CN112624941A - Method for producing entacapone - Google Patents
Method for producing entacapone Download PDFInfo
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- CN112624941A CN112624941A CN202011624351.1A CN202011624351A CN112624941A CN 112624941 A CN112624941 A CN 112624941A CN 202011624351 A CN202011624351 A CN 202011624351A CN 112624941 A CN112624941 A CN 112624941A
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- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 title claims abstract description 34
- 229960003337 entacapone Drugs 0.000 title claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960000583 acetic acid Drugs 0.000 claims abstract description 16
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 14
- INFACQKUQJGVFF-UHFFFAOYSA-N 4-hydroxy-5-methoxy-2-nitrobenzaldehyde Chemical compound COC1=CC(C=O)=C([N+]([O-])=O)C=C1O INFACQKUQJGVFF-UHFFFAOYSA-N 0.000 claims abstract description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 12
- BBFJODMCHICIAA-UHFFFAOYSA-N 3,4-dihydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC(C=O)=CC([N+]([O-])=O)=C1O BBFJODMCHICIAA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 8
- 238000006396 nitration reaction Methods 0.000 claims abstract description 8
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims abstract description 8
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000012141 vanillin Nutrition 0.000 claims abstract description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000007664 blowing Methods 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 description 15
- 239000002994 raw material Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 5
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- -1 3, 4-dihydroxy-5-nitrophenyl Chemical group 0.000 description 1
- RYSHIRFTLKZVIH-UHFFFAOYSA-N N,N-diethylcyanoacetamide Chemical compound CCN(CC)C(=O)CC#N RYSHIRFTLKZVIH-UHFFFAOYSA-N 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for producing entacapone, which comprises nitration reaction, demethylation reaction and condensation reaction, wherein the nitration reaction is finished by glacial acetic acid, vanillin and 65% nitric acid within 3-5 hours; the demethylation reaction is completed by the reaction of nitrovanillin, dichloromethane, tetrabutylammonium bromide, anhydrous aluminum chloride and pyridine; the condensation reaction is completed by the reaction of isopropanol, 3, 4-dihydroxy-5-nitrobenzaldehyde, N-N-diethyl cyanoacetamide and piperidine. The method for producing entacapone provided by the invention has the advantages of high yield, high purity and stable quality.
Description
Technical Field
The invention relates to the technical field of production of neurological drugs, in particular to a production method of entacapone.
Background
The chemical name of entacapone is: (E) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -N, N-diethyl-2-acrylamide of formula: C14H15N3O5, molecular weight: 305.28. belongs to a catechol-O-methyltransferase (COMT) inhibitor, which is a reversible, specific COMT inhibitor mainly acting on the periphery and is used together with a levodopa preparation.
Clinical tests show that the levodopa added with the product can prolong the on time by 16 percent and shorten the off time by 24 percent. This product mainly inhibits COMT in the surrounding tissues. The COMT inhibition effect in erythrocytes is closely related to the plasma concentration of the product, and shows the reversibility of the COMT inhibition effect.
Disclosure of Invention
The invention provides a method for producing entacapone, which comprises the following steps:
step S1, nitration, comprising:
step S11: adding glacial acetic acid and vanillin into a reaction tank, dropwise adding 65% nitric acid at 15-30 ℃, reacting for 3-5 hours at 20-30 ℃, adding purified water, and stirring for 1 hour;
step S12: centrifugal filtration;
step S13: drying by blowing at 40-50 ℃ for 12-14 hours to obtain an intermediate nitrovanillin;
step S2, demethylation reaction, comprising:
step S21: adding nitrovanillin, dichloromethane and tetrabutylammonium bromide into a reaction tank, adding anhydrous aluminum chloride at 0-5 ℃, adding pyridine at 0-10 ℃, performing reflux reaction for 23-25 hours, adding 3N hydrochloric acid, and stirring for 3 hours;
step S22: centrifugal filtration;
step S23: drying by blowing at 40-50 ℃ for 10-13 hours to obtain an intermediate 3, 4-dihydroxy-5-nitrobenzaldehyde;
step S3, a condensation reaction comprising:
step S31: adding isopropanol, 3, 4-dihydroxy-5-nitrobenzaldehyde, N-N-diethyl cyanoacetamide and piperidine into a reaction tank, and carrying out reflux reaction for 22-24 hours;
step S32: concentrating under reduced pressure, adding glacial acetic acid and hydrochloric acid, stirring at 20-25 deg.C for 19-21 hr, adding purified water at 10-15 deg.C, and stirring for 2 hr;
step S33: centrifugal filtration;
step S34: drying by blowing at 35-45 ℃ for 14-16 hours;
step S35, acid dissolution: adding the dried material and glacial acetic acid into a reaction tank, heating to 90 ℃, adding 40% hydrobromic acid, stirring for 20 minutes, and filtering to a crystallization tank;
step S36: cooling the feed liquid to 20-25 ℃, reacting for 20 hours, cooling to 10-15 ℃, and stirring for 5 hours;
step S37: centrifugal filtration;
step S38: drying by blowing at 40-50 ℃ for 4-6 hours to obtain crude Entacapone;
step S4, a refining step, comprising:
step S41: adding crude Entacapone and methanol into a crystallizing tank, refluxing for 2 hours, cooling to 5-10 ℃, and crystallizing for 5 hours;
step S42: centrifugal filtration;
step S43: and (4) drying by blowing at 40-50 ℃ for 9-11 hours to obtain the Entacapone finished product.
In the step S11, the mass ratio of each reactant added is as follows: 1 part of vanillin, 0.8 part of 65% nitric acid and 1.8-2.2 parts of glacial acetic acid.
Wherein, in the step S12, the filter cake is washed with purified water.
In the step S21, the mass ratio of each reactant added is as follows: 1 part of nitrovanillin, 3.3-3.5 parts of dichloromethane, 0.015-0.017 part of tetrabutylammonium bromide, 0.90-1.00 part of anhydrous aluminum chloride and 1.3-1.5 parts of pyridine.
Wherein, in the step S22, the filter cake is washed with purified water.
In the step S31, the mass ratio of each reactant added is as follows: 3.9 to 4.1 portions of isopropanol, 0.9 to 1.1 portions of 3, 4-dihydroxy-5 nitrobenzaldehyde, 0.90 to 0.95 portion of N-N-diethyl cyanoacetamide and 0.55 to 0.57 portion of piperidine.
Wherein, in the step S37, the filter cake is washed with glacial acetic acid and methanol in this order.
Wherein, in the step S42, the filter cake is washed by methanol.
The method for producing entacapone provided by the invention has the advantages of high yield, high purity and stable quality.
Drawings
FIG. 1: the invention discloses a nitration reaction process line diagram of an entacapone production process.
FIG. 2: the invention discloses a demethylation reaction process scheme of an Entacapone production process.
FIG. 3: the invention discloses a condensation reaction process scheme of an entacapone production process.
FIG. 4: the Entacapone process flow diagram of the invention is shown in figure 1.
FIG. 5: the Entacapone process flow diagram of the invention is shown in figure 2.
Detailed Description
In order to further understand the technical scheme and the advantages of the present invention, the following detailed description of the technical scheme and the advantages thereof is provided in conjunction with the accompanying drawings.
1-5 are a complete process flow diagram of the production process of entacapone of the present invention, as shown in fig. 1-5, the production process of entacapone of the present invention mainly comprises the following steps:
first, nitration process
Referring to fig. 1, fig. 4 and table 1, the nitration process, i.e., the process for preparing intermediate 1 (nitrovanillin), involves the following detailed operation steps and raw material ratios:
table 1: raw material proportion of nitration process
| Name of article | Process proportioning | Remarks for note |
| Vanillin | 1 | Starting |
| 65% nitric acid | 0.8 | For reactions |
| Glacial acetic acid | 2±0.2 | Solvent for reaction |
| Purified water | 6±0.2 | For dispersing |
| Purified water | 2±0.2 | For washing |
1. Reaction stage
Adding vanillin and glacial acetic acid into a reaction kettle in sequence; stirring and cooling to 15 ℃, dropwise adding 65% nitric acid, and keeping the temperature between 15 and 30 ℃. After the dropwise addition is finished, the reaction is carried out for 4 +/-1 hours at the temperature of 20-30 ℃, and after the HPLC detection, the raw materials are subjected to complete reaction, and then the post-treatment is carried out.
2. Post-treatment stage
Adding purified water, stirring for 1 hour, centrifuging, filtering, and washing the filter cake with purified water. And (3) drying the wet product in a hot air circulation oven at 45 +/-5 ℃ for 13 +/-1 hours in a blowing manner to obtain a first intermediate: nitrovanillin.
The yield of the product obtained in the step: 95 plus or minus 5 percent (calculated by vanillin), the purity is more than or equal to 94.0 percent, and the product is yellow green or yellow powder.
Second, demethylation step
Referring to fig. 2, 4 and table 2, the demethylation step, i.e., the preparation of intermediate 2(3, 4-dihydroxy-5-nitrobenzaldehyde), involves the following detailed steps and raw materials:
table 2: raw material proportion of demethylation process
| Name of article | Mass ratio of | Remarks for note |
| Nitro vanillin | 1 | —— |
| Anhydrous aluminum trichloride | 0.95 | For reactions |
| Pyridine compound | 1.4±0.1 | For reactions |
| Tetrabutylammonium bromide | 0.016 | For reactions |
| Methylene dichloride | 3.4±0.1 | Solvent for reaction |
| 3N hydrochloric acid | 10.5±0.1 | For crystallization |
| Purified water | 4.2±0.1 | For washing |
1. Reaction stage
Adding dichloromethane, nitrovanillin and tetrabutylammonium bromide into a reaction kettle, stirring and cooling to 0-5 ℃, adding anhydrous aluminum trichloride, keeping the temperature between 0-10 ℃, and stirring for 30 minutes. Then pyridine is dripped at the temperature of 0-10 ℃. After the dropwise addition, the reaction was carried out for 1 hour under heat. Heating to reflux, reacting for 24 + -1 hr while maintaining the temperature, and performing post-treatment after HPLC detection.
2. Post-treatment stage
Cooling to 10-20 ℃, adding 3N hydrochloric acid while stirring, and keeping the temperature below 45 ℃. Stirring for 3 hr, centrifugal filtering, and washing the filter cake with purified water. And (3) drying the wet product in a hot air circulation oven at 45 +/-5 ℃ for 11 +/-1 hours in a blowing manner to obtain an intermediate 2: 3, 4-dihydroxy-5-nitrobenzaldehyde.
The yield of the product obtained in the step: 75 +/-5% (calculated as nitrovanillin), purity of more than or equal to 95.0%, and yellow green or yellow powder of the product.
Third, condensation step
Referring to fig. 3-5 and table 3, the condensation process, the crude Entacapone preparation process, involves the following detailed operation steps and raw material ratios:
table 3: raw material proportion of condensation process
Adding isopropanol into a reaction kettle, sequentially adding 3, 4-dihydroxy-5-nitrobenzaldehyde and N, N-diethyl cyanoacetamide while stirring, then adding piperidine, heating to reflux, carrying out heat preservation reaction for 23 +/-1 hours, carrying out HPLC (high performance liquid chromatography) detection, and carrying out aftertreatment after the raw materials are completely reacted.
Cooling the reaction liquid to 50-60 ℃, and distilling under reduced pressure. And after the distillation is finished, adding glacial acetic acid, heating to 70 ℃, stirring for dissolving, adding hydrochloric acid, cooling to 20-25 ℃, keeping the temperature, stirring for reacting for 20 +/-1 hours, and detecting by HPLC (high performance liquid chromatography) to complete the reaction. And (3) introducing ice salt water into the reaction kettle, cooling the temperature to 10-15 ℃, adding purified water, stirring for 2 hours, centrifuging, filtering, and washing the filter cake with the purified water. The wet product is dried by air blowing for 15 plus or minus 1 hour at 40 plus or minus 5 ℃ in a drying oven.
Adding the dried solid material and glacial acetic acid into a reaction kettle, stirring and heating to 90 ℃, adding 0.1 time of 40 percent hydrobromic acid by weight after dissolution, preserving heat and stirring for 20 minutes, and filtering by a filter to a crystallizing tank in a clean area.
And slowly cooling the feed liquid to 20-25 ℃, preserving heat, stirring for 20 hours, cooling to 10-15 ℃, preserving heat, stirring, crystallizing for 5 hours, centrifuging, filtering, and washing a filter cake with glacial acetic acid and methanol in sequence. And (3) drying the wet product in a hot air circulating oven by blowing at 45 +/-5 ℃ for 5 +/-1 hours to obtain the crude product of entacapone.
Yield: 90 plus or minus 10 percent.
Fourthly, a refining step
Referring to fig. 5 and table 4, the refining process, the process for preparing Entacapone finished product, involves the following detailed operation steps and raw material ratios:
table 4: raw material proportion of refining procedure
Adding crude Entacapone and methanol into a reaction kettle, stirring and heating to reflux, and stirring for 2 hours under heat preservation. Slowly cooling to 5-10 ℃, carrying out heat preservation and crystallization for 5 hours, carrying out centrifugal filtration, washing a filter cake with methanol, and transferring the filter cake to a drying process. The drying temperature is controlled to be 45 +/-5 ℃, and the drying time is 10 +/-1 hour. The temperature was recorded every hour. Sampling and inspecting, and stopping drying when the drying weight loss is less than or equal to 0.5%.
The finally prepared Entacapone finished product is yellow green or yellow powder, the drying weight loss is less than or equal to 0.5%, the residue on ignition is less than or equal to 0.1%, and the purity is more than or equal to 99.5%.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that the scope of the present invention is not limited thereto, and those skilled in the art will appreciate that various changes and modifications can be made without departing from the spirit and scope of the present invention.
Claims (8)
1. A method for producing entacapone, comprising the steps of:
step S1, nitration, comprising:
step S11: adding glacial acetic acid and vanillin into a reaction tank, dropwise adding 65% nitric acid at 15-30 ℃, reacting for 3-5 hours at 20-30 ℃, adding purified water, and stirring for 1 hour;
step S12: centrifugal filtration;
step S13: drying by blowing at 40-50 ℃ for 12-14 hours to obtain an intermediate nitrovanillin;
step S2, demethylation reaction, comprising:
step S21: adding nitrovanillin, dichloromethane and tetrabutylammonium bromide into a reaction tank, adding anhydrous aluminum chloride at 0-5 ℃, adding pyridine at 0-10 ℃, performing reflux reaction for 23-25 hours, adding 3N hydrochloric acid, and stirring for 3 hours;
step S22: centrifugal filtration;
step S23: drying by blowing at 40-50 ℃ for 10-13 hours to obtain an intermediate 3, 4-dihydroxy-5-nitrobenzaldehyde;
step S3, a condensation reaction comprising:
step S31: adding isopropanol, 3, 4-dihydroxy-5-nitrobenzaldehyde, N-N-diethyl cyanoacetamide and piperidine into a reaction tank, and carrying out reflux reaction for 22-24 hours;
step S32: concentrating under reduced pressure, adding glacial acetic acid and hydrochloric acid, stirring at 20-25 deg.C for 19-21 hr, adding purified water at 10-15 deg.C, and stirring for 2 hr;
step S33: centrifugal filtration;
step S34: drying by blowing at 35-45 ℃ for 14-16 hours;
step S35, acid dissolution: adding the dried material and glacial acetic acid into a reaction tank, heating to 90 ℃, adding 40% hydrobromic acid, stirring for 20 minutes, and filtering to a crystallization tank;
step S36: cooling the feed liquid to 20-25 ℃, reacting for 20 hours, cooling to 10-15 ℃, and stirring for 5 hours;
step S37: centrifugal filtration;
step S38: drying by blowing at 40-50 ℃ for 4-6 hours to obtain crude Entacapone;
step S4, a refining step, comprising:
step S41: adding crude Entacapone and methanol into a crystallizing tank, refluxing for 2 hours, cooling to 5-10 ℃, and crystallizing for 5 hours;
step S42: centrifugal filtration;
step S43: and (4) drying by blowing at 40-50 ℃ for 9-11 hours to obtain the Entacapone finished product.
2. The method for producing entacapone according to claim 1, wherein in the step S11, the mass ratio of each reactant added is as follows: 1 part of vanillin, 0.8 part of 65% nitric acid and 1.8-2.2 parts of glacial acetic acid.
3. The method for producing entacapone according to claim 1, wherein in step S12, the filter cake is washed with purified water.
4. The method for producing entacapone according to claim 1, wherein in the step S21, the mass ratio of each reactant added is as follows: 1 part of nitrovanillin, 3.3-3.5 parts of dichloromethane, 0.015-0.017 part of tetrabutylammonium bromide, 0.90-1.00 part of anhydrous aluminum chloride and 1.3-1.5 parts of pyridine.
5. The method for producing entacapone according to claim 1, wherein in step S22, the filter cake is washed with purified water.
6. The method for producing entacapone according to claim 1, wherein in the step S31, the mass ratio of each reactant added is as follows: 3.9 to 4.1 portions of isopropanol, 0.9 to 1.1 portions of 3, 4-dihydroxy-5 nitrobenzaldehyde, 0.90 to 0.95 portion of N-N-diethyl cyanoacetamide and 0.55 to 0.57 portion of piperidine.
7. The method for producing entacapone according to claim 1, wherein in step S37, the filter cake is washed sequentially with glacial acetic acid and methanol.
8. The method for producing entacapone according to claim 1, wherein in step S42, the filter cake is washed with methanol.
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| CN1926095A (en) * | 2003-12-29 | 2007-03-07 | 苏文生命科学有限公司 | Improved method for preparing entacapone |
| CN103130681A (en) * | 2013-03-19 | 2013-06-05 | 上海奥博生物医药技术有限公司 | Novel method for preparing entacapone |
| CN104402764A (en) * | 2014-11-26 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method for entacapone |
| CN104744301A (en) * | 2013-12-26 | 2015-07-01 | 李磊 | Method for producing entacapone |
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