hydrochloride (a compound B, 105g, yield: 100%). 1HNMR (D2O): 2.58(m, 2H), 3.03(dd, J ═ 6.7Hz, 1H), 3.20(dd, J ═ 6.7Hz, 1H), 4.64(m, 1H), 7.15(s, 1H), 3.31(m, 2H), 7.73(m, 4H), 8.45(s, 1H).
EXAMPLE 2 preparation of Boc-Creatinine methyl ester (Compound C)
Creatinine methyl benzoate Phenylanhydrate hydrochloride (Compound B, 30g, 73.8mmol) was dissolved in 100mL of water at room temperature and NaHCO was added dropwise3(18.6g in 150mL of water, 221.4mmol, 3eq), a large amount of gas evolved during the addition. After the dropwise addition, the BOC is dropwise added2THF of O (19.4g, 89mmol, 1.2eq in THF200 mL). After the addition was complete, the mixture was stirred at room temperature and HPLC monitored for the completion of the starting material reaction (19.1 min for starting material T and 23.6min for product T). And (3) post-treatment: after THF was evaporated under reduced pressure, DCM was added for extraction, and dried (anhydrous sodium sulfate) to give 33g of crude product (70.2mmol, yield 95%) after desolventization.
EXAMPLE 3 preparation of anserine methyl ester benzoic anhydride (Compound D)
Boc-anhydrocarnosine methyl ester (compound C) (40g, 85mmol) was dissolved in acetonitrile (300ml) at room temperature. TEA (25.8g, 255mmol, 3eq) was added and Me was added dropwise2SO4(63.3g, 510 mmol, 6eq), stirring at room temperature for about 12h to complete the reaction, monitoring by hplc (23.2 min for starting material T and 19.1min for product T), after completion of the starting material reaction, evaporating acetonitrile, adding 200mL of water, washing twice with DCM (100mL 2) to remove impurities, adjusting the pH of the aqueous phase to 10 or more with dilute ammonia water to precipitate a large amount of white solid, filtering and drying to obtain anhydroanserine methyl ester (compound D) (20g, yield 61%), and confirming the results by HNMR. 1HNMR (CDCl 3): 2.62(m, 2H), 3.06(m, 2H), 3.49(s, 3H), 3.36(s, 3H), 3.91(m, 2H), 4.72(m, 1H), 6.45(m, 1H), 6.66(s, 1H), 7.29(s, 1H), 7.75(m, 2H), 7.78(m, 2H).
EXAMPLE 4 preparation of Anserin Benzoanhydride (Compound E)
After the addition of NaOH (1M, 104mL, 2eq) at room temperature and about 8h after completion of the addition, the reaction was monitored by HPLC (starting material T19.2 min, product T5.3 min, and impurity T10.7 min), the reaction was followed by dilution with 100mL of water, evaporation of acetonitrile, washing twice with DCM (100mL x 2) to remove impurities, adjusting the pH of the aqueous phase to 3-4 with dilute hydrochloric acid to precipitate a white solid, filtration, and drying to give anserine anhydride (compound e15.4g, yield 80%).
Example 5 preparation of anserine (Compound F)
Anserine anhydride (compound E) (10g, 27mmol) was dissolved in n-butylamine (50ml) at room temperature, the starting material disappeared instantaneously, monitored by HPLC, and all of the starting material was converted to the product and one by-product (n-butylaniline phthalate). The n-butylamine was distilled off under reduced pressure. And evaporating to dryness to obtain a yellow solid (foul smell) crude product. Adding 50mL of LPCM and 30mL of water to separate liquid, wherein a byproduct is in an organic phase, adding 50mg of activated carbon into a water phase, stirring for 2 hours at 60 ℃, filtering, evaporating water to obtain a light yellow oily substance, adding 50mL of ethanol, pulping, precipitating a white solid, and filtering to obtain a crude product. The white crude product was recrystallized from water and ethanol to give pure anserine (compound F) (5.4g, yield 64%, purity 98.4%), and HNMR confirmed the results. 1HNMR (D2O): 2.54(m, 2H), 2.84(m, 1H), 3.409(m, 3H), 3.54(s, 3H), 4.36(m, 1H), 6.70(s, 1H), 7.51 (s, 1H).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The method for synthesizing anserine is characterized by comprising the following steps:
(1) compound A and alcohol R1And (3) carrying out esterification reaction on OH to obtain a compound B, wherein the structural formula of the compound A is as follows:
the structural formula of the compound B is as follows:
wherein R is1Is optionally substituted or unsubstituted C1-C10 aliphatic alkane, optionally substituted or unsubstituted C7-C17 alkylbenzene or optionally substituted or unsubstitutedAromatic hydrocarbons having substituted C7-C17;
(2) reacting the compound B with a carbonylation reagent in a solvent B under an alkaline condition to obtain a compound C, wherein the reaction temperature is 0-80 ℃, and the molar ratio of the compound B to the carbonylation reagent to a base is 1: 1-10: 0.1-5, compound C has the formula:
wherein R is2Is optionally substituted or unsubstituted C1-C10 aliphatic alkane, optionally substituted or unsubstituted C7-C17 alkylbenzene or optionally substituted or unsubstituted C7-C17 aromatic hydrocarbon;
(3) in a solvent C, reacting a compound C with a methylating agent under an alkaline condition to obtain a methylated intermediate, decarbonylating a protecting group of the methylated intermediate under an acidic condition to obtain a compound D, wherein the reaction temperature is-10-100 ℃, and the molar ratio of the compound C to the methylating agent to a base is 1: 1-10: 0.5-10, compound D has the formula:
(4) compound D deprotection group R1To obtain a compound E, wherein the structural formula of the compound E is as follows:
(5) removing the protecting group of phthalic anhydride by using the compound E to obtain a compound F, wherein the structural formula of the compound F is as follows:
2. method of anserine according to claim 1The synthesis method is characterized in that R is1Is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl, p-methoxyphenyl or p-methoxybenzyl, and R is2Is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl, p-methoxyphenyl or p-methoxybenzyl.
3. The method for synthesizing anserine according to claim 1, wherein in the step (1), in the solvent A, the compound A and the alcohol are subjected to esterification reaction under the action of the catalyst to obtain the compound B, the reaction temperature is 0-70 ℃, and the molar ratio of the compound A to the alcohol to the catalyst is 1: 1-10: 0.01-2; the catalyst is selected from concentrated sulfuric acid, phosphoric acid or thionyl chloride, and the solvent A is selected from toluene, reactant alcohol or a mixture thereof.
4. The method for synthesizing anserine according to claim 1, wherein in the step (2), the solvent B is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, butyl acetate, ethylene glycol dimethyl ether, acetone, butanone, THF, dioxane, DMF, water, dichloromethane or chloroform, the carboacylating agent is selected from benzyl chloroformate, fluorenylmethyl chloroformate or di-tert-butyl dicarbonate, and the base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, trimethylamine or triethylamine.
5. The method for synthesizing anserine according to claim 1, wherein in step (3), the solvent C is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, butyl acetate, ethylene glycol dimethyl ether, acetone, butanone, dioxane, tetrahydrofuran, DMF, dichloromethane or water, the methylating agent is selected from methyl iodide, dimethyl sulfate or dimethyl carbonate, and the base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or triethylamine.
6. The method for synthesizing anserine according to claim 1 or 5, wherein in step (3), the methylating agent is dimethyl sulfate, the compound C is reacted with the methylating agent to directly obtain the compound D, the reaction temperature is 20-60 ℃, and the molar ratio of the compound C, the methylating agent and the base is 1: 2-6: 1-5.
7. The method for synthesizing anserine according to claim 6, wherein in the step (3), the solvent is distilled off after the reaction is completed, extraction is performed, aqueous phase is added with ammonia water to adjust pH to 10 or more, and the compound D is subjected to solid-liquid separation and drying.
8. The method for synthesizing anserine according to claim 1, wherein in step (4), compound D deprotects group R in solvent D under the action of base1Obtaining a compound E, wherein the reaction temperature is-10-100 ℃, and the molar ratio of the compound D to the alkali is 1: 1-10, the solvent D is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, DMF, acetone, butanone, dichloromethane or water, and the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium bicarbonate or potassium carbonate.
9. The method for synthesizing anserine according to claim 1, wherein in the step (5), in the solvent E, the compound E is deprotected under the action of a phthalic anhydride removing reagent to obtain the compound F, the reaction temperature is-10-100 ℃, and the molar ratio of the compound E to the phthalic anhydride removing reagent is 1: 1-50, the solvent E is selected from toluene, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, DMF, acetone, butanone, dichloromethane or water, and the phthalic anhydride removing reagent is selected from hydrazine hydrate, n-butylamine, n-pentylamine, isobutylamine or hexylamine.
10. The method for synthesizing anserine according to claim 1, wherein the method comprises the following steps:
(1) dissolving a compound A in methanol, dropwise adding thionyl chloride at room temperature, and reacting at 20-50 ℃ after dropwise adding to obtain a compound B, wherein the molar ratio of the compound A to the methanol to the thionyl chloride is 1: 2-4: 0.1-1.5;
(2) dissolving a compound B in water, dropwise adding sodium bicarbonate, dropwise adding a THF (tetrahydrofuran) solution of di-tert-butyl dicarbonate after dropwise adding is finished, and reacting at 20-50 ℃ to obtain a compound C, wherein the molar ratio of the compound B to the di-tert-butyl dicarbonate to the sodium bicarbonate is 1: 2-5: 1-3;
(3) dissolving a compound C and triethylamine in acetonitrile, dropwise adding dimethyl sulfate, reacting at 20-60 ℃ after dropwise adding, evaporating to remove a solvent after the reaction is finished, extracting, adding ammonia water into a water phase to adjust the pH value to be more than 10, carrying out solid-liquid separation, and drying a compound D, wherein the molar ratio of the compound C to the dimethyl sulfate to the triethylamine is 1: 2-6: 1-5;
(4) dissolving a compound D in acetonitrile, dropwise adding a sodium hydroxide solution, and reacting at 20-60 ℃ after dropwise adding to obtain a compound E, wherein the molar ratio of the compound D to the sodium hydroxide is 1: 2-6;
(5) dissolving a compound E and n-butylamine in toluene to obtain a compound F, wherein the reaction temperature is 40-80 ℃, and the molar ratio of the compound E to the n-butylamine is 1: 5-20.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111055935.6A CN113956204A (en) | 2021-09-09 | 2021-09-09 | Synthesis method of anserine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111055935.6A CN113956204A (en) | 2021-09-09 | 2021-09-09 | Synthesis method of anserine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113956204A true CN113956204A (en) | 2022-01-21 |
Family
ID=79461159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111055935.6A Pending CN113956204A (en) | 2021-09-09 | 2021-09-09 | Synthesis method of anserine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113956204A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005082571A (en) * | 2003-09-11 | 2005-03-31 | Hamari Chemicals Ltd | Method for synthesizing l-anserine |
| CN108727269A (en) * | 2018-07-13 | 2018-11-02 | 南京纽邦生物科技有限公司 | A kind of preparation method of N (τ)-methyl-L-histidine derivative and its application in synthesizing anserine |
| CN109748874A (en) * | 2019-02-12 | 2019-05-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of anserine and its intermediate |
-
2021
- 2021-09-09 CN CN202111055935.6A patent/CN113956204A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005082571A (en) * | 2003-09-11 | 2005-03-31 | Hamari Chemicals Ltd | Method for synthesizing l-anserine |
| CN108727269A (en) * | 2018-07-13 | 2018-11-02 | 南京纽邦生物科技有限公司 | A kind of preparation method of N (τ)-methyl-L-histidine derivative and its application in synthesizing anserine |
| CN109748874A (en) * | 2019-02-12 | 2019-05-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of anserine and its intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3103280C (en) | Method of preparing high chiral purity lactam intermediate and brivaracetam | |
| CN110950765A (en) | Preparation method of terbutaline sulfate | |
| WO2022052683A1 (en) | Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate | |
| CN113956204A (en) | Synthesis method of anserine | |
| KR100199335B1 (en) | Process for the synthesis of nabumetone | |
| CN113651772A (en) | Preparation method of cloperastine hydrochloride | |
| JP4721339B2 (en) | Method for producing N-alkoxycarbonylamino acid | |
| CN111440079A (en) | Synthesis method of D L-threo-p-chlorophenylserine | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN112694453B (en) | Preparation method of N-methylated nitrogen-containing aromatic heterocyclic compound | |
| CN113698355B (en) | Synthesis method of 4, 5-dihydroxypyridazine | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| PL195617B1 (en) | An improved process for the preparation of thiazolidine-2,4-dione derivatives | |
| EP1086074B1 (en) | New process | |
| CN115448871B (en) | Preparation method of tirofiban hydrochloride | |
| US4751314A (en) | Preparation of tetrachloro-3-iminoisoindolin-1-one | |
| AU6083599A (en) | Method for pressureless production of alpha,alpha-dimethylphenyl acetic acid from alpha,alpha-dimethyl benzyl cyanide | |
| KR101521607B1 (en) | Process of isolating methyl-4-formylbenzoate and dimethylterephtalate with high yield | |
| EP3245190B1 (en) | Method for preparing 4-cyanopiperidine hydrochloride | |
| CN116410178A (en) | Preparation method of omeprazole thioether | |
| CN114933562A (en) | Efficient preparation method of chloroquine based on catalysis of (2-hydroxybenzyl) disubstituted phosphine oxide | |
| KR100359503B1 (en) | Method of preparing an aromatic propionic acid derivative | |
| CN115466214A (en) | Preparation method of varenicline intermediate | |
| CN113336753A (en) | Riociguat synthesis method | |
| CA2314988A1 (en) | Process for the preparation of isopropyl-methyl-¬2-(3-n-propoxyphenoxy)ethyl|amine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220121 |