CN113248429A - Preparation method of rebamipide bulk drug - Google Patents
Preparation method of rebamipide bulk drug Download PDFInfo
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- CN113248429A CN113248429A CN202110609576.8A CN202110609576A CN113248429A CN 113248429 A CN113248429 A CN 113248429A CN 202110609576 A CN202110609576 A CN 202110609576A CN 113248429 A CN113248429 A CN 113248429A
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- rebamipide
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- solution
- bulk drug
- hydrochloric acid
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- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229950004535 rebamipide Drugs 0.000 title claims abstract description 70
- 239000003814 drug Substances 0.000 title claims abstract description 65
- 229940079593 drug Drugs 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 108
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000008367 deionised water Substances 0.000 claims abstract description 51
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 229960000583 acetic acid Drugs 0.000 claims abstract description 27
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 27
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 15
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 claims abstract description 14
- BBAHJCUCNVVEQU-UHFFFAOYSA-N 4-(bromomethyl)-1h-quinolin-2-one Chemical compound C1=CC=C2C(CBr)=CC(=O)NC2=C1 BBAHJCUCNVVEQU-UHFFFAOYSA-N 0.000 claims abstract description 10
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 123
- 239000000243 solution Substances 0.000 claims description 73
- 238000003756 stirring Methods 0.000 claims description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- 238000010992 reflux Methods 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 49
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000005406 washing Methods 0.000 claims description 39
- 238000010438 heat treatment Methods 0.000 claims description 33
- 238000001816 cooling Methods 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 238000001291 vacuum drying Methods 0.000 claims description 15
- 159000000000 sodium salts Chemical class 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims 4
- 239000007787 solid Substances 0.000 claims 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 238000004886 process control Methods 0.000 abstract description 2
- TVZDIFXOIOIPJG-UHFFFAOYSA-N 2,3,4-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(Cl)=C1Cl TVZDIFXOIOIPJG-UHFFFAOYSA-N 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 description 35
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 210000001156 gastric mucosa Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- -1 quinolone compound Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of rebamipide bulk drug, which comprises the following steps: preparing a crude product of a rebamipide raw material medicament by using a compound tri and 4-chlorobenzoyl chloride; and step two, purifying the rebamipide bulk drug. Wherein, the compound III is prepared from a compound II, deionized water and concentrated hydrochloric acid, the compound II is prepared from a compound I, glacial acetic acid and concentrated hydrochloric acid, and the compound I is prepared from acetamidomalonic acid diethyl ester and 4-bromomethyl quinolone. And the invention utilizes the process control method, and the impurities in the synthesized compound I, the impurities in the synthesized compound II and the impurities in the synthesized compound III are respectively purified by a common purification method, and the purity of the rebamipide bulk drug is improved by combining the crystallization purification method of the crude product of the rebamipide bulk drug.
Description
Technical Field
The invention belongs to the technical field of preparation of raw material medicines, and particularly relates to a preparation method of a rebamipide raw material medicine.
Background
Rebamipide (Rebamipide), a quinolone compound represented by formula (1), has the chemical name of 2- (4-chlorobenzoylamino) -3- [ 2 (1H) -quinolone-4-yl ] propionic acid, and has the following molecular formula:
rebamipide is an active new-generation gastric mucosa protective agent, can improve the histological healing quality of gastric ulcer, reduce ulcer recurrence, has good effect on treating gastric mucosa injury caused by non-steroidal anti-inflammatory drugs (NSAIDs), alcohol and other factors, still has good curative effect on gastric mucosa lesion which cannot eradicate helicobacter pylori infection, is a unique gastric mucosa protective agent with the functions of increasing PG synthesis, eliminating and inhibiting free radicals, and has higher clinical application value.
The existing preparation technology of rebamipide generally adopts a synthetic route as disclosed in japanese patent (JP2008-143794a), as follows:
the adoption of the synthesis process has the following defects that the prepared product has obvious impurities, including various intermediates and reaction byproducts, and the impurities are remained in the product; although the rebamipide crude product can be refined by repeated recrystallization and other methods, the refining times are more, the solvent consumption is large, the purity is not improved ideally, the total yield is low, the production cost is increased, and the industrial production is not facilitated.
Therefore, the invention provides a preparation method of the rebamipide bulk drug, which improves the purity of the rebamipide bulk drug finally obtained.
Disclosure of Invention
The invention aims to provide a preparation method of a rebamipide bulk drug, which realizes the control of impurities generated in the synthesis process by adjusting the synthesis process so as to improve the purity of the rebamipide bulk drug finally obtained.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of rebamipide bulk drug comprises the following process route:
the preparation method of the rebamipide bulk drug comprises the following steps:
adding a sodium hydroxide solution into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding a compound tri and dimethylacetamide at 0-3 ℃ and 150r/min, stirring at a constant temperature and constant speed for 8-15min, slowly dropwise adding a toluene solution of 4-chlorobenzoyl chloride, controlling the temperature of a reaction system to be less than 5 ℃ in the dropwise adding process, continuously reacting at the system temperature of less than 5 ℃ for 4-7h after the dropwise adding is completed, then adding methanol, heating to 65-75 ℃, dropwise adding glacial acetic acid while stirring, cooling to 20-25 ℃ after the glacial acetic acid is completely added, filtering, washing a filter cake with deionized water, and then washing with methanol to obtain a crude product of the rebamipide bulk drug;
step two, purifying the rebamipide bulk drug, namely adding the crude rebamipide bulk drug obtained in the step one and methanol into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dripping sodium hydroxide at the stirring speed of 100-150r/min, controlling the system temperature at 20-25 ℃ in the dripping process, reacting for 3-4h, filtering, washing a filter cake with methanol, and drying for 0.5-1h in a vacuum drying oven at 45-50 ℃ to obtain the sodium salt of the rebamipide bulk drug; adding deionized water, methanol and sodium salt of the rebamipide bulk drug into a three-neck flask with a thermometer, a reflux pipe and a stirrer, stirring at a stirring speed of 100-150r/min, heating to 65-75 ℃ to obtain suspension, filtering by using a 1.0-micron microporous filter, washing a filter cake by using a mixed solution of the deionized water and the methanol according to a mass ratio of 1-1.2:1, collecting filtrate, heating to 65-75 ℃, adding glacial acetic acid, cooling to 20-25 ℃, filtering, washing the filter cake by using the deionized water, then washing by using the methanol, and drying in a vacuum drying oven at 50-55 ℃ for 0.5-1h to obtain the rebamipide bulk drug.
Further, in the step one, the mass ratio of the sodium hydroxide solution, the compound III, the dimethylacetamide, the toluene solution of the 4-chlorobenzoyl chloride, the methanol and the glacial acetic acid is 450-28-30: 95-110:380-400:17-20, the mass concentration of the sodium hydroxide solution is 3-5%, and the mass concentration of the toluene solution of the 4-chlorobenzoyl chloride is 26-30%.
Further, in the second step, the mass ratio of the crude product of the rebamipide bulk drug, methanol and sodium hydroxide is 150-; deionized water, methanol and the sodium salt of the rebamipide bulk drug obtained in the step two are added into the mixture according to the mass ratio of 600-650:480-510: 110-120.
In the first step, the compound III is prepared by the following steps:
step S1, adding the compound I and glacial acetic acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding concentrated hydrochloric acid, heating to 95-103 ℃ at a stirring speed of 100 plus 150r/min for reflux, carrying out reflux reaction for 7-9h, cooling the reaction system to 25-35 ℃, adding acetone, and stirring at a stirring speed of 100 plus 150r/min for 1-1.5h to obtain a reaction solution; centrifuging the obtained reaction solution, taking a filter cake, washing with acetone, and drying in a vacuum box at 40-50 ℃ for 1-2h to obtain a compound II;
step S2, adding the compound II, deionized water and concentrated hydrochloric acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, heating to 98-105 ℃, and stirring at a stirring speed of 100-150r/min until the compound II, the deionized water and the concentrated hydrochloric acid are completely dissolved; then cooling to 95-98 ℃, adding seed crystals, slowly cooling to 15 ℃, then filtering, washing a filter cake with deionized water, and then drying in a vacuum drying oven for 0.5-1h at 45-50 ℃ to obtain a compound III.
Further, in step S1, the mass ratio of the first compound, the glacial acetic acid, the concentrated hydrochloric acid and the acetone is 110-125:170-200:195-210:550-575, and the concentration of the concentrated hydrochloric acid is 35-37%.
Further, in step S2, the mass ratio of the compound II, the concentrated hydrochloric acid and the deionized water is 120-.
Further, in step S1, the preparation of compound one comprises the following steps:
adding absolute ethyl alcohol and diethyl acetamidomalonate into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dropwise adding sodium methoxide at the stirring speed of 100-150r/min, then continuously stirring at the stirring speed of 100-150r/min at the temperature of 30-50 ℃ for reacting for 18-25min, then adding 4-bromomethyl quinolone, heating to 78-85 ℃ for refluxing, carrying out reflux reaction for 1.5-2.5h, cooling to 60-70 ℃, adding a potassium hydroxide aqueous solution, heating to 78-85 ℃ for refluxing again, carrying out reflux reaction for 2.5-3.5h, then taking out a reaction liquid, carrying out reduced pressure concentration at the temperature of 40-60 ℃ to remove ethanol, dropwise adding deionized water into the obtained concentrated liquid, then dropwise adding a hydrochloric acid solution at the stirring speed of 100-150r/min at the temperature of 28-32 ℃, keeping the temperature and the stirring speed unchanged, keeping the dripping time of the hydrochloric acid solution at 2-2.5h, and continuously stirring for 1-1.5h after the hydrochloric acid is completely dripped to obtain a concentrated reaction solution; and centrifuging the obtained concentrated reaction solution, washing a filter cake for 3 times by using deionized water, and drying the filter cake for 1 to 2 hours in a vacuum box at the temperature of between 50 and 55 ℃ to obtain a compound I.
Further, the mass ratio of the absolute ethyl alcohol, the diethyl acetamidomalonate, the sodium methoxide, the 4-bromomethyl quinolone, the aqueous solution of potassium hydroxide, the deionized water and the hydrochloric acid solution is 880-890:100-105:20-30:100-115:1150-1200: 1100-1200-1280; the mass fraction of the aqueous solution of potassium hydroxide is 47-50%; the mass fraction of the hydrochloric acid solution is 18-21%.
The invention has the beneficial effects that:
the invention utilizes a process control method, respectively removes impurities and purifies impurities in the synthesized compound I, the synthesized compound II and the synthesized compound III by a common purification method, and improves the purity of the rebamipide bulk drug by combining a crystallization purification method of a crude product of the rebamipide bulk drug, reduces the impurity content in a product in each reaction process, avoids repeated crystallization purification of the rebamipide bulk drug, and reduces the production cost of the rebamipide bulk drug. The preparation method is simple, easy to operate and convenient for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
step one, preparing a crude product of rebamipide bulk drug, namely adding a sodium hydroxide solution into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding a compound tri-and dimethylacetamide at 0 ℃ and 150r/min, stirring at constant temperature and constant speed for 10min, then slowly dropwise adding a toluene solution of 4-chlorobenzoyl chloride, controlling the temperature of a reaction system to be less than 5 ℃ in the dropwise adding process, continuously reacting at the system temperature of 3 ℃ for 5h after dropwise adding is completed, then adding methanol, heating to 75 ℃, dropwise adding glacial acetic acid while stirring, cooling to 22 ℃ after glacial acetic acid is completely added, filtering, washing with deionized water, and then washing with methanol to obtain the crude product of rebamipide bulk drug, wherein the toluene solution of the sodium hydroxide solution, the compound tri-and dimethylacetamide and the 4-chlorobenzoyl chloride, The mass ratio of the methanol to the glacial acetic acid is 450:28:95:380:17, the mass concentration of the sodium hydroxide solution is 3%, and the mass concentration of the toluene solution of the 4-chlorobenzoyl chloride is 26%;
step two, purifying the rebamipide bulk drug, namely adding the crude rebamipide bulk drug obtained in the step one and methanol into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dripping sodium hydroxide at the stirring speed of 150r/min, controlling the system temperature at 22 ℃ in the dripping process, reacting for 4h, filtering, washing a filter cake with methanol, and drying for 1h in a vacuum drying oven at 50 ℃ to obtain the sodium salt of the rebamipide bulk drug; adding deionized water, methanol and sodium salt of a rebamipide bulk drug into a three-neck flask with a thermometer, a reflux pipe and a stirrer, stirring at a stirring speed of 150r/min, heating to 75 ℃ to obtain a suspension, filtering by using a 1.0-micron microporous filter, washing a filter cake by using a mixed solution of deionized water and methanol according to a mass ratio of 1.2:1, collecting a filtrate, heating to 75 ℃, adding glacial acetic acid, cooling to 25 ℃, filtering, washing the filter cake by using the deionized water, then washing by using the methanol, and then drying for 1h at 55 ℃ in a vacuum drying oven to obtain the rebamipide bulk drug, wherein the mass ratio of the crude product of the rebamipide bulk drug, the methanol and the sodium hydroxide is 150:750: 14; deionized water, methanol and sodium salt of the rebamipide bulk drug obtained in the step two are added in a mass ratio of 600:480: 110.
Wherein, the compound III is prepared by the following steps:
step S1, adding the compound I and glacial acetic acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding concentrated hydrochloric acid, heating to 103 ℃ at a stirring speed of 150r/min, refluxing, reacting for 8 hours, cooling the reaction system to 30 ℃, adding acetone, and stirring at a stirring speed of 150r/min for 1.5 hours to obtain a reaction solution; centrifuging the obtained reaction solution, taking a filter cake, washing the filter cake with acetone, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound II, wherein the adding mass ratio of the compound I to the glacial acetic acid to the concentrated hydrochloric acid to the acetone is 110:170:190:550, and the concentration of the concentrated hydrochloric acid is 35%;
step S2, adding the compound II, deionized water and concentrated hydrochloric acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, heating to 105 ℃, and stirring at a stirring speed of 150r/min until the compound II, the deionized water and the concentrated hydrochloric acid are completely dissolved; and then cooling to 96 ℃, adding seed crystals, slowly cooling to 15 ℃, filtering, washing a filter cake with deionized water, and then drying in a vacuum drying oven for 0.5h at 45 ℃ to obtain a compound III, wherein the mass ratio of the compound II to concentrated hydrochloric acid to deionized water is 120:1800:1100, and the concentration of the concentrated hydrochloric acid is 35%.
Further, in step S1, the preparation of compound one comprises the following steps:
adding absolute ethyl alcohol and diethyl acetamidomalonate into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dropwise adding sodium methoxide at the stirring speed of 150r/min, then continuously stirring at the stirring speed of 150r/min at 30 ℃ for 25min for reaction, then adding 4-bromomethyl quinolone, heating to 78 ℃ for reflux, carrying out reflux reaction for 1.5h, cooling to 65 ℃, adding an aqueous solution of potassium hydroxide, heating to 80 ℃ for reflux again, carrying out reflux reaction for 2.5h, then taking out a reaction solution, carrying out reduced pressure concentration at 40 ℃ -0.08MPa for removing ethanol, dropwise adding deionized water into the obtained concentrated liquid, then dropwise adding a hydrochloric acid solution at the stirring speed of 150r/min at 28 ℃, keeping the temperature constant, keeping the stirring speed constant, keeping the dropwise adding time of the hydrochloric acid solution for 2.5h, continuously stirring for 1.5h after the hydrochloric acid is completely dropwise added, obtaining a concentrated reaction solution; centrifuging the obtained concentrated reaction solution, washing a filter cake with deionized water for 3 times, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound I, wherein the mass ratio of the absolute ethyl alcohol, the diethyl acetamidomalonate, the sodium methoxide, the 4-bromomethyl quinolone, the aqueous solution of potassium hydroxide, the deionized water and the hydrochloric acid solution is 880:100:20:100:1150:1100: 1200; the mass fraction of the aqueous solution of potassium hydroxide is 47%; the mass fraction of the hydrochloric acid solution is 18%.
The purity of the obtained rebamipide bulk drug is tested to be 99.8%.
Example 2:
step one, preparing a crude product of rebamipide bulk drug, namely adding a sodium hydroxide solution into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding a compound tri-and dimethylacetamide at 0 ℃ and 150r/min, stirring at constant temperature and constant speed for 10min, then slowly dropwise adding a toluene solution of 4-chlorobenzoyl chloride, controlling the temperature of a reaction system to be less than 5 ℃ in the dropwise adding process, continuously reacting at the system temperature of 3 ℃ for 5h after dropwise adding is completed, then adding methanol, heating to 75 ℃, dropwise adding glacial acetic acid while stirring, cooling to 22 ℃ after glacial acetic acid is completely added, filtering, washing with deionized water, and then washing with methanol to obtain the crude product of rebamipide bulk drug, wherein the toluene solution of the sodium hydroxide solution, the compound tri-and dimethylacetamide and the 4-chlorobenzoyl chloride, The mass ratio of methanol to glacial acetic acid is 480:29:100:390:18, the mass concentration of the sodium hydroxide solution is 4%, and the mass concentration of the toluene solution of 4-chlorobenzoyl chloride is 28%;
step two, purifying the rebamipide bulk drug, namely adding the crude rebamipide bulk drug obtained in the step one and methanol into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dripping sodium hydroxide at the stirring speed of 150r/min, controlling the system temperature at 22 ℃ in the dripping process, reacting for 4h, filtering, washing a filter cake with methanol, and drying for 1h in a vacuum drying oven at 50 ℃ to obtain the sodium salt of the rebamipide bulk drug; adding deionized water, methanol and sodium salt of a rebamipide bulk drug into a three-neck flask with a thermometer, a reflux pipe and a stirrer, stirring at a stirring speed of 150r/min, heating to 75 ℃ to obtain a suspension, filtering by using a 1.0-micron microporous filter, washing a filter cake by using a mixed solution of deionized water and methanol according to a mass ratio of 1.2:1, collecting a filtrate, heating to 75 ℃, adding glacial acetic acid, cooling to 25 ℃, filtering, washing the filter cake by using the deionized water, then washing by using the methanol, and then drying for 1h at 55 ℃ in a vacuum drying oven to obtain the rebamipide bulk drug, wherein the mass ratio of the crude product of the rebamipide bulk drug, the methanol and the sodium hydroxide is 155:780: 16; deionized water, methanol and sodium salt of the rebamipide bulk drug obtained in the step two are added in a mass ratio of 630:490: 115.
Wherein, the compound III is prepared by the following steps:
step S1, adding the compound I and glacial acetic acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding concentrated hydrochloric acid, heating to 103 ℃ at a stirring speed of 150r/min, refluxing, reacting for 8 hours, cooling the reaction system to 30 ℃, adding acetone, and stirring at a stirring speed of 150r/min for 1.5 hours to obtain a reaction solution; centrifuging the obtained reaction solution, taking a filter cake, washing the filter cake with acetone, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound II, wherein the adding mass ratio of the compound I, the glacial acetic acid, the concentrated hydrochloric acid and the acetone is 115:180:200:565, and the concentration of the concentrated hydrochloric acid is 36%;
step S2, adding the compound II, deionized water and concentrated hydrochloric acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, heating to 105 ℃, and stirring at a stirring speed of 150r/min until the compound II, the deionized water and the concentrated hydrochloric acid are completely dissolved; and then cooling to 96 ℃, adding seed crystals, slowly cooling to 15 ℃, filtering, washing a filter cake with deionized water, and then drying in a vacuum drying oven for 0.5h at 45 ℃ to obtain a compound III, wherein the mass ratio of the compound II to concentrated hydrochloric acid to deionized water is 125:190:1150, and the concentration of the concentrated hydrochloric acid is 36%.
Further, in step S1, the preparation of compound one comprises the following steps:
adding absolute ethyl alcohol and diethyl acetamidomalonate into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dropwise adding sodium methoxide at the stirring speed of 150r/min, then continuously stirring at the stirring speed of 150r/min at 30 ℃ for 25min for reaction, then adding 4-bromomethyl quinolone, heating to 78 ℃ for reflux, carrying out reflux reaction for 1.5h, cooling to 65 ℃, adding an aqueous solution of potassium hydroxide, heating to 80 ℃ for reflux again, carrying out reflux reaction for 2.5h, then taking out a reaction solution, carrying out reduced pressure concentration at 40 ℃ -0.08MPa for removing ethanol, dropwise adding deionized water into the obtained concentrated liquid, then dropwise adding a hydrochloric acid solution at the stirring speed of 150r/min at 28 ℃, keeping the temperature constant, keeping the stirring speed constant, keeping the dropwise adding time of the hydrochloric acid solution for 2.5h, continuously stirring for 1.5h after the hydrochloric acid is completely dropwise added, obtaining a concentrated reaction solution; centrifuging the obtained concentrated reaction solution, washing a filter cake with deionized water for 3 times, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound I, wherein the adding mass ratio of absolute ethyl alcohol, diethyl acetamidomalonate, sodium methoxide, 4-bromomethyl quinolone, aqueous solution of potassium hydroxide, deionized water and hydrochloric acid solution is 885:102:25:110:1170:1150: 1250; the mass fraction of the aqueous solution of potassium hydroxide was 48%; the mass fraction of the hydrochloric acid solution is 19%.
The purity of the obtained rebamipide bulk drug is tested to be 99.7%.
Example 3:
step one, preparing a crude product of rebamipide bulk drug, namely adding a sodium hydroxide solution into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding a compound tri-and dimethylacetamide at 0 ℃ and 150r/min, stirring at constant temperature and constant speed for 10min, then slowly dropwise adding a toluene solution of 4-chlorobenzoyl chloride, controlling the temperature of a reaction system to be less than 5 ℃ in the dropwise adding process, continuously reacting at the system temperature of 3 ℃ for 5h after dropwise adding is completed, then adding methanol, heating to 75 ℃, dropwise adding glacial acetic acid while stirring, cooling to 22 ℃ after glacial acetic acid is completely added, filtering, washing with deionized water, and then washing with methanol to obtain the crude product of rebamipide bulk drug, wherein the toluene solution of the sodium hydroxide solution, the compound tri-and dimethylacetamide and the 4-chlorobenzoyl chloride, The mass ratio of the methanol to the glacial acetic acid is 600:30:110:400:20, the mass concentration of the sodium hydroxide solution is 5%, and the mass concentration of the toluene solution of the 4-chlorobenzoyl chloride is 30%;
step two, purifying the rebamipide bulk drug, namely adding the crude rebamipide bulk drug obtained in the step one and methanol into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dripping sodium hydroxide at the stirring speed of 150r/min, controlling the system temperature at 22 ℃ in the dripping process, reacting for 4h, filtering, washing a filter cake with methanol, and drying for 1h in a vacuum drying oven at 50 ℃ to obtain the sodium salt of the rebamipide bulk drug; adding deionized water, methanol and sodium salt of a rebamipide bulk drug into a three-neck flask with a thermometer, a reflux pipe and a stirrer, stirring at a stirring speed of 150r/min, heating to 75 ℃ to obtain a suspension, filtering by using a 1.0-micron microporous filter, washing a filter cake by using a mixed solution of deionized water and methanol according to a mass ratio of 1.2:1, collecting a filtrate, heating to 75 ℃, adding glacial acetic acid, cooling to 25 ℃, filtering, washing the filter cake by using the deionized water, then washing by using the methanol, and then drying for 1h at 55 ℃ in a vacuum drying oven to obtain the rebamipide bulk drug, wherein the mass ratio of the crude product of the rebamipide bulk drug, the methanol and the sodium hydroxide is 160:900: 18; deionized water, methanol and sodium salt of the rebamipide bulk drug obtained in the step two are added according to the mass ratio of 650:510: 120.
Wherein, the compound III is prepared by the following steps:
step S1, adding the compound I and glacial acetic acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, adding concentrated hydrochloric acid, heating to 103 ℃ at a stirring speed of 150r/min, refluxing, reacting for 8 hours, cooling the reaction system to 30 ℃, adding acetone, and stirring at a stirring speed of 150r/min for 1.5 hours to obtain a reaction solution; centrifuging the obtained reaction solution, taking a filter cake, washing the filter cake with acetone, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound II, wherein the adding mass ratio of the compound I, the glacial acetic acid, the concentrated hydrochloric acid and the acetone is 125:200:210:575, and the concentration of the concentrated hydrochloric acid is 37%;
step S2, adding the compound II, deionized water and concentrated hydrochloric acid into a three-neck flask with a thermometer, a reflux pipe and a stirrer, heating to 105 ℃, and stirring at a stirring speed of 150r/min until the compound II, the deionized water and the concentrated hydrochloric acid are completely dissolved; and then cooling to 96 ℃, adding seed crystals, slowly cooling to 15 ℃, filtering, washing a filter cake with deionized water, and then drying in a vacuum drying oven for 0.5h at 45 ℃ to obtain a compound III, wherein the mass ratio of the compound II to concentrated hydrochloric acid to deionized water is 130:210:1200, and the concentration of the concentrated hydrochloric acid is 37%.
Further, in step S1, the preparation of compound one comprises the following steps:
adding absolute ethyl alcohol and diethyl acetamidomalonate into a three-neck flask with a thermometer, a reflux pipe and a stirrer, dropwise adding sodium methoxide at the stirring speed of 150r/min, then continuously stirring at the stirring speed of 150r/min at 30 ℃ for 25min for reaction, then adding 4-bromomethyl quinolone, heating to 78 ℃ for reflux, carrying out reflux reaction for 1.5h, cooling to 65 ℃, adding an aqueous solution of potassium hydroxide, heating to 80 ℃ for reflux again, carrying out reflux reaction for 2.5h, then taking out a reaction solution, carrying out reduced pressure concentration at 40 ℃ -0.08MPa for removing ethanol, dropwise adding deionized water into the obtained concentrated liquid, then dropwise adding a hydrochloric acid solution at the stirring speed of 150r/min at 28 ℃, keeping the temperature constant, keeping the stirring speed constant, keeping the dropwise adding time of the hydrochloric acid solution for 2.5h, continuously stirring for 1.5h after the hydrochloric acid is completely dropwise added, obtaining a concentrated reaction solution; centrifuging the obtained concentrated reaction solution, washing a filter cake with deionized water for 3 times, and drying the filter cake in a vacuum box at 50 ℃ for 2 hours to obtain a compound I, wherein the mass ratio of the absolute ethyl alcohol, the diethyl acetamidomalonate, the sodium methoxide, the 4-bromomethyl quinolone, the aqueous solution of potassium hydroxide, the deionized water and the hydrochloric acid solution is 890:105:30:115:1200:1200: 1280; the mass fraction of the aqueous solution of potassium hydroxide is 50 percent; the mass fraction of the hydrochloric acid solution is 21%.
The purity of the obtained rebamipide bulk drug is tested to be 99.9%.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (3)
1. A preparation method of rebamipide bulk drug is characterized by comprising the following steps:
step one, preparing a crude product of rebamipide bulk drug: stirring and mixing a sodium hydroxide solution, a compound III and dimethylacetamide at 0-5 ℃, keeping the temperature, dropwise adding a toluene solution of 4-chlorobenzoyl chloride into the mixed solution, reacting for 3-6h, adding methanol, heating to 65-75 ℃, dropwise adding glacial acetic acid, cooling to 20-25 ℃, keeping the temperature for 9-11h, and filtering to obtain a crude product of the rebamipide raw material medicine;
step two, purifying the rebamipide raw material medicine: the crude product of the rebamipide bulk drug reacts with a sodium hydroxide solution to produce a sodium salt solid of the rebamipide bulk drug, and the sodium salt solid is recrystallized and purified to obtain the rebamipide bulk drug.
2. The method for preparing rebamipide bulk drug according to claim 1, wherein in the first step, the compound III is prepared by the following steps:
step S1, mixing the compound I and glacial acetic acid, adding concentrated hydrochloric acid, heating to 95-103 ℃ under stirring, refluxing, reacting for 7-9h under reflux, cooling the reaction system to 25-35 ℃, adding acetone, and stirring for 1-1.5h to obtain a reaction solution; centrifuging the reaction solution, washing, and drying in a vacuum drying oven to obtain a compound II;
and step S2, uniformly mixing the compound II, deionized water and concentrated hydrochloric acid, heating the solution to 98-105 ℃, cooling the temperature of the mixed solution to 95-98 ℃ after the solution is completely dissolved, adding seed crystals, slowly cooling to 15 ℃, filtering, washing, and drying in a vacuum drying oven to obtain the compound III.
3. The method for preparing rebamipide drug substance according to claim 2, wherein in step S1, the preparation of compound one comprises the following steps:
uniformly mixing absolute ethyl alcohol and diethyl acetamidomalonate, dropwise adding sodium methoxide while stirring, reacting at 30-50 ℃ for 18-25min, adding 4-bromomethyl quinolone, heating to 78-85 ℃ for reflux, performing reflux reaction for 1.5-2.5h, cooling to 60-70 ℃, adding an aqueous solution of potassium hydroxide, heating to 78-85 ℃ for reflux again, performing reflux reaction for 2.5-3.5h, taking out a reaction solution, performing reduced pressure concentration at 40-60 ℃, dropwise adding deionized water into the obtained concentrated solution, dropwise adding a hydrochloric acid solution at 28-32 ℃, keeping the temperature of the system unchanged, dropwise adding the hydrochloric acid solution for 2-2.5h, and continuously reacting for 1-1.5h after the hydrochloric acid is completely dropwise added to obtain a concentrated reaction solution; and taking out the concentrated reaction solution, centrifuging, filtering, washing, and drying in a vacuum drying oven to obtain the compound I.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004131506A (en) * | 2002-10-11 | 2004-04-30 | Hanmi Pharm Co Ltd | Improved method for preparation of rebamipide |
| CN1922145A (en) * | 2004-12-01 | 2007-02-28 | 大塚制药株式会社 | Improved process for preparing rebamipide |
| CN1989108A (en) * | 2005-04-28 | 2007-06-27 | 大塚制药株式会社 | Method for producing carbostyryl compound |
| JP2008143794A (en) * | 2006-12-06 | 2008-06-26 | Otsuka Pharmaceut Co Ltd | Method for producing carbostyryl compound for medicine |
| JP2010043053A (en) * | 2008-08-11 | 2010-02-25 | Dongwoo Syntech Co Ltd | Process for producing high purity rebamipide |
-
2021
- 2021-06-01 CN CN202110609576.8A patent/CN113248429A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004131506A (en) * | 2002-10-11 | 2004-04-30 | Hanmi Pharm Co Ltd | Improved method for preparation of rebamipide |
| CN1922145A (en) * | 2004-12-01 | 2007-02-28 | 大塚制药株式会社 | Improved process for preparing rebamipide |
| CN1989108A (en) * | 2005-04-28 | 2007-06-27 | 大塚制药株式会社 | Method for producing carbostyryl compound |
| JP2008143794A (en) * | 2006-12-06 | 2008-06-26 | Otsuka Pharmaceut Co Ltd | Method for producing carbostyryl compound for medicine |
| JP2010043053A (en) * | 2008-08-11 | 2010-02-25 | Dongwoo Syntech Co Ltd | Process for producing high purity rebamipide |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028579A (en) * | 2022-06-21 | 2022-09-09 | 福建海西新药创制有限公司 | Synthetic method of rebamipide bulk drug |
| CN115028579B (en) * | 2022-06-21 | 2023-07-18 | 福建海西新药创制股份有限公司 | Synthesis method of rebamipide bulk drug |
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