CN113121466A - Recrystallization solvent of acotiamide hydrochloride and refining method thereof - Google Patents
Recrystallization solvent of acotiamide hydrochloride and refining method thereof Download PDFInfo
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- CN113121466A CN113121466A CN202010097001.8A CN202010097001A CN113121466A CN 113121466 A CN113121466 A CN 113121466A CN 202010097001 A CN202010097001 A CN 202010097001A CN 113121466 A CN113121466 A CN 113121466A
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- 229950005462 acotiamide Drugs 0.000 title claims abstract description 77
- TWHZNAUBXFZMCA-UHFFFAOYSA-N Acotiamide Chemical compound C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 TWHZNAUBXFZMCA-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 239000002904 solvent Substances 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000001953 recrystallisation Methods 0.000 title claims abstract description 22
- 238000007670 refining Methods 0.000 title claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000000047 product Substances 0.000 claims abstract description 36
- NPTDXIXCQCFGKC-UHFFFAOYSA-N n-[2-[di(propan-2-yl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide;trihydrate;hydrochloride Chemical compound O.O.O.Cl.C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 NPTDXIXCQCFGKC-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 95
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 77
- 238000001035 drying Methods 0.000 claims description 41
- 238000002425 crystallisation Methods 0.000 claims description 31
- 230000008025 crystallization Effects 0.000 claims description 31
- 238000004537 pulping Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000008064 anhydrides Chemical group 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 description 38
- 239000008213 purified water Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- VQEKQYLTAIVCBW-UHFFFAOYSA-N n-[2-[di(propan-2-yl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 VQEKQYLTAIVCBW-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- -1 acotiamide hydrochloride anhydride Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DSJYSRTZHXBOCX-UHFFFAOYSA-N ac1l9i4c Chemical compound O.O.O.O DSJYSRTZHXBOCX-UHFFFAOYSA-N 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 229950003102 efonidipine Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NSVFSAJIGAJDMR-UHFFFAOYSA-N 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical compound CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 NSVFSAJIGAJDMR-UHFFFAOYSA-N 0.000 description 1
- 208000028048 Accommodation disease Diseases 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D2009/0086—Processes or apparatus therefor
- B01D2009/009—Separation of organic compounds by selective or extractive crystallisation with the aid of auxiliary substances forming complex or molecular compounds, e.g. with ureum, thioureum or metal salts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a recrystallization solvent of acotiamide hydrochloride and a refining method thereof, belonging to the technical field of medicine refining. The invention provides a recrystallization solvent of acotiamide hydrochloride, which takes DMF as a good solvent and water as a poor solvent. The invention further provides a refining method of acotiamide hydrochloride, which comprises the following steps: a. adding the acotiamide hydrochloride crude product into DMF, fully dissolving with or without water, carrying out solid-liquid separation, and collecting a solution, wherein the acotiamide hydrochloride crude product is an anhydride or hydrate; b. slowly adding water into the solution under the heating condition, and then cooling and crystallizing to obtain the acotiamide hydrochloride trihydrate refined product. The invention enables the yield of acotiamide hydrochloride trihydrate to reach more than 95 percent, not only obviously improves the product yield, but also can avoid the problem that a large amount of precipitated solids block pipelines when the solution is filtered or enters a clean area, and has better effects on enlarging production operation and improving the product yield.
Description
Technical Field
The invention relates to a recrystallization solvent of acotiamide hydrochloride and a refining method thereof, belonging to the technical field of medicine refining.
Background
Acotiamide was first developed by Zeria new drug industry co.japan, and was later introduced by astella pharmaceuticals and Zeria pharmaceutical industry in japan as the first approved therapeutic drug for functional dyspepsia in the world. The acotiamide oral tablet mainly acts through a mechanism of inhibiting acetylcholinesterase in the digestive tract, and can promote gastric motility, improve gastric accommodation disorder and enhance fundus distension. The active component is acotiamide hydrochloride trihydrate, and the structural formula is as follows:
at present, acotiamide hydrochloride trihydrate is mainly prepared by the following steps:
after the acotiamide hydrochloride shown in the formula II is obtained, recrystallization is carried out by using a mixed solvent of isopropanol and water for purification, and the final product, namely the acotiamide hydrochloride trihydrate, can be prepared. However, the use of the above recrystallization solvent has a drawback of low yield. For example, the recrystallization method is repeated in the Chinese patent application 201310504022.7, and as a result, the yield can only reach 82% after the crystallization is finished, and the yield is further lost by 10% after the re-purification. Moreover, the inventor of the present invention finds that the product loss problem caused by recrystallization is more serious in the large-scale production process, and if the 20% isopropanol aqueous solution is adopted to be dissolved and filtered after being heated according to the conventional method, a large amount of solids are easily separated out when the filtrate enters a clean zone, so that the product loss is caused, and a pipeline is also blocked.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention aims to provide a recrystallization solvent of acotiamide hydrochloride. The invention also aims to provide a method for purifying acotiamide hydrochloride.
The invention provides a recrystallization solvent of acotiamide hydrochloride, which takes DMF (namely N, N-dimethylformamide) as a good solvent and water as a poor solvent; the preparation method comprises the following steps of (1) taking the acotiamide hydrochloride crude product as a raw material, wherein the dosage of the good solvent is 5-15 times, and the dosage of the poor solvent is 5-15 times; the acotiamide hydrochloride crude product is an anhydrate or a hydrate.
Wherein, the hydrate includes but is not limited to monohydrate, dihydrate and trihydrate.
Further, the amount of the good solvent is 5 times of the mass of the acotiamide hydrochloride crude product.
Further, the dosage of the poor solvent is 5-10 times of the mass of the acotiamide hydrochloride crude product.
Preferably, the amount of the poor solvent is 5 times based on the mass of the acotiamide hydrochloride crude product.
Further, when the crude product is an anhydride or a non-trihydrate hydrate, in addition to the recrystallization solvent, additional water is preferably added during refining to form a trihydrate, and the addition amount of the additional water is 1-5 times of the mass of the crude acotiamide hydrochloride. Preferably, the additional water is added in an amount of 1 time the mass of the crude acotiamide hydrochloride.
The invention provides a refining method of acotiamide hydrochloride, which comprises the following two steps:
step a, adding acotiamide hydrochloride crude product into DMF (dimethyl formamide), wherein the mass of the DMF is 5-15 times that of the crude product, fully dissolving, carrying out solid-liquid separation, and collecting a solution; or adding the acotiamide hydrochloride crude product into DMF (dimethyl formamide), wherein the mass of the DMF is 5-15 times that of the crude product, fully dissolving the acotiamide hydrochloride crude product in water, carrying out solid-liquid separation, and collecting a solution; wherein the acotiamide hydrochloride crude product is an anhydrate or a hydrate;
and b, slowly adding water into the solution obtained in the step a under a heating condition, wherein the mass of the water is 5-15 times that of the crude product, and then cooling and crystallizing to obtain a refined acotiamide hydrochloride trihydrate product.
Further, the acotiamide hydrochloride crude product is a hydrate.
Wherein, when water is added in the step a, the acotiamide hydrochloride crude product is favorable for forming acotiamide hydrochloride trihydrate; especially when the acotiamide hydrochloride crude product is an anhydride or a non-trihydrate hydrate, the water added in the step a is favorable for ensuring that the acotiamide hydrochloride trihydrate is generated. And the added amount of the water is not included in the poor solvent of the present invention.
Further, the mass of the DMF in the step a is 5-10 times of that of the crude product.
Preferably, the mass of DMF in step a is 5 times of the crude product.
Further, the step a is fully dissolved at the temperature of 20-30 ℃.
Further, the adding amount of water in the step a is 1-5 times of the mass of the crude product.
Preferably, the amount of water added in step a is 1 time of the mass of the crude product.
Further, the step b satisfies at least one of the following conditions:
the mass of water in the step b is 5-10 times of that of the crude product;
preferably, the mass of water in step b is 5 times of the mass of the crude product;
the heating temperature in the step b is 75-85 ℃;
the crystallization in the step b is carried out at room temperature;
the crystallization in the step b is stirring crystallization;
the crystallization time in the step b is 1-10 hours;
preferably, the crystallization time in step b is 5 hours.
Further, the refining method also comprises the following acetone pulping steps: and centrifuging after crystallization, pulping the obtained solid substance by using acetone, centrifuging again, and drying under reduced pressure to obtain the product.
Further, the refining party satisfies at least one of the following conditions:
the dosage of the acetone is 1-10 times of the mass of the acotiamide hydrochloride crude product;
preferably, the dosage of the acetone is 1-5 times of the mass of the acotiamide hydrochloride crude product;
further preferably, the dosage of the acetone is 5 times of the mass of the acotiamide hydrochloride crude product;
the time for pulping the acetone is less than 5 hours;
preferably, the time for pulping the acetone is 0.5 hour;
the temperature of the reduced pressure drying is 30-35 ℃;
the time for drying under reduced pressure is 1.0-2.0 hours;
preferably, the time of the reduced pressure drying is 1.2-1.5 hours;
the end point of the reduced pressure drying is that the water content of the acotiamide hydrochloride refined product is 9.5-10.5%.
According to the invention, a specific amount of DMF (dimethyl formamide) is used as a good solvent, water is used as a poor solvent, and acotiamide hydrochloride is recrystallized. The amplification production shows that when the scheme is adopted, the medicine solution is filtered at normal temperature and enters a clean area, and no solid is precipitated. The invention enables the yield of acotiamide hydrochloride trihydrate to reach more than 95 percent, not only obviously improves the product yield, but also can avoid the problem that a large amount of precipitated solids block pipelines when the solution is filtered or enters a clean area, and has better effects on enlarging production operation and improving the product yield. In addition, when the refining method of the invention adds the step of pulping by acetone, the drying time can be greatly shortened, the production efficiency can be further improved, and the time and the electric power cost can be saved.
Drawings
FIG. 1 is a hydrogen spectrum of the product obtained in example 1;
figure 2 is a TGA profile of the product obtained in example 1.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
It should be appreciated that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments and features of the various embodiments described in this specification can be combined and combined by one skilled in the art without contradiction.
Example 1
Adding 16.83kg of acotiamide hydrochloride anhydrous crude product into 84.15kg of DMF, adding 16.83kg of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 84.15kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 16.83kg of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 16.41kg of acotiamide hydrochloride trihydrate refined product, wherein the yield is 97.5%, and the purity is 99.7%. The hydrogen spectrum of the product is shown in figure 1, and the TGA spectrum is shown in figure 2.
Example 2
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 500.0g of DMF, adding 100.0g of purified water, fully dissolving at 20-30 ℃, and filtering insoluble substances.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, and slowly adding 1.0kg of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100.0g of acetone, and filtering; drying at 30-35 ℃ under reduced pressure to obtain 96.7g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 96.7%, and the purity is 99.8%.
Example 3
Adding 3.86kg of acotiamide hydrochloride anhydrous crude product into 19.3kg of DMF, adding 3.86kg of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 19.3kg of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 3.86g of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 3.74kg of acotiamide hydrochloride trihydrate refined product, wherein the yield is 96.9%, and the purity is 99.9%.
Example 4
Adding 18.04kg of acotiamide hydrochloride hydrate crude product into 90.20kg of DMF, adding 18.04kg of purified water, fully dissolving at 20-30 ℃, and performing fine filtration to enter a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 90.2kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 90kg of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 17.41kg of acotiamide hydrochloride trihydrate refined product, wherein the yield is 96.5%, and the purity is 99.7%.
Example 5
100.0g of the acotiamide hydrochloride anhydride crude product is added into 1.00kg of DMF, 100.0g of purified water is added, the mixture is fully dissolved at the temperature of 20-30 ℃, and insoluble substances are filtered.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, and slowly adding 1.5kg of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100.0g of acetone, and filtering; drying at 30-35 ℃ under reduced pressure to obtain 95.2.0g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 95.2%, and the purity is 99.6%.
Example 6
100.0g of the acotiamide hydrochloride anhydride crude product is added to 1.5kg of DMF, 100.0g of purified water is added, the mixture is fully dissolved at 20-30 ℃, and insoluble substances are filtered.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, preserving heat, and slowly adding 1.00kg of purified water; naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100.0g of acetone, and filtering; and drying at 30-35 ℃ under reduced pressure to obtain 95.7g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 95.7%, and the purity is 99.7%.
Example 7
Adding 15.13kg of acotiamide hydrochloride anhydrous crude product into 75.65kg of DMF, adding 15.13kg of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 75.65kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 14.59kg of the acotiamide hydrochloride trihydrate refined product, wherein the yield is 96.4%, and the purity is 99.7%.
Example 8
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 1.5kg of DMF, adding 100.0g of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 1.5kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; and drying at 30-35 ℃ under reduced pressure to obtain 95.1g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 95.1%, and the purity is 99.8%.
Example 9
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 1.0kg of DMF, adding 100.0g of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 1.0kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; and drying at 30-35 ℃ under reduced pressure to obtain 95.3g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 95.3%, and the purity is 99.7%.
Example 10
Adding 15.00kg of acotiamide hydrochloride anhydrous crude product into 75.01kg of DMF, adding 75.00kg of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 75.05kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 150.00kg of acetone, and filtering; and drying at 30-35 ℃ under reduced pressure to obtain 14.46kg of the acotiamide hydrochloride trihydrate refined product, wherein the yield is 96.4%, and the purity is 99.8%.
In experiments, the applicant also finds that the acetone pulping step has great influence on the drying process when the acotiamide hydrochloride is refined by the method. As described in the above examples, when drying under reduced pressure is employed, the drying temperature is 30 to 35 ℃, and the drying end point is 9.5% to 10.5% of the moisture content in the purified product, the drying time in the above examples is counted as follows:
TABLE 1 influence of the acetone pulping process of examples 1 to 10 of the present invention on drying time
| Examples | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Acotiamide hydrochloride crude product: acetone (g-g) | 1:1 | 1:1 | 1:1 | 1:5 | 1:1 | 1:1 | / | / | / | 1:10 |
| Beating time of acetone (minutes) | 30 | 30 | 30 | 30 | 30 | 30 | / | / | / | 30 |
| Acetone beating speed (rpm) | 100 | 100 | 100 | 100 | 100 | 100 | / | / | / | 100 |
| Drying time (hours) | 1.5 | 1.5 | 1.4 | 1.2 | 1.5 | 1.5 | 12 | 24 | 28 | 1.5 |
The results in the table show that when the refining method of the invention is added with the step of pulping with acetone, the drying time can be greatly reduced; the drying time is about 12-28 hours when the acetone pulping step is not carried out, the drying time is mainly influenced by the filtering condition, if the filtering condition is long and the filtrate is fully filtered, the drying time is short, otherwise, the drying time is long. When the amount of the added acetone is 1-10 times of the mass of the crude product, the drying time can be shortened to 1.2-1.5 hours, and the influence of the filtration condition is avoided; especially, when the using amount of the acetone is 5 times of the mass of the crude product, the drying time can be shortened to 1.2 hours, so that the process cost is greatly reduced, and the process efficiency is improved.
Comparative example 1 Effect of DMF amount on recrystallization yield
Acotiamide hydrochloride was purified according to the procedure of example 1, except that the crude product: the mass ratio of DMF was 1: 1. Under the condition, although the drug solution is filtered and enters a clean zone, a large amount of solids are not separated out, the crude product cannot be completely dissolved even if the drug solution is heated, the product loss is nearly 30 percent during subsequent filtration, and the final product yield is only 66.2 percent.
Comparative example 2 Effect of DMF amount on recrystallization yield
Acotiamide hydrochloride was purified according to the procedure of example 1, except that the crude product: the mass ratio of DMF was 1: 16. At this time, the solid precipitated during the crystallization of the drug solution was reduced, resulting in a product loss of approximately 20% and a final product yield of 75.3%.
Comparative example 3 Effect of solvent addition sequence on recrystallization yield
100g of acotiamide hydrochloride anhydride crude product is added into a mixed solution of 500.0g of DMF and 600.0g of purified water, fully dissolved at 20-30 ℃, and insoluble substances are filtered.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100g of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 76.7g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 76.7%, and the purity is 99.7%.
Comparative example 4 Effect of solvent type on recrystallization yield
2.44kg of the crude acotiamide hydrochloride anhydride was added to a mixed solution of 12.20kg of isopropanol and 2.44kg of purified water; sufficiently dissolving at 20-30 ℃, and filtering insoluble substances.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, and slowly adding 12.21kg of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 2.45kg of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 1.62kg of acotiamide hydrochloride trihydrate refined product, wherein the yield is 66.2% and the purity is 99.6%.
Comparative example 5 Effect of amount of poor solvent on recrystallization yield
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 500.0g of DMF, adding 100.0g of purified water, fully dissolving at 20-30 ℃, and filtering insoluble substances.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, and slowly adding 400.0g of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100.0g of acetone, and filtering; drying at 30-35 ℃ under reduced pressure to obtain 76.7g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 76.7%, and the purity is 99.5%.
Comparative example 6 Effect of amount of poor solvent on recrystallization yield
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 500.0g of DMF, adding 100.0g of purified water, fully dissolving at 20-30 ℃, and filtering insoluble substances.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, and slowly adding 1.6kg of purified water while keeping the temperature; naturally cooling to room temperature, stirring for 5 hours for crystallization, and filtering; pulping the filter cake for 30 minutes by using 100.0g of acetone, and filtering; drying at 30-35 ℃ under reduced pressure to obtain 79.7g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 79.7%, and the purity is 99.8%.
Comparative example 7 Effect of amount of Water added in step a on recrystallization yield
Adding 100.0g of acotiamide hydrochloride anhydrous crude product into 500.0g of DMF, adding 600.0g of purified water, fully dissolving at 20-30 ℃, finely filtering, and entering a clean area.
Heating the acotiamide hydrochloride solution after fine filtration to 75-85 ℃, and slowly adding 1.5kg of purified water while keeping the temperature; cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 100.0g of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 85.1g of acotiamide hydrochloride trihydrate refined product, wherein the yield is 85.1%, and the purity is 99.7%.
Comparative example 8 Acotiamide hydrochloride purification Using existing Process
17.26kg of the crude acotiamide hydrochloride anhydrate was added to 69.0L of 20% aqueous isopropanol; fully dissolving at 75-85 ℃, transferring the acotiamide solution to a clean area by using a heat-preservation barrel, filtering by using filter cloth, and discarding the filtered filter cake.
Heating the filtered acotiamide hydrochloride solution to 75-85 ℃, naturally cooling to room temperature, stirring for 5 hours for crystallization, and centrifuging; pulping the filter cake for 30 minutes by using 17.26g of acetone, and centrifuging; drying at 30-35 ℃ under reduced pressure to obtain 11.43kg of acotiamide hydrochloride trihydrate refined product, wherein the yield is 66.2% and the purity is 99.6%.
In summary, the inventors have made various attempts to obtain the refining method of the present invention through a large number of experiments, such as the kind of solvent, the way of adding the solvent, the adding proportion, the refining temperature, the way of crystallization, and other parameters, and especially, have studied methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, diethyl ether, tetrahydrofuran, 1, 4-dioxane, DMF, DMSO, and the like in order to screen the kind of solvent, and finally unexpectedly found that the technical problems to be solved by the present invention can be solved by using specific amounts of DMF and water as the solvent.
Claims (10)
1. A recrystallization solvent for acotiamide hydrochloride, characterized in that: DMF is used as a good solvent, and water is used as a poor solvent; the preparation method comprises the following steps of (1) taking the acotiamide hydrochloride crude product as a raw material, wherein the dosage of the good solvent is 5-15 times, and the dosage of the poor solvent is 5-15 times; the acotiamide hydrochloride crude product is an anhydrate or a hydrate.
2. The recrystallization solvent as claimed in claim 1, wherein: the dosage of the good solvent is 5 times of the mass of the acotiamide hydrochloride crude product.
3. The recrystallization solvent as claimed in claim 1, wherein: the dosage of the poor solvent is 5-10 times of the mass of the acotiamide hydrochloride crude product; preferably, the amount of the poor solvent is 5 times based on the mass of the acotiamide hydrochloride crude product.
4. The refining method of acotiamide hydrochloride is characterized by comprising the following steps: the method comprises the following two steps:
step a, adding acotiamide hydrochloride crude product into DMF (dimethyl formamide), wherein the mass of the DMF is 5-15 times that of the crude product, fully dissolving, carrying out solid-liquid separation, and collecting a solution; or adding the acotiamide hydrochloride crude product into DMF (dimethyl formamide), wherein the mass of the DMF is 5-15 times that of the crude product, fully dissolving the acotiamide hydrochloride crude product in water, carrying out solid-liquid separation, and collecting a solution; wherein the acotiamide hydrochloride crude product is an anhydrate or a hydrate;
and b, slowly adding water into the solution obtained in the step a under a heating condition, wherein the mass of the water is 5-15 times that of the crude product, and then cooling and crystallizing to obtain a refined acotiamide hydrochloride trihydrate product.
5. The refining process of claim 4, wherein: the mass of DMF in step a is 5 times of the crude product.
6. The refining process of claim 4, wherein: step a, fully dissolving at 20-30 ℃.
7. The refining process of claim 4, wherein: the adding amount of the water in the step a is 1-5 times of the mass of the crude product; preferably, the amount of water added is 1 time the mass of the crude product.
8. The refining process of claim 4, wherein: step b satisfies at least one of the following:
the mass of water in the step b is 5-10 times of that of the crude product;
preferably, the mass of water in step b is 5 times of the mass of the crude product;
the heating temperature is 75-85 ℃;
the crystallization is carried out at room temperature;
the crystallization is stirring crystallization;
the crystallization time is 1-10 hours;
preferably, the time for the crystallization is 5 hours.
9. The purification process according to any one of claims 4 to 8, wherein: also comprises the following acetone pulping steps: and centrifuging after crystallization, pulping the obtained solid substance by using acetone, centrifuging again, and drying under reduced pressure to obtain the product.
10. The refining process of claim 9, wherein: at least one of the following is satisfied:
the dosage of the acetone is 1-10 times of the mass of the acotiamide hydrochloride crude product;
preferably, the dosage of the acetone is 1-5 times of the mass of the acotiamide hydrochloride crude product;
further preferably, the dosage of the acetone is 5 times of the mass of the acotiamide hydrochloride crude product;
the time for pulping the acetone is less than 5 hours;
preferably, the time for pulping the acetone is 0.5 hour;
the temperature of the reduced pressure drying is 30-35 ℃;
the time for drying under reduced pressure is 1.0-2.0 hours;
preferably, the time of the reduced pressure drying is 1.2-1.5 hours;
the end point of the reduced pressure drying is that the water content of the acotiamide hydrochloride refined product is 9.5-10.5%.
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