CN116143771A - Preparation method of high-purity lurasidone intermediate - Google Patents
Preparation method of high-purity lurasidone intermediate Download PDFInfo
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- CN116143771A CN116143771A CN202111374229.8A CN202111374229A CN116143771A CN 116143771 A CN116143771 A CN 116143771A CN 202111374229 A CN202111374229 A CN 202111374229A CN 116143771 A CN116143771 A CN 116143771A
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- 229960001432 lurasidone Drugs 0.000 title claims abstract description 10
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000010438 heat treatment Methods 0.000 claims abstract description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000047 product Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 17
- 238000010992 reflux Methods 0.000 claims abstract description 17
- 239000012065 filter cake Substances 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000007605 air drying Methods 0.000 claims description 8
- 238000007664 blowing Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 229960002863 lurasidone hydrochloride Drugs 0.000 description 2
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 101100341170 Caenorhabditis elegans irg-7 gene Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a high-purity lurasidone intermediate. The method comprises the following steps: 1) Mixing a crude product of a compound shown in a formula II with toluene, and heating to dissolve; adding active carbon into the mixture, refluxing, stirring and decoloring for 20-40min, filtering to remove the active carbon while the mixture is hot, and collecting filtrate; 2) Heating the filtrate to dissolve, adding methanol, and stirring for 20-40min; then slowly cooling to room temperature, crystallizing for 0.5-1 hour, centrifuging, collecting a filter cake, and drying to obtain a white solid; 3) Mixing the white solid obtained in the step 2) with toluene and methanol, heating the system to dissolve, stirring for 0.5-1.5h, slowly cooling to room temperature, crystallizing for 1.5-2.5 h, centrifuging, collecting filter cakes, and drying to obtain a refined product of the compound shown in the formula II.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of a high-purity lurasidone intermediate.
Background
Lurasidone hydrochloride was co-developed by japanese alumni (Dainippon Sumitomo) and martial arts, with us Food and Drug Administration (FDA) approval on 28 th 2010, european drug administration (EMA) approval on 21 st 3 th 2014, and national drug administration (NMPA) approval on 24 th 1 st 2019. Is marketed in the United states by Sumitomo Dakida, in Europe by Takeda, and in China by Sunovion, a Sunoson company, under the trade name
Lurasidone hydrochloride is a central dopamine D2 (DRD 2) and 5-hydroxytryptamine (5-HT 2A) receptor antagonist. The composition can be used as single drug or combined with lithium agent and sodium valproate for treating schizophrenia and bipolar I disorder (bipolar depression).
In the preparation process of lurasidone hydrochloride, genotoxic impurities (shown in a formula III) with the following epoxy structure are extremely easy to generate, and the content of the genotoxic impurities directly influences the quality of products.
Therefore, the purification of the impurities in the raw materials needs to be studied deeply, and the quality of the raw materials is controlled according to specific impurities, so that the quality of the raw materials is further improved.
Disclosure of Invention
The invention aims to provide a preparation method of a high-purity lurasidone intermediate, which can particularly reduce the content of impurities shown in a formula III in the lurasidone intermediate.
The preparation method of the high-purity lurasidone intermediate provided by the invention comprises the following steps:
1) Mixing a crude product of a compound (lurasidone intermediate) shown in a formula II with toluene, and heating to dissolve; adding active carbon into the mixture, refluxing, stirring and decoloring for 20-40min, filtering to remove the active carbon while the mixture is hot, and collecting filtrate;
2) Heating the filtrate to dissolve, adding methanol, and stirring for 20-40min; then slowly cooling to room temperature, crystallizing for 0.5-1 hour, centrifuging, collecting a filter cake, and drying to obtain a white solid;
3) Mixing the white solid obtained in the step 2) with toluene and methanol, heating the system to dissolve, stirring for 0.5-1.5h, slowly cooling to room temperature, crystallizing for 1.5-2.5 h, centrifuging, collecting a filter cake, and drying to obtain the product.
In the above method step 1), the content of the compound (impurity) represented by the formula III in the compound represented by the formula II is not more than 150ppm.
In the step 1) of the method, the ratio of the compound shown in the formula II to toluene is 780g:2-3L, which can be 780g:2.4L.
In the above method step 1), the temperature of heating to the solvent may be 50 ℃.
In the step 1) of the method, the addition amount of the activated carbon can be 3% -6% of the mass of the compound shown in the formula II, and further can be 3.5% -5%.
In the above method step 1), the decoloring time may be specifically 30min.
In the above method step 2), the temperature of heating to the solvent may be 50 ℃.
In the step 2) of the method, the volume ratio of the methanol to the toluene in the step 1) is 4:1-6:1, and can be specifically 5:1.
In the above method step 2), the drying temperature is 40-50 ℃, and the drying mode may be air drying.
In the above method step 3), the mixture ratio of the white solid, toluene and methanol may be 700g:2.8L:14L.
In the above method step 3), the temperature of heating to the solvent may be 50 ℃.
In the above method step 3), the crystallization time may be specifically 2 hours.
In the above method step 3), the drying temperature is 40-50 ℃, and the drying mode may be air drying.
The method of the invention also comprises the step of preparing the refined product of the compound shown as the formula II obtained in the step 3) into hydrochloride, and the method is concretely as follows: adding acetone and refined products of the compound shown in the formula II in batches under stirring, and heating the system until reflux is clear; dropwise adding concentrated hydrochloric acid into the system, continuously stirring and refluxing for 0.5h after the dropwise adding, stopping heating, and slowly cooling to 20-30 ℃; continuously cooling to 0-5 ℃ in ice water bath, stirring and crystallizing for 1h; filtering, and drying the filter cake by blowing at 55-60 ℃ to obtain the finished product.
The lurasidone intermediate refined by the method disclosed by the invention has the impurity (the compound shown in the formula III) content as low as 8.4ppm, and is beneficial to improving the quality of bulk drugs.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.
Example 1,
To a 10L four-necked flask, 2.4L toluene and 780g of a crude product of intermediate 3 (represented by formula II) were successively added with stirring. The system is heated to 50 ℃ for dissolving, 30g of active carbon is added into the system, and the mixture is refluxed, stirred and decolored for 30min. Filtering to remove active carbon while the active carbon is hot, collecting filtrate, transferring the filtrate into a 20L reaction kettle, and heating the system again to 50 ℃ for dissolving. Methanol 12L was added to the system and stirring was continued for 0.5 hours with heating (50 ℃ C.). Slowly cooling to room temperature, crystallizing for 0.5 hr, and centrifuging. Collecting filter cake, and air drying at 40-50deg.C to obtain 700g white solid (i.e. primary refined product).
Adding the white solid, 2.8L toluene and 14L methanol into a 20L reaction kettle, heating the system to 50 ℃ for dissolving, stirring for 1h, slowly cooling to room temperature, crystallizing for 2h, centrifuging, collecting a filter cake, and drying by blowing at 40-50 ℃ to obtain 630g of white solid (namely a secondary refined product).
Adding 6kg of acetone and the secondary refined product in portions under stirring, and heating the system until the solution is clear under reflux. 1kg of concentrated hydrochloric acid is added into the system dropwise, and stirring and reflux are continued for 0.5h after the addition is finished. Stopping heating and slowly cooling to 20-30 ℃. Continuously cooling to 0-5 ℃ in ice water bath, stirring and crystallizing for 1h. Filtering, and drying the filter cake by blowing at 55-60 ℃ to obtain 550g of finished product.
And respectively measuring the contents of impurities shown in the formula III in the crude product, the primary refined product, the secondary refined product and the final finished product of the intermediate 3.
The specific measurement method is as follows:
the sample solution is taken to be a proper amount of the sample (intermediate 3), precisely weighed, dissolved by adding dimethyl sulfoxide and quantitatively diluted to a solution of about 5mg per 1 ml.
The reference substance solution is prepared by taking a proper amount of impurity reference substance shown in formula III, precisely weighing, adding dimethyl sulfoxide for dissolving, and quantitatively diluting to obtain a solution containing about 0.1 μg per 1 ml.
The chromatographic conditions are that octadecylsilane chemically bonded silica is used as a chromatographic column, and the specification of the chromatographic column is as follows: 4.6X105 mm,3 μm; 0.005mol/L potassium dihydrogen phosphate solution (pH value is adjusted to 7.0 by 0.2mol/L sodium hydroxide solution) -acetonitrile (40:60, v/v) is taken as a mobile phase; the flow rate is 1.0ml per minute; the detection wavelength is 230nm; the temperature of the sample injection chamber is 25 ℃; the sample volume was 50. Mu.l.
The system applicability requires that the theoretical plate number in the control solution chromatogram is not less than 3000 calculated according to the IM-F peak.
The measuring method precisely measures the solution of the sample and the solution of the reference substance, respectively injects the solution into a liquid chromatograph, and records the chromatograms.
Three batches of crude intermediate 3 were co-purified and the impurity detection (detection of formula III content) results are summarized in table 1.
TABLE 1 impurity detection data summary table
| Batch of | Crude product | Disposable refined product | Secondary refined product | Finished product |
| First batch of | 98.2ppm | 53.5ppm | 22.6ppm | 11.3ppm |
| Second batch | 110ppm | 46ppm | 22ppm | 10ppm |
| Third batch | 113.5ppm | 63.7ppm | 33.4ppm | 8.4ppm |
Comparative example 1:
50.0g of crude intermediate 3 (formula II) (second batch in Table 1) was successively added to a 1L three-necked flask under stirring, 350ml of ethyl acetate was heated to reflux, and 5.0g of activated carbon was added thereto, followed by refluxing, stirring and decoloring for 30 minutes. Filtering while the mixture is hot, removing active carbon, and collecting filtrate. Transferring to a 1L three-neck flask, continuously refluxing for 0.5h, firstly adopting water bath to cool to below 35 ℃, then cooling to 0-5 ℃ in a cold trap, and maintaining the temperature and stirring for 5h. Suction filtration, filter cake collection, and forced air drying at 40-50 ℃ to obtain 42.2g of white solid. The detection result of the impurity was 102.5ppm.
Comparative example 2:
50.0g of crude intermediate 3 (represented by formula II) (second batch in Table 1) was sequentially added to a 2L three-necked flask under stirring, 800ml of acetone was heated to reflux, dissolved, 5.0g of activated carbon was added thereto, and reflux stirring decolorization was continued for 30 minutes. Filtering while the mixture is hot, removing active carbon, and collecting filtrate. Transferring to a 2L three-neck flask, continuously refluxing for 0.5h, firstly adopting water bath to cool to below 35 ℃, then cooling to 0-5 ℃ in a cold trap, and maintaining the temperature and stirring for 5h. Suction filtration, filter cake collection, and forced air drying at 40-50 ℃ to obtain 40.1g of white solid. The detection result of the impurity was 98.3ppm.
Comparative example 3:
50.0g of crude intermediate 3 (represented by formula II) in the form of a second batch in Table 1 was sequentially added to a 2L three-necked flask with stirring, 900ml of absolute ethanol was heated to reflux, dissolved, 5.0g of activated carbon was added thereto, and the mixture was continuously refluxed, stirred and decolorized for 30 minutes. Filtering while the mixture is hot, removing active carbon, and collecting filtrate. Transferring to a 2L three-neck flask, continuously refluxing for 0.5h, firstly adopting water bath to cool to below 35 ℃, then cooling to 0-5 ℃ in a cold trap, and maintaining the temperature and stirring for 5h. Suction filtration, filter cake collection, and forced air drying at 40-50 ℃ to obtain 47.6g of white solid. The detection result of the impurity was 103.7ppm.
Claims (9)
1. A preparation method of a high-purity lurasidone intermediate, which comprises the following steps:
1) Mixing a crude product of a compound shown in a formula II with toluene, and heating to dissolve; adding active carbon into the mixture, refluxing, stirring and decoloring for 20-40min, filtering to remove the active carbon while the mixture is hot, and collecting filtrate;
2) Heating the filtrate to dissolve, adding methanol, and stirring for 20-40min; then slowly cooling to room temperature, crystallizing for 0.5-1 hour, centrifuging, collecting a filter cake, and drying to obtain a white solid;
3) Mixing the white solid obtained in the step 2) with toluene and methanol, heating the system to dissolve, stirring for 0.5-1.5h, slowly cooling to room temperature, crystallizing for 1.5-2.5 h, centrifuging, collecting a filter cake, and drying to obtain a refined product of the compound shown in the formula II;
2. the method according to claim 1, characterized in that: in the step 1), the content of the compound shown in the formula III in the compound shown in the formula II is not higher than 150ppm;
in the step 1), the ratio of the compound shown in the formula II to toluene is 780g:2-3L;
in the step 1), heating to the temperature of the solution at 50 ℃;
in the step 1), the addition amount of the activated carbon is 3% -6% of the mass of the compound shown in the formula II;
in the step 1), the decoloring time is 30min.
3. The method according to claim 1 or 2, characterized in that:
in the step 2), the volume ratio of the methanol to the toluene in the step 1) is 4:1-6:1.
4. A method according to any one of claims 1-3, characterized in that:
in the step 2), heating to the temperature of the solution at 50 ℃;
in the step 2), the drying temperature is 40-50 ℃, and the drying mode is forced air drying.
5. The method according to any one of claims 1-4, wherein: in the step 3), the proportion of the white solid, toluene and methanol is 700g:2.8L:14L.
6. The method according to any one of claims 1-5, wherein: in the step 3), the temperature of heating to the solution is 50 ℃.
7. The method according to any one of claims 1-6, wherein: in the step 3), the crystallization time is 2 hours.
8. The method according to any one of claims 1-7, wherein: in the step 3), the drying temperature is 40-50 ℃, and the drying mode is forced air drying.
9. The method according to any one of claims 1-8, wherein: the method also comprises the step of preparing the refined product of the compound shown in the formula II obtained in the step 3) into hydrochloride, and specifically comprises the following steps: adding acetone and refined products of the compound shown in the formula II in batches under stirring, and heating the system until reflux is clear; dropwise adding concentrated hydrochloric acid into the system, continuously stirring and refluxing for 0.5h after the dropwise adding, stopping heating, and slowly cooling to 20-30 ℃; continuously cooling to 0-5 ℃ in ice water bath, stirring and crystallizing for 1h; filtering, and drying the filter cake by blowing at 55-60 ℃ to obtain the finished product.
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- 2021-11-19 CN CN202111374229.8A patent/CN116143771B/en active Active
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|---|---|---|---|---|
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