CN104788447A - Production process using semi-synthetic method to prepare vincamine - Google Patents
Production process using semi-synthetic method to prepare vincamine Download PDFInfo
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- CN104788447A CN104788447A CN201510188608.6A CN201510188608A CN104788447A CN 104788447 A CN104788447 A CN 104788447A CN 201510188608 A CN201510188608 A CN 201510188608A CN 104788447 A CN104788447 A CN 104788447A
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- CN
- China
- Prior art keywords
- vincamine
- acid
- semi
- vincadifformine
- tabersonine
- Prior art date
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- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 title claims abstract description 84
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960002726 vincamine Drugs 0.000 title claims abstract description 42
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- FNGGIPWAZSFKCN-ACRUOGEOSA-N tabersonine Chemical class N1C2=CC=CC=C2[C@]2([C@H]34)C1=C(C(=O)OC)C[C@]3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-ACRUOGEOSA-N 0.000 claims abstract description 14
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 102000004020 Oxygenases Human genes 0.000 claims abstract description 6
- 108090000417 Oxygenases Proteins 0.000 claims abstract description 6
- GIGFIWJRTMBSRP-ACRUOGEOSA-N (-)-vincadifformine Chemical compound C1C(C(=O)OC)=C2NC3=CC=CC=C3[C@@]22CCN3CCC[C@]1(CC)[C@@H]23 GIGFIWJRTMBSRP-ACRUOGEOSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000012074 organic phase Substances 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- GIGFIWJRTMBSRP-UHFFFAOYSA-N DL-Vincadifformin Natural products C1C(C(=O)OC)=C2NC3=CC=CC=C3C22CCN3CCCC1(CC)C23 GIGFIWJRTMBSRP-UHFFFAOYSA-N 0.000 claims description 18
- NAMSIRMSFVGAKD-UHFFFAOYSA-N vincadifformine Natural products CCC12CCCN3CCC4(C13)C(Nc1cc(OC)ccc41)=C(C2)C(=O)OC NAMSIRMSFVGAKD-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- -1 Pd-CaCO 3 Chemical compound 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 238000001308 synthesis method Methods 0.000 claims description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 239000011941 photocatalyst Substances 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 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 description 2
- 102000008109 Mixed Function Oxygenases Human genes 0.000 claims description 2
- 108010074633 Mixed Function Oxygenases Proteins 0.000 claims description 2
- 230000033228 biological regulation Effects 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000033444 hydroxylation Effects 0.000 abstract description 4
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 229910001220 stainless steel Inorganic materials 0.000 description 9
- 239000010935 stainless steel Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- JSLDLCGKZDUQSH-RTBUJCADSA-N 19-epivindolinine Natural products O=C(OC)[C@H]1[C@@]23[C@H](C)[C@]4([C@@H]5N(CC=C4)CC[C@]25c2c(N3)cccc2)C1 JSLDLCGKZDUQSH-RTBUJCADSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KILNDJCLJBOWAN-UHFFFAOYSA-N Tabersonine Natural products CCC12CC(=C3N(C)c4cc(OC)ccc4C35CCN(CC=C1)C25)C(=O)OC KILNDJCLJBOWAN-UHFFFAOYSA-N 0.000 description 3
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 3
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 3
- 229910052721 tungsten Inorganic materials 0.000 description 3
- 239000010937 tungsten Substances 0.000 description 3
- FNGGIPWAZSFKCN-UHFFFAOYSA-N xi-tabersonine Natural products N1C2=CC=CC=C2C2(C34)C1=C(C(=O)OC)CC3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-UHFFFAOYSA-N 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 241000863480 Vinca Species 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- 241000208327 Apocynaceae Species 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241000863486 Vinca minor Species 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002894 chemical waste Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a production process using a semi-synthetic method to prepare vincamine. The production process comprises the following steps: using a tabersonine salt as a reaction starting raw material, performing hydrogeneration catalytic reduction, enzyme method hydroxylation and rearranged crystallization to obtain vincamine. The process is simple and short in process route; the obtained vincamine is high in yield and good in purity; the whole production process is low in cost and suitable for industrial production; the enzyme method hydroxylation is performed by oxygenase, so that the process is clean, safe and environment-friendly.
Description
Technical field
The present invention relates to the synthesis technique of chemicals, specifically a kind of semi-synthesis method prepares the production technique of vincamine.
Background technology
Vincamine, Chinese (3 α, 4 β, 16 α) by name-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylate methyl ester, molecular formula is C
21h
26n
2, belong to single indole alkaloids, be mainly used in treating cerebral ischemia, clinical indication is applicable to cerebrovascular disorder, cerebral embolism, cerebral thrombosis and hemorrhage sequela etc.Because vincamine can penetrate hemato encephalic barrier, in vasodilation, increase cerebral blood flow (CBF), there is good effect, and on heart, blood vessel and blood pressure etc. without impact, be the first-line drug for the treatment of cerebral ischemia.
Vincamine is that extraction and isolation obtains from apocynaceae plant periwinkle (Vinca minor) the earliest, but in periwinkle, the content of vincamine is only 0.7 ‰, and Main Resources is distributed in Europe, and production cost is high, and limitation is large.From the fifties in last century so far, many scientists are devoted to study the synthesis of vincamine, mainly contain semi-synthesis method and complete synthesizing process two kinds of methods.
In US Patent No. 3892755 with biological extraction tabersonine for starting raw material, after hydrogenating reduction, with metachloroperbenzoic acid or p-nitrobenzoic acid oxidation, then with triphenylphosphine reduction, finally use sour water transposition, obtain vincamine.The method metachloroperbenzoic acid or p-nitrobenzoic acid oxidation, in product, metachloroperbenzoic acid or p-nitrobenzoic acid not easily remove.
In Spanish patent FR2577926A1, be starting raw material with tabersonine equally, after hydrogenating reduction, hydrogenation thing made vitriol, use single peroxy maleic acid to be oxidized, then obtain vincamine through reduction transposition.In reaction, single peroxy maleic acid used needs with system, adds production process.
In Chinese patent CN102276599B, tabersonine hydrochloride is adopted to be raw material, through palladium carbon shortening, single peroxy maleic acid oxidation, by reduction translocation reaction, obtained vincamine.Palladium carbon shortening efficiency is lower.And also to use single peroxy maleic acid in this operation.
And existing complete synthesizing process, be all for raw material with indoles parent nucleus derivative.The complete synthesis route of vincamine is long, and the overall yield of these methods is all no more than 10%, high cost, can not realize suitability for industrialized production.
In sum, the method for producing vincamine at present both at home and abroad also exists following problems: complete synthesis operational path is long, and it is large that manufacturing enterprise bears operational risk, produce a large amount of chemical waste and cause very large burden by environment, and all requiring high to production unit, cost is higher, and productive rate is low.In semisynthesis, easily produce difficult impurity, need to use column chromatography and remove, for suitability for industrialized production is made troubles.
Summary of the invention
The object of this invention is to provide the production technique that a kind of semi-synthesis method prepares vincamine, this production technique overcomes the shortcoming in existing vincamine synthetic technology, the industrialization process route of a kind of high yield, the semi-synthetic vincamine of high-quality tabersonine salt is provided, and environmental friendliness, low cost, concise in technology.
For achieving the above object, the technical solution used in the present invention is: a kind of semi-synthesis method prepares the production technique of vincamine, and concrete implementation step is as follows:
Step 1): put in reactor by tabersonine salt, add organic solvent and dissolved, and add hydrogenation catalyst in backward reactor, under 1 ~ 3atm, hydrogenation room temperature reaction, to reacting completely, obtains vincadifformine;
Step 2): in reactor, the acid solution of described vincadifformine pH4 ~ 5 is carried out being dissolved to disperseing completely, add oxygenase again and carry out catalyzed reaction, temperature of reaction controls at 20 ~ 50 DEG C, to reacting completely, and stopped reaction, acid unnecessary in removal system, extracted organic phase, after described organic phase drying, concentrating under reduced pressure, obtains 16-hydroxyl-vincadifformine;
Step 3): described 16-hydroxyl-vincadifformine is joined in reactor, add organic acid, stir, to dissolving completely, adding photocatalyst and carrying out photochmeical reaction, to reacting completely, add the frozen water with organic acid equivalent afterwards, and regulation system pH to 8 ~ 9, then carry out extracted organic phase, described organic phase obtains target product vincamine after concentrated, decolouring, filtration, crystallization, recrystallization.
Here, the synthetic route of this production technique is as follows:
Wherein: formula 1 is tabersonine salt; Formula 2 is vincadifformine; Formula 3 is 16-hydroxyl-vincadifformine; Formula 4 is vincamine.
Preferably, step 1) in organic solvent be 40% ~ 100% methyl alcohol or 50% ~ 95% ethanol.Certain organic solvent solubilized tabersonine salt here.
Further preferably, described step 1) in organic solvent and the weightmeasurement ratio of tabersonine salt be 4 ~ 15:1.
Preferably, described step 1) in hydrogenation catalyst be Raney's nickel, nickel borides, Pd/C, Pd-CaCO3, chlorine three (triphenyl phosphine) closes rhodium, chlorine three (triphenyl phosphine) closes one or more combination in rubidium.
Preferably, described step 2) in oxygenase be hydroxylase.
Preferably, described step 3) in organic acid be one or more combination in glacial acetic acid, formic acid, propionic acid, halo glacial acetic acid, halopropanoic acid.
Preferably, described step 1) in tabersonine salt be hydrochloric acid tabersonine salt or sulfuric acid tabersonine salt.
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages: semi-synthesis method of the present invention prepares the production technique of vincamine, its technique is simple, have employed and obtain tabersonine salt with natural renewable resources extraction and isolation, then obtain vincamine through reduction, hydroxylation and rearrangement.The equipment adopted in this production technique is simple, and have employed oxygenase and carry out enzyme process hydroxylation as catalyzer, and make clean in whole preparation process, safe and environmentally friendly, the purity of the vincamine obtained is high.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further elaborated.Should be understood that these embodiments are for illustration of ultimate principle of the present invention, principal character and advantage, and the present invention is not limited by the following examples.The implementation condition adopted in embodiment can do further adjustment according to specific requirement, and not marked implementation condition is generally the condition in normal experiment.Embodiment is raw materials used is industrial goods.
Embodiment 1
This example provides a kind of preparation method of vincamine, be specifically implemented as follows:
1) taking hydrochloric acid tabersonine salt 5.0kg drops in the stainless steel cauldron of 100L, add 75% ethanol 50L, stirring at room temperature is dissolved completely to hydrochloric acid tabersonine salt, and in backward reactor, add 250g Raney's nickel, pass into hydrogen, stir after 0.5h, and control hydrogen pressure at 1.1atm, under room temperature, react 8h.After having reacted, pass into nitrogen 10min, Filtration of catalyst Raney's nickel, concentrated to obtain the thick product of vincadifformine, then with ethyl acetate-ethanol, crystallization is carried out to this thick product and obtain the hydrochloric acid vincadifformine 4.8kg that purity is greater than 99.0%;
2) by step 1) in obtained hydrochloric acid vincadifformine put in 100L stainless steel cauldron, add the aqueous acetic acid 60L of pH=4.5, stirring at room temperature is dissolved to hydrochloric acid vincadifformine, is filled with nitrogen protection afterwards, lucifuge room temperature reaction 8h.TLC detection reaction process, disappears to vincadifformine intermediate, generates 16-hydroxyl-vincadifformine, and adds 5%NaHCO in backward reaction solution
3solution, regulates pH to 8, separates organic phase, and with 20L dichloromethane extraction twice, merge organic phase, with anhydrous sodium sulphate 500g dried overnight, concentrating under reduced pressure must be the 16-hydroxyl-vincadifformine crude product of oily mater.16-hydroxyl-vincadifformine 4.0kg is obtained again with dichloromethane-acetone crystallization;
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add glacial acetic acid 70L, stirring at room temperature is dissolved, then adds the rose-red 350g of photocatalyst, opens tungsten lamp.TLC detection reaction process, substantially disappears to 16-hydroxyl-vincadifformine, adds frozen water 70L, then adjusts pH to 8 with 1%NaOH, with dichloromethane extraction secondary, merges organic phase and is concentrated into 20L volume, add decolorizing with activated carbon 30min.Filter to obtain organic phase, with anhydrous sodium sulphate 500g dried overnight, mother liquor adds a certain amount of methanol crystallization, obtains vincamine crude product.Crude product, again with methylene dichloride and methanol system recrystallization, obtains the vincamine sterling 2.9kg that purity is 99.1%.
Embodiment 2
This example provides a kind of preparation method of vincamine, be specifically implemented as follows:
1) take sulfuric acid tabersonine salt 5.0kg to drop in the L stainless steel cauldron of 100, add 40% methyl alcohol 100L, stirring at room temperature is dissolved completely to sulfuric acid tabersonine salt, then add 50g nickel borides, pass into hydrogen, stir after 0.5h, and control hydrogen pressure at 1.1atm, reaction 12h.After having reacted, pass into nitrogen 10min, Filtration of catalyst nickel borides, concentrated to obtain the thick product of vincadifformine, then obtain with ethyl acetate-ethanol crystallization the sulfuric acid vincadifformine 4.0kg that purity is greater than 99.0%;
2) by step 1) in the sulfuric acid vincadifformine of gained be placed in 100L stainless steel cauldron, add pH=5 aqueous acetic acid 80L, stirring at room temperature is dissolved, and be filled with nitrogen protection afterwards, lucifuge room temperature reaction is about 12h.TLC detection reaction process, disappears to vincadifformine intermediate, generates 16-hydroxyl-vincadifformine.5%NaHCO is added in reaction solution
3solution, regulates pH to 8.Separate organic phase, then with 20L dichloromethane extraction twice, merge organic phase, with anhydrous sodium sulphate 500g dried overnight, concentrating under reduced pressure must be the 16-hydroxyl-vincadifformine crude product of oily mater.16-hydroxyl-vincadifformine 3.7kg is obtained again with dichloromethane-acetone crystallization;
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add trichoroacetic acid(TCA) 60L, stirring at room temperature is dissolved, then adds rose-red 250g, open tungsten lamp, TLC detection reaction process, substantially disappears to 16-hydroxyl-vincadifformine, adds frozen water 60L, pH to 8 is adjusted again with 1%NaOH, with dichloromethane extraction secondary, merge organic phase and be concentrated into 20L volume, add decolorizing with activated carbon 30min.Filter to obtain organic phase, with anhydrous sodium sulphate 500g dried overnight, mother liquor adds a certain amount of methanol crystallization, obtains vincamine crude product, and this crude product, again with methylene dichloride and methanol system recrystallization, obtains the vincamine sterling 2.8kg that purity is 99.0%.
Embodiment 3
This example provides a kind of preparation method of vincamine, be specifically implemented as follows:
1) take hydrochloric acid tabersonine salt 5.0kg to drop in 100L stainless steel cauldron, add 95% ethanol 80L, stirring at room temperature is dissolved completely to hydrochloric acid tabersonine salt, then adds 500g PdCO
3, pass into hydrogen, stir after 0.5h, and control hydrogen pressure 1.1atm, reaction 8h, after having reacted, passes into nitrogen 10min, Filtration of catalyst PdCO
3, concentrated to obtain the thick product of vincadifformine, then to obtain with ethyl acetate-ethanol crystallization the hydrochloric acid vincadifformine 4.6kg that purity is greater than 99.0%;
2) by step 1) the hydrochloric acid vincadifformine of gained is placed in 100L stainless steel cauldron, and add pH=4 aqueous acetic acid 50L, stirring at room temperature is dissolved, and be filled with nitrogen protection afterwards, lucifuge room temperature reaction is about 10h.TLC detection reaction process, disappears to vincadifformine intermediate, generates 16-hydroxyl-vincadifformine, in reaction solution, adds 5%NaHCO
3solution, regulates pH to 8, separates organic phase, again with 20L dichloromethane extraction twice, merge organic phase, with anhydrous sodium sulphate 500g dried overnight, concentrating under reduced pressure must be the 16-hydroxyl-vincadifformine crude product of oily mater, then obtains 16-hydroxyl-vincadifformine 3.4kg with dichloromethane-acetone crystallization;
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add propionic acid 90L, stirring at room temperature is dissolved, add rose-red 450g again, open tungsten lamp, TLC detection reaction process, substantially disappears to 16-hydroxyl-vincadifformine, adds frozen water 90L, pH to 9 is adjusted again with 1%NaOH, with dichloromethane extraction secondary, merge organic phase and be concentrated into 20L volume, add decolorizing with activated carbon 30min, filter to obtain organic phase, with anhydrous sodium sulphate 500g dried overnight, mother liquor adds a certain amount of methanol crystallization, obtains vincamine crude product.Crude product, again with methylene dichloride and methanol system recrystallization, obtains the sterling 2.8kg that purity is 99.2% vincamine.
Above-described embodiment is only for illustrating technical conceive of the present invention and feature; its object is to person skilled in the art can be understood content of the present invention and be implemented; can not limit the scope of the invention with this; all equivalences done according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (7)
1. semi-synthesis method prepares a production technique for vincamine, it is characterized in that, concrete implementation step is as follows:
Step 1): put in reactor by tabersonine salt, adds organic solvent and is dissolved, and add hydrogenation catalyst in backward reactor, and under 1 ~ 3atm, hydrogenation room temperature reaction, to reacting completely, obtains vincadifformine;
Step 2): in reactor, the acid solution of described vincadifformine pH4 ~ 5 is carried out being dissolved to disperseing completely, add oxygenase again and carry out catalyzed reaction, temperature of reaction controls at 20 ~ 50 DEG C, to reacting completely, and stopped reaction, acid unnecessary in removal system, extracted organic phase, after described organic phase drying, concentrating under reduced pressure, obtains 16-hydroxyl-vincadifformine;
Step 3): described 16-hydroxyl-vincadifformine is joined in reactor, add organic acid, stir, to dissolving completely, adding photocatalyst and carrying out photochmeical reaction, to reacting completely, add the frozen water with organic acid equivalent afterwards, and regulation system pH to 8 ~ 9, then carry out extracted organic phase, described organic phase obtains target product vincamine after concentrated, decolouring, filtration, crystallization, recrystallization.
2. semi-synthesis method according to claim 1 prepares the production technique of vincamine, it is characterized in that: the organic solvent in step 1) is 40% ~ 100% methyl alcohol or 50% ~ 95% ethanol.
3. semi-synthesis method according to claim 1 and 2 prepares the production technique of vincamine, it is characterized in that: the weightmeasurement ratio of the organic solvent in described step 1) and tabersonine salt is 4 ~ 15:1.
4. semi-synthesis method according to claim 1 prepares the production technique of vincamine, it is characterized in that: the hydrogenation catalyst in described step 1) is Raney's nickel, nickel borides, Pd/C, Pd-CaCO
3, chlorine three (triphenyl phosphine) closes rhodium, chlorine three (triphenyl phosphine) closes one or more combination in rubidium.
5. semi-synthesis method according to claim 1 prepares the production technique of vincamine, it is characterized in that: described step 2) in oxygenase be hydroxylase.
6. semi-synthesis method according to claim 1 prepares the production technique of vincamine, it is characterized in that: the organic acid in described step 3) is one or more the combination in glacial acetic acid, formic acid, propionic acid, halo glacial acetic acid, halopropanoic acid.
7. semi-synthesis method according to claim 1 prepares the production technique of vincamine, it is characterized in that: the tabersonine salt in described step 1) is hydrochloric acid tabersonine salt or sulfuric acid tabersonine salt.
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| CN113321643A (en) * | 2021-06-17 | 2021-08-31 | 四川大学 | Intermediate, preparation method and application thereof in synthesizing vincamine |
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Denomination of invention: A production process of vinblastine by semi synthetic method Effective date of registration: 20210930 Granted publication date: 20160831 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |
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Date of cancellation: 20221031 Granted publication date: 20160831 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |