CN113620876B - Synthesis method of 5' -methoxy laudan - Google Patents
Synthesis method of 5' -methoxy laudan Download PDFInfo
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- CN113620876B CN113620876B CN202110911973.0A CN202110911973A CN113620876B CN 113620876 B CN113620876 B CN 113620876B CN 202110911973 A CN202110911973 A CN 202110911973A CN 113620876 B CN113620876 B CN 113620876B
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- laudan
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 179
- 238000006243 chemical reaction Methods 0.000 claims abstract description 155
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 96
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 48
- 235000019253 formic acid Nutrition 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 32
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 25
- 238000010992 reflux Methods 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 66
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical group C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims description 34
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 22
- 230000002378 acidificating effect Effects 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 8
- 229920002866 paraformaldehyde Polymers 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 6
- 229940095564 anhydrous calcium sulfate Drugs 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 abstract description 45
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 abstract description 40
- IYDXQGNUXUOZOC-UHFFFAOYSA-N 6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCNC1CC1=CC(OC)=C(OC)C(OC)=C1 IYDXQGNUXUOZOC-UHFFFAOYSA-N 0.000 abstract description 40
- 238000003786 synthesis reaction Methods 0.000 abstract description 28
- PDZYOCOHQGFKLC-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)acetaldehyde Chemical compound COC1=CC(CC=O)=CC(OC)=C1OC PDZYOCOHQGFKLC-UHFFFAOYSA-N 0.000 abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 15
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 abstract description 12
- 239000011968 lewis acid catalyst Substances 0.000 abstract description 11
- 229910052723 transition metal Inorganic materials 0.000 abstract description 11
- 150000003624 transition metals Chemical class 0.000 abstract description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 3
- 238000013386 optimize process Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 90
- 239000000047 product Substances 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 229910052757 nitrogen Inorganic materials 0.000 description 45
- 238000002390 rotary evaporation Methods 0.000 description 44
- 238000012544 monitoring process Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 238000005406 washing Methods 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 25
- 230000002194 synthesizing effect Effects 0.000 description 24
- 238000003756 stirring Methods 0.000 description 21
- 239000012141 concentrate Substances 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 19
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 17
- 239000012046 mixed solvent Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000005303 weighing Methods 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- ALQIPWOCCJXSKZ-UHFFFAOYSA-N 6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-3,4-dihydro-1h-isoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C)C1CC1=CC(OC)=C(OC)C(OC)=C1 ALQIPWOCCJXSKZ-UHFFFAOYSA-N 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical group O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 10
- 238000003825 pressing Methods 0.000 description 8
- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- UCYRAEIHXSVXPV-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)indiganyl trifluoromethanesulfonate Chemical compound [In+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F UCYRAEIHXSVXPV-UHFFFAOYSA-K 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011085 pressure filtration Methods 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- -1 amine compound Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- AAWZDTNXLSGCEK-WYWMIBKRSA-N (-)-quinic acid Chemical compound O[C@@H]1C[C@](O)(C(O)=O)C[C@@H](O)[C@H]1O AAWZDTNXLSGCEK-WYWMIBKRSA-N 0.000 description 1
- RFMMMVDNIPUKGG-RXMQYKEDSA-N (2r)-2-acetamidopentanedioic acid Chemical compound CC(=O)N[C@@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-RXMQYKEDSA-N 0.000 description 1
- UIKHKLFBHLPAPO-HTQZYQBOSA-N (2r,3r)-2,3-diacetyl-2,3-dihydroxybutanedioic acid Chemical compound CC(=O)[C@@](O)(C(O)=O)[C@@](O)(C(C)=O)C(O)=O UIKHKLFBHLPAPO-HTQZYQBOSA-N 0.000 description 1
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- DDSJXCGGOXKGSJ-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)acetic acid Chemical compound COC1=CC(CC(O)=O)=CC(OC)=C1OC DDSJXCGGOXKGSJ-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- 229930182847 D-glutamic acid Natural products 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 5' -methoxy laudan, belonging to the technical field of organic synthesis. The preparation method comprises the steps of taking 3, 4-dimethoxy phenethylamine and 3,4, 5-trimethoxyphenylacetaldehyde as starting materials through an optimized process by utilizing a Pictet-Spengler reaction, taking methylene dichloride as a solvent, catalyzing with a transition metal type Lewis acid catalyst, carrying out dehydration reaction by a dehydrating agent at 23-27 ℃, or refluxing in formic acid, dehydrating by phosphorus pentoxide, and then taking formic acid as a solvent to react 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline with a methyl donor to obtain 5' -methoxy laudan; the technical scheme of the invention has short synthetic route steps, does not use toxic and harmful reagents phosphorus oxychloride and toluene, simultaneously avoids the steps of hydrogenation reduction and the like, has high total reaction yield, and the obtained 5' -methoxy laudan has high purity, low process cost, environment-friendly process, simple process operation and practical production value and can be used for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 5' -methoxy laudan.
Background
Miku ammonium chloride is a non-depolarizing muscle relaxant with shortest action time and fastest recovery, is approved to be marketed by the FDA in 1992 month 1, has no influence on cardiovascular system, intracranial pressure and intraocular pressure in the prior art, has little histamine release effect in the prior art, is used for tracheal intubation and muscle relaxation maintenance, has short action time and no accumulation, can flexibly control the blocking relaxation of neuromuscular in a flexible intravenous administration mode in operation, is very suitable for operation of children, has been applied and paid more attention in clinical anesthesia operation, has been simulated by continuous manufacturers in recent years, has complex chemical structure, has great difficulty in synthesis and preparation, and has the important raw materials for preparing (R) -5' -methoxy laudorine by resolution.
In the prior art, 3, 4-dimethoxy phenethylamine and 3,4, 5-trimethoxyphenylacetic acid are used as starting materials, the synthetic route shown in the following reaction formula is adopted to prepare 5 '-methoxy laudan through 1-amidation, 2-ring closure, 3-N-methylation and 4-hydrogenation reduction, and then the (R) -5' -methoxy laudan is prepared through the steps of 5 th resolution and the like, the steps are long and complicated, the yield is low, phosphorus oxychloride is used as a dehydrating agent in the patent CN107778233A, toluene is used as an azeotropic water carrying agent to carry out synthetic improvement on the ring closure reaction of the step 2, so that the yield of the ring closure reaction is improved in one step, but phosphorus oxychloride and toluene are both toxic reagents, hydrogen chloride is released in the reaction, the corrosion to equipment and the environmental pollution are caused, and the physical injury is caused to operators when the operators produce the liquid crystal organic electroluminescent material; the resolution of 5 '-methoxylaudan using any of D-tartaric acid, D-malic acid, D-aspartic acid, D-glutamic acid, D-mandelic acid, N-acetyl-D-glutamic acid, D-pyroglutamic acid, D-quinic acid, D-camphorsulfonic acid, D-camphoric acid, diacetyl-D-tartaric acid is mentioned in patent CN107778234a to produce (R) -5' -methoxylaudan, and the resolution of 5 '-methoxylaudan using D- (-) -dibenzoyltartaric acid to produce (R) -5' -methoxylaudan is mentioned in US4761418A as a more viable approach, where 5 '-methoxylaudan is an important starting material for the resolution of key intermediate (R) -5' -methoxylaudan. Therefore, how to synthesize 5' -methoxy laudan with high efficiency and environmental protection is a key step for researching and preparing Miku ammonium chloride.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthesis method of 5' -methoxy laudan with the advantages of short synthesis step, high yield and low cost.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a method for synthesizing 5' -methoxy laudan, which comprises the following steps:
(1) Reacting a compound shown in a formula II with a compound shown in a formula III under an acidic condition to obtain a compound shown in a formula IV;
(2) The compound shown in the formula IV reacts with a methyl donor under an acidic condition to obtain the compound shown in the formula I.
According to the technical scheme, a compound shown in a formula II and a compound shown in a formula III are subjected to condensation cyclization under an acidic condition by utilizing a modified Mannich reaction, namely a Pictet-Spengler reaction, so that a compound shown in a closed-loop product formula IV is obtained, and then the compound shown in the formula IV is reacted with a methyl donor under the acidic condition, so that the compound shown in the formula I is obtained. The technical scheme of the invention has the advantages of short synthetic route steps, only two steps of reaction, no toxic and harmful reagents phosphorus oxychloride and toluene, no steps of hydrogenation reduction and the like, high total reaction yield, high purity of the obtained 5' -methoxy laudan, low process cost, environment-friendly process, simple process operation, practical production value and suitability for industrial production.
As a preferred embodiment of the method for synthesizing 5' -methoxy laudan, in the step (1), the molar ratio of the compound represented by the formula II to the compound represented by the formula III is 1:1.0-1.2.
As a preferred embodiment of the synthesis method of 5' -methoxy laudan, in the step (1), the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1:1.1.
The compound shown in the formula II is relatively expensive, the compound shown in the formula III is relatively cheap, the molar ratio of the compound shown in the formula II to the compound shown in the formula III is preferably 1:1.0-1.2, the first-step reaction yield obtained by the reaction in the molar ratio is relatively high, and the yield shows a rising and stabilizing trend, so that the compound shown in the formula III is considered to be reacted as completely as possible and is excessively wasted, the best in terms of yield and cost is achieved, and the molar ratio of the compound shown in the formula II to the compound shown in the formula III is preferably 1:1.1.
As a preferred embodiment of the synthesis method of 5' -methoxy laudan, in the step (1), the reaction under the acidic condition means that a transition metal type Lewis acid catalyst is added into methylene dichloride for catalysis, and a dehydrating agent is added for dehydration, wherein the reaction temperature is 23-27 ℃ and the reaction time is 22-24 hours.
In the step (1), the imine is activated under the acidic condition, and then carbon on the imine and benzene ring carbon rich in electrons relatively generate electrophilic or nucleophilic action to form new C-C bond ring closure to generate isoquinoline, and the reaction mechanism under the acidic condition is shown as the following reaction formula:
as a preferred embodiment of the synthesis method of 5' -methoxy laudan, in the step (1), the molar ratio of the transition metal type Lewis acid catalyst to the compound represented by the formula II is 0.05-0.1: 1.
as a preferred embodiment of the synthesis method of 5' -methoxy laudan, in the step (1), the molar ratio of the transition metal type Lewis acid catalyst to the compound represented by the formula II is 0.075-0.1: 1.
The use amount of the transition metal type Lewis acid catalyst is too small to achieve an effective catalytic effect, so that the reaction yield is reduced, and the use amount of the transition metal type Lewis acid catalyst is too high, so that the cost is increased.
As a preferred embodiment of the method for synthesizing 5' -methoxylaudan according to the present invention, in the step (1), the transition metal type lewis acid catalyst includes any one of bismuth triflate, ytterbium triflate, and indium triflate; the empty orbitals of the central metal atoms on the transition metal type Lewis acid catalyst can bind lone pair electrons on nitrogen atoms, so that imine carbon is less influenced by the lone pair electrons, and further the imine carbon is favorable for electrophilic action on carbon on benzene rings to form new carbon-carbon bonds.
As a preferred embodiment of the method for synthesizing 5' -methoxylaudan of the present invention, in the step (1), the transition metal type lewis acid catalyst is ytterbium triflate; compared with bismuth triflate and indium triflate, the catalyst has better catalytic effect and higher yield of the obtained product.
As a preferred embodiment of the method for synthesizing 5' -methoxy laudan according to the present invention, in the step (1), the dehydrating agent comprises 3A molecular sieve or anhydrous calcium sulfate; the dehydrating agent is added into the reaction system to remove water in the reaction system in time, so that the reaction is further promoted, and the reaction yield is improved.
In the step (1), the reaction under acidic conditions means that the reaction is performed using a monoacid as a solvent, wherein the monoacid includes any one of formic acid, acetic acid and trifluoroacetic acid.
In a preferred embodiment of the method for synthesizing 5' -methoxypsorafen according to the present invention, in the step (1), when the monoacid is formic acid or acetic acid, the reaction is a reflux reaction, and the reaction time is 8 to 10 hours.
In the preferred embodiment of the method for synthesizing 5' -methoxylaudan according to the present invention, in the step (1), when the monoacid is trifluoroacetic acid, the reaction temperature is room temperature and the reaction time is 22 to 24 hours, and since the amine compound may decompose trifluoroacetic acid at the reflux temperature, if trifluoroacetic acid is used as the solvent, the reaction is performed at room temperature.
As a preferred embodiment of the synthesis method of 5' -methoxy laudan, in the step (1), a dehydrating agent can be added into the reaction system, wherein the dehydrating agent is phosphorus pentoxide, the adding of the dehydrating agent can timely remove water in the reaction system, the reaction is further promoted, the reaction yield is improved, and if the reaction system is formic acid, the adding of the dehydrating agent phosphorus pentoxide can directly carry out N-methylation reaction without separation by adding methyl donor trioxymethylene or paraformaldehyde after the first step of reaction.
In the step (1), the reaction under the acidic condition refers to that ethanol is taken as a solvent, and the pH value of a reaction system is regulated to be 1-3 by any one of p-toluenesulfonic acid, trifluoromethanesulfonic acid and hydrogen chloride gas; when the pH value is 1-3, the formation of new carbon-carbon bonds mainly causes ring closure at the 3-methoxy para position of the compound shown in the formula III.
In the step (2), the acidic condition means a reaction in a formic acid solution, and the reaction is a reflux reaction for 4 to 6 hours.
As a preferred embodiment of the synthesis method of 5' -methoxy laudan according to the present invention, in the step (2), the methyl donor comprises trioxymethylene or paraformaldehyde, wherein the trioxymethylene or paraformaldehyde is decomposed to release formaldehyde for methylation during the reaction, and the molar ratio of the formaldehyde released by the decomposition to the compound represented by formula iv is 1:1, but the formaldehyde released by decomposition is partially lost in the reaction, the molar ratio of formaldehyde released by decomposition to the compound of formula IV is preferably 1.1 to 1.2:1.
In a preferred embodiment of the method for synthesizing 5' -methoxylaudan according to the present invention, the step (2) further comprises refining the compound represented by formula i, wherein the refining method is to recrystallize with an ethanol-water mixed solvent.
Compared with the prior art, the invention has the beneficial effects that: the invention uses 3, 4-dimethoxy phenethylamine and 3,4, 5-trimethoxyphenylacetaldehyde as starting materials through an optimized process by utilizing an improved Mannich reaction, namely a Pictet-Spengler reaction, uses methylene dichloride as a solvent to carry out dehydration reaction through a dehydrating agent at the temperature of 23-27 ℃ under the catalysis of a transition metal type Lewis acid catalyst, or carries out dehydration reaction through phosphorus pentoxide after refluxing in formic acid, and then uses formic acid as a solvent to carry out the reaction between 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and methyl donor trioxyformaldehyde or paraformaldehyde to obtain 5' -methoxy laucaine; the technical scheme of the invention has the advantages of short synthetic route steps, only two steps of reaction, no toxic and harmful reagents phosphorus oxychloride and toluene, no steps of hydrogenation reduction and the like, high total reaction yield, high purity of the obtained 5' -methoxy laudan, low process cost, environment-friendly process, simple process operation, practical production value and suitability for industrial production.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
The synthetic route of 5' -methoxy laudan is shown in the above reaction scheme, and the compounds in the reaction are obtained by the conventional purchase route unless otherwise specified. The intermediate 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline of the compound shown in the formula IV is synthesized by taking the compound shown in the formula II, namely 3,4, 5-trimethoxyphenylacetaldehyde, and the compound shown in the formula III, namely 3, 4-dimethoxy phenethylamine, as raw materials, then the compound shown in the formula I, namely 5 '-methoxy laudan, is synthesized by continuing the reaction, and the nuclear magnetic characterization is given by purifying and weighing the product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline of the first reaction in the example 1, and the nuclear magnetic characterization of the 5' -methoxy laudan is also given, so that the compound with the structure shown is obtained by confirming the two nuclear magnetic characterization. The products obtained in the subsequent examples were all compared with the nuclear magnetism in example 1, and the target product was determined without any difference.
Example 1
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, ethanol is used as a solvent, and hydrogen chloride gas is used for regulating the pH value; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total reaction yield was 52.73%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
weighing 21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxy phenethylamine, placing into a three-mouth bottle, adding 150mL of ethanol, stirring under the protection of nitrogen to dissolve, then blowing nitrogen to exhaust air in the bottle, introducing hydrogen chloride gas to adjust the pH value to 1-3, filling hydrogen chloride into a balloon to connect the reaction bottle, sealing the reaction bottle mouth with an acid-resistant rubber cushion, stirring at 23-27 ℃ for reaction for 20-24 hours, and blowing nitrogen after TLC monitoring reaction is finishedRemoving excessive hydrogen chloride gas, regulating pH value to 6-7 with ammonia water, concentrating by vacuum rotary evaporation, separating concentrate by column chromatography, recrystallizing with ethanol-water to obtain target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline 20.7g with yield of 55.4%, and [ M+H ]] + :374.20。
Nuclear magnetic characterization: 1 H NMR(400MHz,CDCl 3 )：2.62(ddd,J＝15.9,5.8,4.9Hz,1H), 2.72(ddd,J＝15.9,7.1,5.3Hz,1H)，2.78(dd,J＝13.5,9.1HZ,1H),2.86(ddd,J＝11.9,7.1,4.9Hz,1H),3.11(dd,J＝13.5,4.5Hz,1H),3.16(d,J＝11.9,5.8,5.3Hz, 1H),3.77(s,3H),3.78(s,9H),3.79(s,3H),4.09(dd,J＝9.1,4.5Hz,1H),6.41(s, 2H)，6.54(s,1H),6.59(s,1H)； 13 C NMR(100MHz,CDCl 3 ):29.22,40.76,42.81, 55.52,55.67,55.77,60.50,105.85,109.05,111.56,127.14,130.00,134.41,136.19,146.67,147.15,152.92。
(2) Synthesis of 5' -methoxy laudanosine:
weighing 20.40g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 1.93g of trioxymethylene dissolved in formic acid in the step (1), heating and refluxing for 4-6H under the protection of nitrogen, reducing the temperature to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the pH value is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 20.13g of the target product 5' -methoxy laudan with the yield of 95.18 percent and [ M+H ]] + :388.21。
Nuclear magnetic characterization: 1 H NMR(400MHZ,CDCl 3 ):7.41(s,3H),6.39(s,3H),6.20(s,6H), 6.18(s,3H),6.16(s,3H),3.89(s,1H),3.65(s,2H),3.38(s,1H)； 13 C NMR (125MHz,CDCl 3 ):152.78,147.24,146.26,136.21,135.42,128.80,125.68, 111.18,111.12,106.76,64.51,60.65,55.91,55.66,55.41,46.62,42.40,41.42, 25.20。
example 2
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction takes formic acid as solvent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction is 56.82%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed into a three-port bottle, 100mL of formic acid is added, stirring and dissolving are carried out under the protection of nitrogen, heating and refluxing are carried out, reaction is carried out for 11-12 hours, TLC monitoring is carried out, after the reaction is finished, concentrated by reduced pressure rotary evaporation, concentrated solution is added into concentrated solution, concentrated ammonia water is added into pH=6-7, dichloromethane is used for dissolving, water washing is carried out, dichloromethane phase is concentrated under reduced pressure, finally, column chromatography separation and ethanol recrystallization are carried out, 22.3g of target product is obtained, the yield is 59.7%, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 22.3g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 2.11g of trioxymethylene into formic acid in the step (1), heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the concentrate is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 21.94g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 3
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction takes acetic acid as solvent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total reaction yield was 49.13%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed into a three-port bottle, 100mL of acetic acid is added, stirring and dissolving are carried out under the protection of nitrogen, heating reflux is carried out, reaction is carried out for 9-10 hours, TLC monitoring is carried out, after the reaction is finished, concentrated by reduced pressure rotary evaporation, concentrated solution is added into concentrated solution, concentrated ammonia water is added into pH value to be 6-7, dichloromethane is used for dissolving, water washing is carried out, dichloromethane phase is then concentrated by reduced pressure, finally, column chromatography separation and ethanol recrystallization are carried out, 19.1g of target product is obtained, the yield is 51.1%, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 19.1g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 1.81g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the pH value is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 18.85g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 4
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction takes trifluoroacetic acid as a solvent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction is 32.84%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of trifluoroacetic acid is added, stirring and dissolving are carried out under the protection of nitrogen, the reaction is carried out at room temperature for 22-24 hours, TLC monitoring is carried out, after the reaction is finished, concentrated by reduced pressure rotary evaporation, concentrated solution is added into concentrated solution, concentrated ammonia water is added into the concentrated solution to adjust pH value to 6-7, dichloromethane is used for dissolving, then water washing is carried out, dichloromethane phase is concentrated by reduced pressure, finally, column chromatography separation and ethanol recrystallization are carried out, 12.9g of target product is obtained, the yield is 34.5%, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 12.90g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 1.22g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the pH value is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 12.73g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 5
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, ethanol is used as a solvent, and p-toluenesulfonic acid is used for regulating the pH value; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total reaction yield was 35.22%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 150mL of ethanol is added, stirring and dissolving are carried out under the protection of nitrogen, then the mixture is blown into nitrogen to exhaust air in the bottle, p-toluenesulfonic acid is added to adjust the pH value to 1-3, heating reflux reaction is carried out for 14-17 hours, after TLC monitoring is finished, decompression concentration is carried out, water is added into the concentrate, sodium hydroxide is used for adjusting the pH value to 6-7, dichloromethane is used for dissolving, water washing is carried out, then decompression concentration is carried out on dichloromethane phase, finally, column chromatography separation and ethanol recrystallization are carried out, thus obtaining 13.8g of target product, yield is 37.0%, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 13.80g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 1.31g of trioxymethylene into formic acid in the step (1), heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the concentrate is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 13.62g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 6
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, ethanol is used as a solvent, and trifluoro methane sulfonic acid is used for regulating the pH value; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction is 29.60%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 150mL of ethanol is added, stirring and dissolving are carried out under the protection of nitrogen, then the mixture is blown into nitrogen to exhaust air in the bottle, trifluoromethanesulfonic acid is added to adjust the pH value to 1-3, heating reflux reaction is carried out for 13-16 hours under the protection of nitrogen, after TLC monitoring is finished, decompression concentration is carried out, water is added into the concentrate, the pH value is adjusted to 6-7 by sodium hydroxide, dichloromethane is used for dissolving, water washing is carried out, then the dichloromethane phase is decompressed and concentrated, finally, column chromatography separation and ethanol recrystallization are carried out, thus obtaining 11.6g of a target product, the yield is 31.1%, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 11.60g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 1.10g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the pH value is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 11.45g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 7
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, taking formic acid as a solvent and phosphorus pentoxide as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction was 81%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxy phenethylamine are weighed and placed in a three-mouth bottle, 100mL of formic acid and 4.8g of phosphorus pentoxide are added, stirring and dissolution are carried out under the protection of nitrogen, then the reaction is heated and refluxed for 8 to 10 hours, after TLC monitoring is carried out, the reaction is cooled to normal temperature, dichloromethane is dissolved, water is washed to pH value=6 to 7 and then filtered, the filtrate is concentrated to dryness by reduced pressure rotary evaporation, ethanol is recrystallized, 31.8g of target product is obtained, the yield is 85.1 percent, and the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the embodiment 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 31.80g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 3.30g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the pH value is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 31.4g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 8
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, taking formic acid as a solvent and phosphorus pentoxide as a dehydrating agent; the second step of reaction takes formic acid as a solvent and trioxymethylene as a methyl donor, wherein the second step of reaction is directly carried out without separation and purification after the first step of reaction is finished; the total yield of the reaction is 81.0%; the specific synthesis method is as follows:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-mouth bottle, 100mL of formic acid and 4.8g of phosphorus pentoxide are added, stirring and dissolving are carried out under the protection of nitrogen, heating and refluxing are carried out, TLC monitoring reaction is carried out for 8-10 hours, cooling is carried out to normal temperature, 3.3g of trioxymethylene is added, heating and refluxing are carried out for 4-6 hours under the protection of nitrogen, TLC monitoring reaction is carried out, cooling is carried out, normal temperature is carried out, filtration is carried out, reduced pressure rotary evaporation is carried out, dichloromethane is dissolved, then water is washed until the pH value is 6-7, reduced pressure rotary evaporation is carried out until the mixture is dried, finally, ethanol-water mixed solvent is recrystallized to obtain 31.4g of yellow solid, the total yield of two-step reaction is 81.0%, and the structure is confirmed to be 5' -methoxy laodeine.
Example 9
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, using bismuth triflate as a catalyst and using a 3A molecular sieve as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total reaction yield was 74.71%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of methylene chloride is added, after stirring and dissolving under the protection of nitrogen, 6.6g (0.01 mol) of bismuth triflate is added, the 3A molecular sieve is stirred and reacted for 22-24 hours under the protection of nitrogen at 23-27 ℃, after the TLC monitoring reaction is finished, the molecular sieve is filtered, washed by methylene chloride and filtered and separated to dryness, the filtrate is obtained, 10g of silica gel is added and stirred for 30 minutes, the filtered, washed by methylene chloride and filtered to dryness are removed, the filtrate is concentrated to dryness under reduced pressure, 29.3g of product is obtained after column chromatography separation, and the yield is 78.50%, and the target compound 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the above example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 29.3g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 3.04g of trioxymethylene into formic acid in the step (1), heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the concentrate is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 28.94g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 10
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and a 3A molecular sieve as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the two steps is 89.18%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of methylene chloride is added, after stirring and dissolving under the protection of nitrogen, 6.2g (0.01 mol) of ytterbium triflate is added, 10g of 3A molecular sieve is stirred and reacted for 22-24 hours under the protection of nitrogen at 23-27 ℃, after TLC monitoring reaction is finished, filter pressing, washing of methylene chloride, filter pressing is carried out until the molecular sieve is separated out dry, so as to obtain a filtrate, 10g of silica gel is added into the filtrate and stirred for 30 minutes, filter pressing, washing of methylene chloride, filter pressing is carried out until the bismuth triflate is separated dry, then the filtrate is concentrated to be dried under the condition of 30-35 ℃ by decompression, 35.0g of product is obtained after column chromatography separation, and the yield is 93.70%, and the target compound 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the above example 1 is identified.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 35.0g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 3.63g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the concentrate is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 34.57g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 11
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, using indium triflate as a catalyst and using a 3A molecular sieve as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction is 72.14%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of methylene chloride is added, after stirring and dissolving under the protection of nitrogen, 5.7g (0.01 mol) of indium triflate is added, 10g of 3A molecular sieve is stirred and reacted for 22-24 hours under the protection of nitrogen at 23-27 ℃, after TLC monitoring reaction is finished, the molecular sieve is filtered, washed by methylene chloride and filtered and separated to dryness, the filtrate is obtained, 10g of silica gel is added and stirred for 30 minutes, the filtered, washed by methylene chloride and filtered to dryness are removed, the filtrate is concentrated to dryness under reduced pressure, 28.3g of product is obtained after column chromatography separation, and the yield is 75.80%, and the target compound 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the above example 1 is identified as the same compound.
(2) Synthesis of 5' -methoxy laudanosine:
and (2) weighing 28.3g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 2.94g of trioxymethylene into formic acid, heating and refluxing for 4-6 h under the protection of nitrogen, cooling to room temperature after TLC monitoring reaction is finished, concentrating by reduced pressure rotary evaporation, dissolving the concentrate by using dichloromethane, washing with water until the pH value is 6-7, concentrating by reduced pressure rotary evaporation until the concentrate is dry, recrystallizing by using an ethanol-water mixed solvent to obtain 27.97g of the target product, wherein the yield is 95.18%, and identifying the target product 5' -methoxy laudanol obtained in the example 1 as the same compound.
Example 12
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and a 3A molecular sieve as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total reaction yield was 88.71%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of methylene chloride is added, stirring and dissolving are carried out under the protection of nitrogen, 4.65g (0.0075 mol) of ytterbium triflate is added, stirring and reacting are carried out for 22-24 hours under the protection of nitrogen at 23-27 ℃, after TLC monitoring reaction is finished, filter pressing and washing are carried out on methylene chloride, filter pressing and drying are carried out on the molecular sieve, so as to obtain a filtrate, 10g of silica gel is added and stirred for 30 minutes, filter pressing and washing are carried out on the silica gel, filter pressing and drying are carried out on the filtrate until bismuth triflate is removed, then the filtrate is concentrated to dryness under the condition of 30-35 ℃ in a reduced pressure, 34.8g of product is obtained through column chromatography, and the yield 93.20% is identified as the same compound as the target compound 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the above example 1.
(2) Synthesis of 5' -methoxy laudanosine:
34.8g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 3.61g of trioxymethylene are dissolved in formic acid, heated and refluxed for 4 to 6 hours under the protection of nitrogen, after TLC monitoring reaction is finished, cooled to room temperature, concentrated by reduced pressure rotary evaporation, the concentrate is dissolved by dichloromethane, then washed by water until the pH value is 6 to 7, concentrated by reduced pressure rotary evaporation until the pH value is dry, and recrystallized by ethanol-water mixed solvent to obtain 34.37g of the target product, the yield is 95.18 percent, and the target product 5' -methoxy laudanol obtained in the example 1 is identified as the same compound.
Example 13
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and a 3A molecular sieve as a dehydrating agent; secondly, formic acid is used as a solvent in the reaction, and trioxymethylene is used as a methyl donor; the total yield of the reaction is 87.66%; the specific synthesis method is as follows:
(1) Synthesis of 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline:
21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxyphenethylamine are weighed and placed in a three-port bottle, 100mL of methylene chloride is added, 3.1g (0.005 mol) of ytterbium triflate is added after stirring and dissolving under the protection of nitrogen, 10g of 3A molecular sieve is stirred and reacted for 22-24 hours under the protection of nitrogen at 23-27 ℃, after TLC monitoring reaction is finished, the molecular sieve is filtered, washed by methylene chloride and filtered to dryness, the filtrate is obtained, 10g of silica gel is added and stirred for 30 minutes, the filtered, washed by methylene chloride and filtered to dryness are removed, the bismuth triflate is recovered, then the filtrate is concentrated to dryness under reduced pressure, 34.4g of the product is obtained after column chromatography separation, and the yield is 92.1%, and the target compound 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline obtained in the above example 1 is identified.
(2) Synthesis of 5' -methoxy laudanosine:
34.4g of the target product 6, 7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -1,2,3, 4-tetrahydroisoquinoline and 3.57g of trioxymethylene are weighed and dissolved in formic acid, heated and refluxed for 4 to 6 hours under the protection of nitrogen, after TLC monitoring reaction is finished, cooled to room temperature, concentrated by reduced pressure rotary evaporation, the concentrate is dissolved by dichloromethane, then washed by water until the pH value is 6 to 7, concentrated by reduced pressure rotary evaporation until the pH value is dry, and recrystallized by ethanol-water mixed solvent to obtain 34.00g of the target product, the yield is 95.18 percent, and the target product 5' -methoxy laudanol obtained in the example 1 is identified as the same compound.
Example 14
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and a 3A molecular sieve as a dehydrating agent; taking formic acid as a solvent and trioxymethylene as a methyl donor in the second step, wherein the second step is directly carried out without a purification step after the first step is finished; the total yield of the reaction is 90.1%; the specific synthesis method is as follows:
weighing 21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxy phenethylamine, placing into a three-port bottle, adding 100mL of methylene dichloride, stirring and dissolving under the protection of nitrogen, adding 4.65g (0.0075 mol) of ytterbium triflate, stirring and reacting for 22-24 hours at 23-27 ℃ under the protection of nitrogen, after the TLC monitoring reaction is finished, carrying out pressure filtration and washing with methylene dichloride, merging to obtain methylene dichloride pressure filtrate, washing with water to recover ytterbium triflate, carrying out reduced pressure rotary evaporation to obtain the filtrate, adding absolute ethyl alcohol (2X 50 mL) for dissolving and carrying out reduced pressure rotary evaporation to dryness, adding 100mL of formic acid, 3.3g of trioxymethylene dichloride, heating and refluxing for 4-6 hours under the protection of nitrogen, after the TLC monitoring reaction is finished, reducing to normal temperature, carrying out reduced pressure rotary evaporation and concentration, dissolving with methylene dichloride, carrying out water washing to pH value of 6-7, carrying out reduced pressure rotary evaporation and concentrating to dryness, and recrystallizing with an ethanol-water mixed solvent to obtain 34.9g of a target product, wherein the total yield is 90.1% of methoxyl.
Example 15
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and a 3A molecular sieve as a dehydrating agent; the second step of reaction takes formic acid as a solvent and paraformaldehyde as a methyl donor, wherein the second step of reaction is directly carried out without a purification step after the first step of reaction is finished; the total yield of the reaction is 90.6%; the specific synthesis method is as follows:
weighing 21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde and 20.0g (0.11 mol) of 3, 4-dimethoxy phenethylamine, placing into a three-port bottle, adding 100mL of methylene dichloride, stirring and dissolving under nitrogen protection, adding 4.65g (0.0075 mol) of ytterbium triflate, stirring and reacting for 22-24 hours at 23-27 ℃ under nitrogen protection, performing pressure filtration and methylene dichloride washing after TLC monitoring reaction is finished, combining to obtain methylene dichloride pressure filtrate, performing water washing and recovering ytterbium triflate, performing reduced pressure rotary evaporation on the filtrate until the filtrate is dry, adding absolute ethyl alcohol (2X 50 mL) for dissolving and performing reduced pressure rotary evaporation until the filtrate is dry, adding 100mL of formic acid, 3.3g of paraformaldehyde, heating and refluxing for 4-6 hours under nitrogen protection, performing reduced pressure rotary evaporation and concentration, performing reduced pressure rotary evaporation and water washing until the pH value is 6-7 after TLC monitoring reaction is finished, performing reduced pressure rotary evaporation and concentration until the target product is 35.1g, and obtaining the target product, wherein the total yield of the target product is 90.6% of the total methoxy pill.
Example 16
The embodiment of the invention discloses a method for synthesizing 5' -methoxy laudan: the first step of reaction, using dichloromethane as a solvent, ytterbium triflate as a catalyst and anhydrous calcium sulfate as a dehydrating agent; taking formic acid as a solvent and trioxymethylene as a methyl donor in the second step, wherein the second step is directly carried out without a purification step after the first step is finished; the total yield of the reaction is 92.1%; the specific synthesis method is as follows:
weighing 21.0g (0.10 mol) of 3,4, 5-trimethoxyphenylacetaldehyde, 20.0g (0.11 mol) of 3, 4-dimethoxy phenethylamine, placing into a three-port bottle, adding 100mL of methylene chloride, stirring and dissolving under nitrogen protection, adding 4.65g (0.0075 mol) of ytterbium triflate, stirring and reacting at 23-27 ℃ for 22-24 hours under nitrogen protection, performing pressure filtration and methylene chloride washing after TLC monitoring reaction, combining to obtain methylene chloride pressure filtrate, performing water washing and recovering ytterbium triflate, performing reduced pressure rotary evaporation on the filtrate until the filtrate is dry, adding 2X 50mL of absolute ethyl alcohol into the filtrate, performing reduced pressure rotary evaporation until the filtrate is dry, adding 100mL of formic acid, 3.3g of trioxymethylene chloride into the filtrate, heating and refluxing for 4-6 hours under nitrogen protection, performing TLC monitoring reaction until the temperature is normal, performing rotary evaporation and concentration under reduced pressure, dissolving the methylene chloride, performing water washing until the pH value is 6-7, performing rotary evaporation under reduced pressure until the dry, performing recrystallization on an ethanol-water mixed solvent to obtain 35.7g, and determining that the target product is in a total yield of 92.1' -methoxy structure is 92.1%
As can be seen from examples 1 to 7, the second reaction conditions are the same, the main difference is that in the first reaction, when formic acid is used as the solvent and phosphorus pentoxide is added as the dehydrating agent, the highest total yield of the two reactions is obtained, which is 81%; it can be further seen from examples 7 and 2 that the introduction of the dehydrating agent phosphorus pentoxide can significantly improve the yield of the first-step reaction; when acetic acid is used as a solvent or ethanol is used as a solvent and an acid is used for pH adjustment, the reaction may occur, but the yield is not preferable and is 55% or less.
As can be seen from examples 7 and 8, when formic acid is used as a solvent and phosphorus pentoxide is added as a dehydrating agent, the second-stage reaction can be directly carried out without post-treatment after the end of the first-stage reaction, since the total yield obtained by the stepwise reaction and the one-stage reaction is uniform, the reaction steps can be saved, and the reaction operation can be simplified.
As can be seen from examples 9 to 13, when methylene chloride is used as a solvent and a transition metal type Lewis acid catalyst is used for catalysis, ytterbium triflate is used as a catalyst, and the molar ratio of ytterbium triflate to 3,4, 5-trimethoxyphenylacetaldehyde is preferred, and the total yield of the two-step reaction obtained by adopting the reaction conditions can reach more than 87%.
As can be seen from examples 13 and 14, when methylene chloride is used as a solvent and ytterbium triflate is used for catalysis, the purification treatment is not needed after the first-step reaction is finished, and the second-step reaction is directly carried out after the post-treatment, so that the total yield obtained by the step reaction and the one-step reaction is consistent, the reaction steps can be saved, and the reaction operation can be simplified.
It can be seen from examples 14 and 15 that the effect of the methyl donor as trioxymethylene or paraformaldehyde in the second reaction step on the total yield of the reaction is not great, and similarly, the effect of the dehydrating agent as 3A molecular sieve or anhydrous calcium sulfate in the second reaction step on the total yield of the reaction is small as can be seen from examples 14 and 16.
Finally, it should be noted that the above-mentioned embodiments illustrate rather than limit the scope of the invention, and that those skilled in the art will understand that changes can be made to the technical solutions of the invention or equivalents thereof without departing from the spirit and scope of the technical solutions of the invention.
Claims (3)
1. The synthesis method of the 5' -methoxy laudan (I) is characterized by comprising the following steps:
(1) Reacting a compound shown in a formula II with a compound shown in a formula III under an acidic condition to obtain a compound shown in a formula IV;
(2) Reacting a compound shown in a formula IV with a methyl donor under an acidic condition to obtain a compound shown in a formula I;
in the step (1), the reaction under the acidic condition is catalyzed by adding ytterbium triflate catalyst into dichloromethane, and dehydrating by adding dehydrating agent, wherein the reaction temperature is 23-27 ℃ and the reaction time is 22-24 hours; the molar ratio of the ytterbium triflate catalyst to the compound shown in the formula II is 0.05-0.1: 1, a step of; the dehydrating agent is molecular sieve or anhydrous calcium sulfate; in the step (2), the methyl donor is trioxymethylene or paraformaldehyde; acidic conditions refer to reaction in formic acid solution;
。
2. the method of claim 1, wherein in the step (1), the molar ratio of the compound represented by the formula II to the compound represented by the formula III is 1:1.0-1.2.
3. The synthesis method according to claim 1, wherein in the step (2), the reaction is a reflux reaction for 4 to 6 hours.
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