CN111533691A - Preparation method of Rosxastat - Google Patents
Preparation method of Rosxastat Download PDFInfo
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- CN111533691A CN111533691A CN202010515633.1A CN202010515633A CN111533691A CN 111533691 A CN111533691 A CN 111533691A CN 202010515633 A CN202010515633 A CN 202010515633A CN 111533691 A CN111533691 A CN 111533691A
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- phenoxyisoquinoline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960000583 acetic acid Drugs 0.000 claims abstract description 16
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 16
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims abstract description 16
- WJGPMRFWBJZJOQ-UHFFFAOYSA-N methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate Chemical compound C1=CC2=C(O)C(C(=O)OC)=NC(C)=C2C=C1OC1=CC=CC=C1 WJGPMRFWBJZJOQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011701 zinc Substances 0.000 claims abstract description 14
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 8
- VGIVLIHKENZQHQ-UHFFFAOYSA-N n,n,n',n'-tetramethylmethanediamine Chemical compound CN(C)CN(C)C VGIVLIHKENZQHQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004471 Glycine Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- YTWDBRIDKWWANA-UHFFFAOYSA-N methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate Chemical compound C1=CC2=C(O)C(C(=O)OC)=NC=C2C=C1OC1=CC=CC=C1 YTWDBRIDKWWANA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical compound OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 2
- 229960003052 roxarsone Drugs 0.000 claims description 2
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 claims 5
- 229960000245 rasagiline Drugs 0.000 claims 5
- 239000008346 aqueous phase Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XJOTXKZIRSHZQV-RXHOOSIZSA-N (3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S,3S)-1-[[(1R,6R,12R,17R,20S,23S,26R,31R,34R,39R,42S,45S,48S,51S,59S)-51-(4-aminobutyl)-31-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]-20-benzyl-23-[(2S)-butan-2-yl]-45-(3-carbamimidamidopropyl)-48-(hydroxymethyl)-42-(1H-imidazol-4-ylmethyl)-59-(2-methylsulfanylethyl)-7,10,19,22,25,33,40,43,46,49,52,54,57,60,63,64-hexadecaoxo-3,4,14,15,28,29,36,37-octathia-8,11,18,21,24,32,41,44,47,50,53,55,58,61,62,65-hexadecazatetracyclo[32.19.8.26,17.212,39]pentahexacontan-26-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)[C@@H](C)O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@@H](NC1=O)[C@@H](C)CC)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1cnc[nH]1)NC3=O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N2)C(=O)NCC(=O)N4)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJOTXKZIRSHZQV-RXHOOSIZSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 101100346764 Mus musculus Mtln gene Proteins 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction 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
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 102000018511 hepcidin Human genes 0.000 description 1
- 108060003558 hepcidin Proteins 0.000 description 1
- 229940066919 hepcidin Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- -1 hydrogen ions Chemical class 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of Rosesastat comprises the steps of taking 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials, putting the raw materials into glacial acetic acid, obtaining 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester after the reaction is finished, dissolving the obtained 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester into the glacial acetic acid, adding zinc, adding diluted hydrochloric acid, and obtaining 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester after the reaction is finished; and mixing the obtained 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat. The method has the advantages of mild reaction conditions, simple and controllable operation, low preparation cost, suitability for large-scale industrial production, high purity of the obtained target product and capability of meeting the production requirements of enterprises.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of a roxarsone.
Background
The roxasistat is a novel Hypoxia Inducible Factor (HIF) -Prolyl Hydroxylase (PH) enzyme inhibitor, and can inhibit the degradation of HIF, activate the transcription of related genes, generate corresponding physiological response, moderately increase the concentration of erythropoietin, improve the sensitivity of an Erythropoietin (EPO) receptor, coordinate the generation of red blood cells, reduce the level of hepcidin, increase the content and activity of a transferrin receptor, promote the absorption and utilization of iron and have good tolerance. The chemical structural formula of the roxasistat is shown as the following formula:
the invention patent WO2014/14834 discloses a synthesis method of the compound, and the reaction process is shown as the following route:
in the route, the reaction time for preparing A2 from A1 is long, about 30 hours is needed, the conversion rate is low, about 60-70 percent, and the production requirements of enterprises cannot be effectively met. A3 is prepared by palladium-carbon hydrogenation reduction and has certain operation difficulty and risk.
Disclosure of Invention
The invention aims to provide a preparation method of the roxasistat, aiming at the defects of the prior art, the preparation method is mild in reaction conditions, simple and controllable in operation, low in preparation cost, suitable for large-scale industrial production, high in purity of the obtained target product and capable of meeting the production requirements of enterprises.
The technical scheme of the invention is as follows: a preparation method of the roxburgh comprises the following steps:
1) dissolving 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials in glacial acetic acid until the reaction is finished to obtain 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-methyl carboxylate;
2) dissolving the 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester obtained in the step 1) in glacial acetic acid, adding zinc, and then adding hydrochloric acid until the reaction is finished to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester;
3) mixing the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester obtained in the step 2) with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat.
The synthetic route of the invention is as follows:
further, the mol ratio of the 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate to the tetramethylmethanediamine in the step 1) is 1: 1-1.5.
Preferably, the molar ratio of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester to tetramethylmethanediamine in step 1) is 1: 1.2.
further, the temperature of the reaction in the step 1) is 55-60 ℃.
Further, in the step 2), the molar ratio of the solute of the methyl 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylate, zinc and hydrochloric acid is 1: 2-5: 0.1-0.2.
Preferably, the molar ratio of the solute of 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester, zinc and hydrochloric acid in the step 2) is 1: 2.5: 0.15.
further, after the reaction in the step 2) is finished, filtering, removing zinc, adding a mixture of dichloromethane and water, oscillating and layering, taking an organic phase, extracting a water phase with dichloromethane, combining with the organic phase, and evaporating the organic phase to obtain the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester.
Further, after the reaction in the step 3) is finished, cooling, filtering, drying a filter cake, then putting the filter cake into a mixed solution of water and ethyl acetate, stirring, layering, taking a water phase, dropwise adding glacial acetic acid, cooling, crystallizing, filtering, and refining the filter cake with acetone to obtain the target product of the rosixostat.
Further, the zinc is in a powder shape and/or a granular shape and/or a flake shape.
Adopt above-mentioned technical scheme to have following beneficial effect:
1. the invention utilizes 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester to react (reduce) with zinc in glacial acetic acid, and hydrochloric acid is added to provide hydrogen ions and enhance the reducibility of zinc, thereby playing a role in catalyzing reaction. The 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-methyl carboxylate obtained by synthesis has the advantages of quick reaction, short reaction time, reaction completion only within about 6 hours, single solvent used in the synthesis process, glacial acetic acid only, and reduced use amount of auxiliary materials, thereby effectively reducing production and management costs of enterprises, avoiding operation risks caused by hydrogenation reaction of palladium and carbon in the traditional synthesis method, reducing reaction procedures, and effectively reducing material cost and production period.
2. After the intermediate of the formula 3 is synthesized, water and dichloromethane are used for extraction treatment, metal salt inorganic impurities in the intermediate of the formula 3 can be efficiently removed, the purity of the intermediate of the formula 3 is improved, the subsequent synthesis of the target product is facilitated, and the yield of the target product is improved.
3. The reaction time for preparing the formula 3 from the formula 2 is only about 6 hours, so that the synthesis efficiency is greatly improved compared with the traditional synthesis route; the yield of the prepared roxasistat is 85-90%, the utilization rate of raw materials is high, the purity of the roxasistat is more than 95%, and the production requirements of enterprises are met.
The following description will be further described with reference to specific embodiments.
Drawings
FIG. 1 is a liquid chromatogram of the objective product of example 5;
FIG. 2 is a nuclear magnetic diagram of the target product of example 5;
FIG. 3 is a mass spectrum of the target product of example 5.
Detailed Description
In the invention, the used 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate is purchased from Moxi pharmaceutical technology company of Tianjin method, and the purity is more than or equal to 99.0 percent; tetramethylmethanediamine, available from Molekay pharmaceutical science and technology, Inc., Changzhou, with a purity of greater than or equal to 98.0%; glycine, a western reagent, more than or equal to 98.0 percent, and sodium methoxide, wherein the content is 5 mol/L.
Example 1
Preparation of methyl 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylate (formula 2), reaction formula:
in a 250ml three-necked round bottom flask, 20g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (formula 1), 8.3g of tetramethyldiamine, and 30g of glacial acetic acid were added. And after the feeding is finished, heating to 55-60 ℃, and reacting for 12 hours until the raw materials in the liquid phase are basically reacted. And cooling to obtain a glacial acetic acid solution containing 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester, wherein the liquid phase purity is 97.0-98.5%.
Example 2
Preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester by the following reaction scheme:
adding 25g of glacial acetic acid solution containing 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester (formula 2) and 13g of zinc powder into a 1L four-mouth bottle, stirring, then adding 7.5g of 5% diluted hydrochloric acid, heating to 50-60 ℃, cooling until the raw materials in a liquid phase basically react, filtering, and carrying out rotary evaporation on the filtrate to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester (formula 3), wherein the purity is 96.9%, and the yield is 87.7%.
Example 3
Preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester
Adding 25g of glacial acetic acid solution containing 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester (formula 2) and 13g of flaky zinc sheet into a 1L four-mouth bottle, stirring, adding 7.5g of 5% diluted hydrochloric acid, and heating to 50-60 ℃. Cooling and filtering the liquid phase until the raw materials basically react, and carrying out rotary evaporation on the filtrate to obtain the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (formula 3).
Example 4
Preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester
Adding 25g of glacial acetic acid solution containing 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester (shown in a formula 2) and 13g of granular zinc particles into a 1L four-mouth bottle, stirring, adding 7.5g of 5% diluted hydrochloric acid, and heating to 50-60 ℃. Cooling, filtering, and rotary evaporating the filtrate to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (formula 3).
Example 5
Preparation of rasagilite (formula 4) according to the following reaction scheme:
20g of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (formula 3) and 13g of glycine are dissolved in 200ml of methanol, and 100g of a sodium methoxide methanol solution is added dropwise. Heating to reflux reaction. And (2) cooling and filtering until the basic reaction of the raw materials in the liquid phase is finished for about 16 hours, drying a filter cake, then putting the filter cake into a mixed solution of water and ethyl acetate, stirring, layering, taking the water phase, dropwise adding glacial acetic acid, cooling, crystallizing, filtering, refining the filter cake by using acetone to obtain 16g of the target product, namely the roxasistat (formula 4), wherein the yield is 70.2%, the liquid chromatogram is shown in figure 1, the purity of the target product, namely the roxasistat, is more than 99%, the nuclear magnetic diagram is shown in figure 2, the mass spectrum is shown in figure 3, and the target product, namely the roxasistat, is obtained by using figures 2 and 3.
Claims (9)
1. A preparation method of a roxarsone is characterized by comprising the following steps:
1) dissolving 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials in glacial acetic acid until the reaction is finished to obtain 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-methyl carboxylate;
2) dissolving the 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester obtained in the step 1) in glacial acetic acid, adding zinc, and then adding hydrochloric acid until the reaction is finished to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester;
3) mixing the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester obtained in the step 2) with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat.
2. The process for the preparation of Rosesastat according to claim 1 wherein the molar ratio of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, tetramethylmethanediamine in step 1) is 1: 1-1.5.
3. The process for the preparation of Rosesastat according to claim 1 or 2 characterized in that the molar ratio of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, tetramethylmethanediamine in step 1) is 1: 1.2.
4. process for the preparation of rasagiline according to claim 1 characterized in that the temperature of the reaction of step 1) is 55-60 ℃.
5. The process for the preparation of Rosesastat according to claim 1 wherein the molar ratio of the solutes of methyl 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylate, zinc, hydrochloric acid in step 2) is 1: 2-5: 0.1-0.2.
6. The process for the preparation of Rosesastat according to claim 1 or 5, wherein the molar ratio of the solute of 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester, zinc, hydrochloric acid in step 2) is 1: 2.5: 0.15.
7. the process for the preparation of rasagiline according to claim 1 wherein after the reaction in step 2) is completed, filtration is carried out to remove zinc, a mixture of dichloromethane and water is added, layers are separated by shaking, the organic phase is taken, the aqueous phase is extracted with dichloromethane, combined with the organic phase and the organic phase is evaporated to dryness to obtain methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate.
8. The preparation method of the rasagiline of claim 1, wherein after the reaction in step 3), the temperature is reduced, the filtering is performed, the filter cake is dried and then placed into a mixed solution of water and ethyl acetate to be stirred, the layering is performed, the water phase is taken, glacial acetic acid is dripped, the temperature is reduced, the crystallization is performed, the filtering is performed, and the filter cake is refined by acetone to obtain the target product of the rasagiline.
9. Process for the preparation of rasagiline according to claim 1 characterized in that the zinc is in powder and/or granular and/or flake form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010515633.1A CN111533691A (en) | 2020-06-08 | 2020-06-08 | Preparation method of Rosxastat |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010515633.1A CN111533691A (en) | 2020-06-08 | 2020-06-08 | Preparation method of Rosxastat |
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| CN115867537A (en) * | 2020-04-21 | 2023-03-28 | 迈兰实验室有限公司 | Improved process for the preparation of a rasagiline base |
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