CN113896728A - 一种罗通定的合成制备方法 - Google Patents
一种罗通定的合成制备方法 Download PDFInfo
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- CN113896728A CN113896728A CN202111331850.6A CN202111331850A CN113896728A CN 113896728 A CN113896728 A CN 113896728A CN 202111331850 A CN202111331850 A CN 202111331850A CN 113896728 A CN113896728 A CN 113896728A
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- Prior art keywords
- rotundine
- fibrauretine
- diphosphine
- dimethoxybenzyl
- dimethoxyphenyl
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- AEQDJSLRWYMAQI-KRWDZBQOSA-N tetrahydropalmatine Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3C[C@H]2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-KRWDZBQOSA-N 0.000 title claims abstract description 82
- 229930189907 rotundine Natural products 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006722 reduction reaction Methods 0.000 claims abstract description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 13
- JIVGSHFYXPRRSZ-UHFFFAOYSA-N 2,3-dimethoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1OC JIVGSHFYXPRRSZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims abstract description 9
- SPBYFEZECXUDFU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-[(2,3-dimethoxyphenyl)methyl]ethanamine;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCNCC1=CC=CC(OC)=C1OC SPBYFEZECXUDFU-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 229940015043 glyoxal Drugs 0.000 claims abstract description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 5
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- RZNLZECAKUHOIU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-[(2,3-dimethoxyphenyl)methyl]ethanamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC1=CC=CC(OC)=C1OC RZNLZECAKUHOIU-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 4
- AJNZWRKTWQLAJK-VGWMRTNUSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-dimethylphospholan-1-yl]phenyl]-2,5-dimethylphospholane Chemical compound C[C@H]1CC[C@H](C)P1C1=CC=CC=C1P1[C@@H](C)CC[C@@H]1C AJNZWRKTWQLAJK-VGWMRTNUSA-N 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 230000009467 reduction Effects 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- RLQYRXCUPVKSAW-UHFFFAOYSA-M 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium;chloride Chemical compound [Cl-].COC1=C(OC)C=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=C1 RLQYRXCUPVKSAW-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RIDQRIPSFYHEGL-UHFFFAOYSA-N fibrauretin Natural products CC12CC=C3C(=O)OC(CC3(C)C1C(=O)C=CC2=O)c4cocc4 RIDQRIPSFYHEGL-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000006257 total synthesis reaction Methods 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- -1 o-bromobenzaldehyde compound Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 241000218176 Corydalis Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 241000218180 Papaveraceae Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- XBNBOGZUDCYNOJ-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1,3,5-trimethylbenzene Chemical compound [Ru+]Cl.CC1=CC(C)=CC(C)=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 XBNBOGZUDCYNOJ-XCPIVNJJSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007278 cyanoethylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 229950008204 levosalbutamol Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(II) nitrate Inorganic materials [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
本发明公开了一种罗通定的制备方法,具体包括以下步骤:(1)3,4‑二甲氧基苯乙胺与2,3‑二甲氧基苯甲醛缩合并还原后,与氯化氢成盐得N‑(2,3‑二甲氧基苄基)‑2‑(3,4‑二甲氧基苯基)‑1‑乙胺盐酸盐;(2)N‑(2,3‑二甲氧基苄基)‑2‑(3,4‑二甲氧基苯基)‑1‑乙胺盐酸盐与乙二醛环合得到黄藤素;(3)黄藤素在双膦‑镍配合物催化作用下,在有机溶剂中进行不对称氢化还原反应得到手性纯的罗通定。本合成制备工艺具有反应条件温和,后处理简单,手性催化剂易于合成且性质稳定,立体选择性高,成品的收率高等优点,适合工业化大生产。
Description
技术领域
本发明涉及一种罗通定的化学合成制备方法,属于药物合成领域。
背景技术
罗通定(Rotundine)又称左旋延胡索乙素或左旋四氢巴马汀,化学名称为2,3,9,10-四甲氧基-5,8,13,13a-四氢-6H-二苯并[a,g]喹嗪,来源于罂粟科植物延胡索的干燥块茎,为多巴胺受体阻断剂。罗通定属于中枢性镇痛药物,具有镇痛、镇静作用,与常见的镇痛药物阿片受体兴奋剂具有不同的作用机制。临床上主要用于治疗因消化系统疾病或功能异常引起的内脏性疼痛(如胃溃疡及十二指肠溃疡的疼痛)、一般性头痛、月经痛、分娩后宫缩痛及紧张性疼痛或疼痛导致的失眠;亦用于镇咳、抗心律失常、降血压及治疗功能性消化不良等。多年来由于过度砍伐,该类药用植物资源严重匮乏,导致罗通定原料药已无法满足市场需求。因此,采用化学合成制备生产罗通定具有很重要的社会和经济价值。
目前报道的合成罗通定的方法有半合成及全合成两类工艺路线。半合成工艺路线主要以盐酸小檗碱或黄藤素为原料:文献[中国医药工业杂志,2012,43(5),323-325]报道以盐酸小檗碱为起始物料,经过去亚甲基、O-甲基化、硼氢化钠还原、L-二对甲基苯甲酰酒石酸拆分和碱化游离五步反应得到罗通定。文献[中国药物化学杂志,2015,25(5),378-381]报道以黄藤素为起始物料,经过硼氢化钾还原、L-酒石酸拆分和碱化游离三步反应得到罗通定。这两种方法最后都是采用拆分的方法,得到单一构型罗通定成品,原料损失比较大,原子经济性低,且起始物料主要来源于天然产物提取物,资源和产量有限,工业大生产有局限性。合成路线如下所示:
全合成目前报道的主要有两条路线:其一是文献[Organic ChemistryFrontiers,2018,5(2),242-246]报道用邻溴苯甲醛类化合物与四氢异喹啉和三甲基乙炔基硅为起始原料,采用三元Redox-A3等四步反应得到环合中间体后,再用四氢铝锂和三氯化铝还原羰基,最后采用Noyori不对称氢转移氢化还原【HCO2H,Et3N,RuCl[(S,S)-TsDPEN](mesitylene)】得到罗通定。该方法采用的起始物料不易得,成本高,且三元Redox-A3反应较复杂,副反应多,影响成品的质量,不适合工业化生产制备。合成路线如下:
另一条全合成路线是中国专利(CN1068113和CN1687064)报道的,以愈创木酚为起始原料,经甲基化、氰乙基化、水解、降解、缩合加氢、环合、还原得到外消旋的罗通定,但没有进行拆分得到单一立体构型的罗通定。合成路线如下:
该路线相对来说工业生产可行性比较强,但终产品是外消旋体,要得到单一构型产品还需要进行化学拆分,该工艺还有待改进。
异喹啉环类化合物不对称氢化还原催化现今报道的主要有铑、钌、铱、钯及配体来进行手性催化[Chemical Science,2016,7,3047-3051],这类贵金属价格昂贵,工业化生产的成本高。
发明内容
本发明的目的在于针对现有的不足,提供一种不对称氢化还原黄藤素制备罗通定的方法,本发明创造性地用镍和双膦配体不对称催化氢化黄藤素,高立体选择性地高效合成罗通定。利用本发明的制备方法,合成效率高、立体选择性高、原子经济性好,降低了合成制备成本,而且不存在消旋化问题,从而有望实现罗通定手性廉价的工业化生产。
为实现本发明的目的,本发明技术方案如下:
(1)以3,4-二甲氧基苯乙胺与2,3-二甲氧基苯甲醛为起始物料,缩合并还原后得到N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺,与氯化氢成盐得到其盐酸盐;
(2)N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺盐酸盐与乙二醛环合得到黄藤素;
(3)黄藤素在双膦-镍配合物催化作用下,在有机溶剂中进行不对称氢化还原反应得到手性纯的罗通定。
本发明涉及的合成路线如下所示:
其原理为:3,4二甲氧基苯乙胺与2,3-二甲氧基苯甲醛缩合还原后成盐,得N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺盐酸盐,再与乙二醛在铜盐的催化下进行环合反应,得到黄藤素,黄藤素在双膦-镍配合物的催化下进行不对称催化氢化还原得到手性纯的罗通定。
在经过精心设计的数个系列实验的基础上,本发明提供了一种黄藤素不对称催化氢化还原制备手性纯的罗通定的制备方法,具体为黄藤素在双膦-镍配合物的催化作用下,在有机溶剂中进行不对称氢化还原反应得到手性纯的罗通定。所述的双膦-镍配合物,其通式为[Ni(L)]X2,其中,
L为选自下述(S,S)-Me-FcPhos、(S,S)-Me-DuPhos、(S,S)-QuinoxP、(S,S)-BenzP中的任意一种手性双膦配体:
X为Cl-、AcO-、NO3 -中的任意一种阴离子;
所述的有机溶剂为选自乙酸乙酯、二氯甲烷、四氢呋喃、甲醇、乙醇或异丙醇中的任意一种单一溶剂或两种及两种以上的混合溶剂;
所述的氢化还原反应的氢气压力为1~10MPa,还原反应温虔为室温至100℃,反应时间为1~48小时。
本发明的制备方法具有反应条件温和,后处理简单,手性催化剂易于合成且性质稳定,立体选择性高,成品的收率高等优点。根据本发明的制备方法,成品的ee值可达到99.6%以上,光学纯度高。本发明为化学合成罗通定的工业化生产提供了可行的方法。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域内的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。
本发明的罗通定制备方法,具体合成路线如下:
实施例1N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺盐酸盐(3)的制备
3,4-二甲氧基苯乙胺(100g)加至夹套,室温度搅拌,加入2,3-二甲氧基苯甲醛(95.9g),加完后,升温至105-110℃反应1h,冷却至室温。用甲醇(160ml)溶解转移至氢化釜,加入雷尼镍(4g),氮气置换3次,再氢气置换4次后,在4atm氢气压力下50℃进行氢化还原,反应结束后,反应液压出反应釜,滤除上层清液,通入氯化氢气体,冷却析晶得到化合物3的白色固体(180.7g,收率89%)。
实施例2黄藤素(4)的制备
氮气保护,乙二醛(11.2g)加入AcOH(60g)中,再加乙酸酐(23.7g),CuCl2(17.5g),N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺盐酸盐(3,21.4g)40mL AcOH溶液,升温至100℃,升温回流反应2h。浓缩回收醋酸,残留物加H2O(200mL),80℃搅1h,趁热过滤,得到棕色粗品。再加入水,室温搅拌,滴加氨水调节Ph为碱性,搅拌2h后,抽滤。滤固加入水(200mL),升温至90度,用浓HCl调节Ph至酸性,冷却至10℃,搅拌析晶1h,抽滤,干燥得到黄色的黄藤素固体(18.5g,82%)。1H NMR(500MHz,DMSO-d6)δ:9.92(s,1H),9.11(s,1H),8.22(d,J=7.2Hz,1H),8.05(d,J=7.2Hz,1H),7.74(s,1H),7.10(s,1H),4.97(t,J=4.4Hz,2H),4.11(s,3H),4.08(s,3H),3.95(s,3H),3.88(s,3H),3.23(t,J=4.4Hz,2H)。
实施例3罗通定(5)的制备
Ni(OAc)2·4H2O(6.4mg,0.5mol%)和(S,S)-QuinoxP(8.6mg,0.5mol%)加入甲醇(20mL)搅拌1h,加入黄藤素(2.0g,5.16mmol)转移到氢化釜,氮气置换3次,再氢气置换4次,后3MPa氢气50℃进行氢化还原24h,后静置0.5h:缓慢泄压后,滤出反应液,浓缩,加去离子水20ml,加氨水调pH至8,打浆0.5h,抽滤,滤饼乙醇重结晶得到罗通定(1.58g,收率86%,99.8%ee)。1H-NMR(500MHz,CD3OD)δ:6.91(d,1H,J=8.4Hz),6.87(d,1H,J=8.4Hz),6.84(s,1H),6.69(s,1H),4.17(d,1H,J=15.6Hz),3.81(s,9H),3.78(s,3H),3.48(d,1H,J=11.4Hz),3.46(d,1H,J=15.6Hz),3.40(dd,1H,J=16.2,3.6Hz),3.17(dd,1H,J=11.4,3.6Hz),3.07(td,1H,J=16.2,5.4Hz),2.66~3.04(m,2H),2.59(td,1H,J=11.4,3.6Hz)。
实施例4罗通定(5)的制备
NiCl2·6H2O(6.2mg,0.5mol%)和(S,S)-Me-FcPhos(10.7mg,0.5mol%)加入乙醇(20mL)搅拌1h,加入黄藤素(2.0g,5.16mmol)转移到氢化釜,氮气置换3次,再氢气置换4次,后3MPa氢气50℃进行氢化还原24h,后静置0.5h:缓慢泄压后,滤出反应液,浓缩,加去离子水20ml,加氨水水调pH=8,打浆0.5h,抽滤,滤饼乙醇重结晶得到罗通定(1.49g,收率81%,99.6%ee)。
实施例5罗通定(5)的制备
Ni(NO3)2·6H2O(7.5mg,0.5mol%)和(S,S)-Me-DuPhos(7.9mg,0.5mol%)加入异丙醇(20mL)搅拌1h,加入黄藤素(2.0g,5.16mmol)转移到氢化釜,氮气置换3次,再氢气置换4次,后3MPa氢气50℃进行氢化还原24h,后静置0.5h,缓慢泄压后,滤出反应液,浓缩,加去离子水20ml,加氨水水调pH=8,打浆0.5h,抽滤,滤饼乙醇重结晶得到罗通定(1.54g,收率84%,99.6%ee)。
实施例6罗通定(5)的制备
Ni(OAc)2·4H2O(6.4mg,0.5mol%)和(S,S)-BenzP(7.3mg,0.5mol%)加入甲醇(20mL)搅拌1h,加入黄藤素(2.0g,5.16mmol)转移到氢化釜,氮气置换3次,再氢气置换4次,后3MPa氢气50℃进行氢化还原24h,后静置0.5h:缓慢泄压后,滤出反应液,浓缩,加去离子水20ml,加氨水水调pH=8,打浆0.5h,抽滤,滤饼乙醇重结晶得到罗通定(1.50g,收率82%,99.7%ee)。
Claims (5)
1.一种罗通定的合成制备方法,其特征在于,包括以下步骤:
(1)以3,4-二甲氧基苯乙胺与2,3-二甲氧基苯甲醛为起始物料,缩合并还原后得到N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺,与氯化氢成盐得到其盐酸盐;
(2)N-(2,3-二甲氧基苄基)-2-(3,4-二甲氧基苯基)-1-乙胺盐酸盐与乙二醛环合得到黄藤素;
(3)黄藤素在双膦-镍配合物催化作用下,在有机溶剂中进行不对称氢化还原反应得到手性纯的罗通定。
3.根据权利要求1和2所述的一种罗通定的合成制备方法,其特征在于,步骤(3)中所述双膦-镍配合物与黄藤素的摩尔比例为1/100~1/20000。
4.根据权利要求1和2所述的一种罗通定的合成制备方法,其特征在于,步骤(3)中所述有机溶剂为选自乙酸乙酯、二氯甲烷、四氢呋喃、甲醇、乙醇或异丙醇中的任意一种单一溶剂或两种及两种以上的混合溶剂。
5.根据权利要求1和2所述的一种罗通定的合成制备方法,其特征在于,步骤(3)中所述的氢化还原反应的氢气压力为1~10MPa,还原反应温度为室温至100℃,反应时间为1~48小时。
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