CN106543171A - A kind of berberine synthesis technique - Google Patents
A kind of berberine synthesis technique Download PDFInfo
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- CN106543171A CN106543171A CN201610956902.1A CN201610956902A CN106543171A CN 106543171 A CN106543171 A CN 106543171A CN 201610956902 A CN201610956902 A CN 201610956902A CN 106543171 A CN106543171 A CN 106543171A
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- berberine
- homopiperony lamine
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- 238000000034 method Methods 0.000 title claims abstract description 27
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229940093265 berberine Drugs 0.000 title claims abstract description 23
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 18
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 32
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 18
- RRIRDPSOCUCGBV-UHFFFAOYSA-N methylenedioxyphenethylamine Chemical compound NCCC1=CC=C2OCOC2=C1 RRIRDPSOCUCGBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 241000790917 Dioxys <bee> Species 0.000 claims abstract description 17
- JBVNWTXRFKZNBQ-UHFFFAOYSA-N 5-(1,3-benzodioxol-5-yl)-3-hexylcyclohex-2-en-1-one Chemical compound C1C(CCCCCC)=CC(=O)CC1C1=CC=C(OCO2)C2=C1 JBVNWTXRFKZNBQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 16
- 229940081310 piperonal Drugs 0.000 claims abstract description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 homopiperony lamine hydrochlorides Chemical class 0.000 claims abstract description 13
- JIVGSHFYXPRRSZ-UHFFFAOYSA-N 2,3-dimethoxybenzaldehyde Chemical class COC1=CC=CC(C=O)=C1OC JIVGSHFYXPRRSZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 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 10
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- 238000009833 condensation Methods 0.000 claims abstract description 8
- 230000005494 condensation Effects 0.000 claims abstract description 8
- 238000006396 nitration reaction Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940015043 glyoxal Drugs 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000011701 zinc Substances 0.000 claims abstract description 7
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 7
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- NDYXFQODWGEGNU-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)ethanamine;hydron;chloride Chemical compound Cl.NCCC1=CC=C2OCOC2=C1 NDYXFQODWGEGNU-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910000497 Amalgam Inorganic materials 0.000 claims description 5
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 5
- 238000006842 Henry reaction Methods 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 3
- 235000002991 Coptis groenlandica Nutrition 0.000 claims description 2
- 241000218202 Coptis Species 0.000 claims 1
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 abstract description 3
- 239000012280 lithium aluminium hydride Substances 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
- 235000019441 ethanol Nutrition 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 235000002566 Capsicum Nutrition 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006002 Pepper Substances 0.000 description 2
- 241000722363 Piper Species 0.000 description 2
- 235000016761 Piper aduncum Nutrition 0.000 description 2
- 235000017804 Piper guineense Nutrition 0.000 description 2
- 235000008184 Piper nigrum Nutrition 0.000 description 2
- 241000607764 Shigella dysenteriae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940007046 shigella dysenteriae Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 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 1
- 240000000724 Berberis vulgaris Species 0.000 description 1
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 244000247747 Coptis groenlandica Species 0.000 description 1
- 244000301850 Cupressus sempervirens Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061166 Gastroenteritis bacterial Diseases 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical compound [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- ONJMNXFNTYIEEA-UHFFFAOYSA-N benzene ethene Chemical compound C1=CC=CC=C1.C=C.C=C.C=C ONJMNXFNTYIEEA-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of berberine synthesis technique, synthetic route is as follows：With catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent, synthesizes piperonyl cyclonene.Piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method.Piperonal reacts nitration by Henry and generates 3,4 dioxy methine styrene of β nitros.3,4 dioxy methine styrene of β nitros generates homopiperony lamine by Clemensen reduction.Homopiperony lamine and the condensation of 2,3 dimethoxy benzaldehydes restore generation 2,3 veratryl homopiperony lamine hydrochlorides of N.2,3 veratryl homopiperony lamine hydrochlorides of N are cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.The synthetic route of the present invention, it is to avoid cyanogenation, reduces toxicity.H is replaced using zinc amalgam2Ni and LiAlH4, cost is substantially reduced, technology difficulty is reduced, product yield is improved.
Description
Technical field
The invention belongs to medicine organic synthesis field, and in particular to a kind of berberine synthesis technique.
Background technology
Berberine is a kind of important alkaloid, is China's application Chinese medicine for a long time.Can be from the coptis, golden cypress, barberry etc.
Extract in plant.It has significant bacteriostasis.Conventional Halomine is called Berberine hydrochloride, and berberine can be to disease-resistant
Pathogenic microorganism, has suppression to various bacteria such as shigella dysenteriae, tubercle bacillus, pneumococcus, typhoid bacillus and corynebacterium diphtheriae etc.
Effect, wherein acting on shigella dysenteriae most strong, is commonly used to treat the disease of digestive tracts such as bacterial gastroenteritis, dysentery.It is clinical main
For treating bacillary dysentery and enterogastritis, its side effect is less.
National bulk drug technique that medicine management general bureau of country in 1980 publishes collect in also play-by-play berberine
Synthesis.But the preparation process route of these methods is very long, cause production cost height, product yield low.
The Chinese patent application of Publication No. CN 1312250A discloses the preparation method of a kind of berberine and its esters,
Catechol is adopted in the invention for initiation material, Jing annulations obtain piperonyl cyclonene, Jing chlorine cyanogenations obtain pepper acetonitrile, Jing
Condensation, catalysis, hydrogenation obtain condensation product hydrochloride, and Jing ring-closure reactions obtain berberine crude product, and Jing is alkalized, hydrochloric acid Huang is obtained into salt
Lian Su.In the method, catechol is adopted for initiation material, hence it is evident that reduce synthetic route, but there is cyanogenation, toxicity is big,
Operating personnel and environment are worked the mischief.
The content of the invention
The present invention seeks to a kind of berberine synthesis technique, solves original berberine synthesis technique high cost, technique is difficult
Degree is big, and low yield is the big problem of toxicity.
The technical scheme is that：A kind of berberine synthesis technique, synthetic route are as follows：
Further, it is the dimethyl sulfoxide in the basic conditions, with catechol and dichloromethane as raw material that formula I arrives formula II
For solvent, at 95-120 DEG C, synthesize piperonyl cyclonene.
Further, formula II is that piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method to formula III.
Further, formula III is that piperonal reacts nitration generation β-nitro -3,4- dioxies time first by Henry to formula IV
Base styrene.
Further, formula IV is β-nitro -3 to formula V, and 4- dioxy methine styrene is by Clemensen reduction generation
Homopiperony lamine.
Further, formula V is that homopiperony lamine and the condensation of 2,3- dimethoxy benzaldehyde restore generation N-2,3- to formula VI
Veratryl homopiperony lamine hydrochloride.
Further, formula VI is N-2 to formula VII, and 3- veratryl homopiperony lamine hydrochlorides are in glyoxal, formic acid, sulfuric acid
Halomine is cyclized under the conditions of copper.
Specifically, synthetic route is：
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, in 95-120
DEG C, synthesize piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride in c, piperonal and nitromethane
Generate β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes under the conditions of Pd/C ammonium formates, formic acid
45-60 DEG C of reaction generates N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized hydrochloric acid under the conditions of glyoxal, formic acid, copper sulphate
Berberine.
The present invention core be：Piperonyl cyclonene synthesizes piperonal, pepper by ViLsmeiar formylateds method by piperonyl cyclonene
Aldehyde reacts nitration by Henry and generates β-nitro -3,4- dioxy methine styrene, β-nitro -3,4- dioxy methine benzene
Ethene generates homopiperony lamine by Clemensen reduction.Above-mentioned steps avoid cyanogenation step, and adopt zinc amalgam generation
For H2Ni and LiAlH4, it is possible to decrease technology difficulty, it is cost-effective.
The present invention is had the advantage that compared with prior art：
1st, synthetic route of the invention, it is to avoid cyanogenation, reduces toxicity.
2nd, the present invention adds sodium acetate, methylamine hydrochloride in prepared by nitro compound, makes reaction in suitable pH environment,
It is easy to nitrification to carry out, in nitro compound reduction reaction, H is replaced using zinc amalgam2Ni and LiAlH4, cost is substantially reduced, is subtracted
Few technology difficulty, improves product yield.
Specific embodiment
A kind of berberine synthesis technique, synthetic route are as follows：
Formula I is that with catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent in the basic conditions to formula II,
95-120 DEG C, synthesize piperonyl cyclonene.Formula II is that piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method to formula III.Formula III is arrived
Formula IV is that piperonal reacts nitration generation β-nitro -3,4- dioxy methine styrene by Henry.Formula IV to formula V be β-
Nitro -3,4- dioxy methine styrene generates homopiperony lamine by Clemensen reduction.Formula V to formula VI be homopiperony lamine with
The condensation of 2,3- dimethoxy benzaldehydes restores generation N-2,3- veratryl homopiperony lamine hydrochlorides.It is N- that formula VI arrives formula VII
2,3- veratryl homopiperony lamine hydrochlorides are cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.
Embodiment
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, in 95-120
DEG C, synthesize piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride in c, piperonal and nitromethane
Generate β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes under the conditions of Pd/C ammonium formates, formic acid
45-60 DEG C of reaction generates N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized hydrochloric acid under the conditions of glyoxal, formic acid, copper sulphate
Berberine.
Wherein, the method detailed of step c is：At room temperature by 2000g piperonals, 5000ml nitromethanes, 410g acetic acid
Sodium, 410g methylamine hydrochlorides are dissolved in putting reactor, are stirred 2 hours, after the completion of reaction, are stopped reaction, plus 30000nl water, are placed in
Divide in liquid ware, add 20000ml dichloromethane to extract every time 3 times, organic phase is dried with magnesium sulfate, elimination drier distills back
Solvent is received, yellow crystal is obtained, is recrystallized with absolute ethyl alcohol, less than 80 DEG C dry β-nitro -3,4- dioxy methine styrene
2330g, yield 91%, mp：152-155℃.
The method detailed of Step d is：The β of 2330g-nitro -3,4- dioxy methine styrene, 95% ethanol of 83000ml
It is placed in the zinc amalgam for just having made, stirs under room temperature, once adds 2300ml concentrated hydrochloric acids, temperature voluntarily to rise to 60-70 DEG C, so
Stir 1.5h afterwards under room temperature, reactant becomes colourless, decompression steams ethanol, remain about 15000ml, filter out cadmia, cool down,
With in ammoniacal liquor and alkaline pH 8-9, with chloroform extraction 3 times, once, organic phase magnesium sulfate dry filter steams chloroform, obtains for washing
Yellow oil, plus 10% anhydrous hydrochloric acid-ethanol is neutralized to neutrality, has white crystal to separate out, suction filtration, filter cake are washed with a small amount of ether
Wash, be dried, obtain homopiperony lamine hydrochloride 1048.5g, yield 54%, mp：153-155℃.
Embodiment described above only expresses the specific embodiment of the application, and its description is more concrete and detailed, but and
Therefore the restriction to the application protection domain can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, on the premise of conceiving without departing from technical scheme, some deformations and improvement can also be made, these belong to this
The protection domain of application.
Claims (8)
1. a kind of berberine synthesis technique, it is characterised in that synthetic route is as follows：
2. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula I to formula II is in alkalescence condition
Under, with catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent, at 95-120 DEG C, synthesizes piperonyl cyclonene.
3. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula II passes through to formula III for piperonyl cyclonene
ViLsmeiar formylateds method synthesizes piperonal.
4. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula III passes through to formula IV for piperonal
Henry reaction nitrations generate β-nitro -3,4- dioxy methine styrene.
5. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula IV to formula V is β-nitro -3,
4- dioxy methine styrene generates homopiperony lamine by Clemensen reduction.
6. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula V to formula VI be homopiperony lamine with
The condensation of 2,3- dimethoxy benzaldehydes restores generation N-2,3- veratryl homopiperony lamine hydrochlorides.
7. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula VI to formula VII is N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride is cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.
8. a kind of berberine synthesis technique according to claim 1, it is characterised in that synthetic route is：
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, at 95-120 DEG C,
Synthesis piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride and generate in c, piperonal and nitromethane
β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- dimethoxy benzyls
Base homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes are under the conditions of Pd/C ammonium formates, formic acid in 45-60
DEG C reaction generate N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized the hydrochloric acid coptis under the conditions of glyoxal, formic acid, copper sulphate
Element.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880012A (en) * | 2017-11-09 | 2018-04-06 | 华中药业股份有限公司 | The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' |
| CN108164498A (en) * | 2018-02-08 | 2018-06-15 | 河南普瑞制药有限公司 | A kind of preparation method of berberine and dopamine intermediate homopiperony lamine |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
| CN109232556A (en) * | 2018-10-08 | 2019-01-18 | 佑华制药（乐山）有限公司 | A kind of Berberine hydrochloride production technology |
| CN109320492A (en) * | 2018-11-30 | 2019-02-12 | 湖北文理学院 | Method for preparing piperine ethylamine hydrochloride and berberine |
| CN109666016A (en) * | 2019-01-09 | 2019-04-23 | 沈阳化工大学 | A method of homopiperony lamine is prepared by raw material of catechol |
| CN110563693A (en) * | 2019-09-30 | 2019-12-13 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | A kind of synthetic method and application of epiberberine |
| CN112341454A (en) * | 2020-11-24 | 2021-02-09 | 四川大学华西医院 | Berberine derivative, preparation method thereof and application thereof as p300 HAT small molecule inhibitor |
| CN113072548A (en) * | 2021-03-19 | 2021-07-06 | 四川大学 | Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
| CN113831318A (en) * | 2021-09-10 | 2021-12-24 | 四川大学 | Synthetic method of piperonylethylamine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1312250A (en) * | 2001-01-19 | 2001-09-12 | 东北制药总厂 | Preparation of berberine and its salts |
| CN102952132A (en) * | 2012-10-19 | 2013-03-06 | 山东科技大学 | Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material |
-
2016
- 2016-10-28 CN CN201610956902.1A patent/CN106543171A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1312250A (en) * | 2001-01-19 | 2001-09-12 | 东北制药总厂 | Preparation of berberine and its salts |
| CN102952132A (en) * | 2012-10-19 | 2013-03-06 | 山东科技大学 | Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material |
Non-Patent Citations (2)
| Title |
|---|
| 陈程等: "盐酸黄连素的合成研究", 《有机化学》 * |
| 马红敏: "新型四氢原小檗碱-阿朴菲二聚体thalibealine及阿朴菲生物碱d-荷苞牡丹碱的全合成研究", 《中国医学科学院中国协和医科大学博士研究生学位论文》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN108164498A (en) * | 2018-02-08 | 2018-06-15 | 河南普瑞制药有限公司 | A kind of preparation method of berberine and dopamine intermediate homopiperony lamine |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
| CN109232556A (en) * | 2018-10-08 | 2019-01-18 | 佑华制药（乐山）有限公司 | A kind of Berberine hydrochloride production technology |
| CN109320492A (en) * | 2018-11-30 | 2019-02-12 | 湖北文理学院 | Method for preparing piperine ethylamine hydrochloride and berberine |
| CN109666016A (en) * | 2019-01-09 | 2019-04-23 | 沈阳化工大学 | A method of homopiperony lamine is prepared by raw material of catechol |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | A kind of synthetic method and application of epiberberine |
| CN110563693A (en) * | 2019-09-30 | 2019-12-13 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN110563693B (en) * | 2019-09-30 | 2022-10-21 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN112341454A (en) * | 2020-11-24 | 2021-02-09 | 四川大学华西医院 | Berberine derivative, preparation method thereof and application thereof as p300 HAT small molecule inhibitor |
| CN112341454B (en) * | 2020-11-24 | 2022-02-11 | 四川大学华西医院 | A kind of berberine derivative, its preparation method and its application as p300 HAT small molecule inhibitor |
| CN113072548A (en) * | 2021-03-19 | 2021-07-06 | 四川大学 | Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
| CN113831318A (en) * | 2021-09-10 | 2021-12-24 | 四川大学 | Synthetic method of piperonylethylamine |
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