CN111393423A - Epipiprazole impurity compound and preparation method thereof - Google Patents
Epipiprazole impurity compound and preparation method thereof Download PDFInfo
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- CN111393423A CN111393423A CN201910004099.5A CN201910004099A CN111393423A CN 111393423 A CN111393423 A CN 111393423A CN 201910004099 A CN201910004099 A CN 201910004099A CN 111393423 A CN111393423 A CN 111393423A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 239000012535 impurity Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 abstract description 7
- 229960001210 brexpiprazole Drugs 0.000 abstract description 7
- 238000005265 energy consumption Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- -1 thiophene-4-yl Chemical group 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- VMIRJNDPLCQEHB-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=C1C=CS2 VMIRJNDPLCQEHB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 2
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- 125000003836 4-phenylbutoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- MBOHAVAGDOGRBS-UHFFFAOYSA-N 7-(4-bromobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCBr)=CC=C21 MBOHAVAGDOGRBS-UHFFFAOYSA-N 0.000 description 1
- DPQAKBJISUNJNK-UHFFFAOYSA-N 7-(4-chlorobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCCl)=CC=C21 DPQAKBJISUNJNK-UHFFFAOYSA-N 0.000 description 1
- SQLHJIOAQRJTEI-UHFFFAOYSA-N 7-(4-iodobutoxy)-1H-quinolin-2-one Chemical compound N1C2=C(C=CC1=O)C=CC(OCCCCI)=C2 SQLHJIOAQRJTEI-UHFFFAOYSA-N 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses an impurity compound of brexpiprazole and a preparation method thereof, wherein the impurity is a compound (I). The method has the advantages of simple and easy operation, mild conditions, high yield, low energy consumption and low pollution, and is suitable for preparing laboratory-level standard products.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an epipiprazole impurity compound and a preparation method thereof.
Background
Brexpiprazole (Brexpiprazole) with chemical structural formula 3 and chemical name of 7- (4- (4- (benzene [ b ] thiophene-4-yl) piperazine-1-yl) butanol) quinoline-2 (1H) -ketone
In dopamine D2 receptors, partial D2 receptor agonists can generate functional antagonism on the limbic pathway of the brain, and can effectively improve the positive symptoms of schizophrenia caused by D2 overactivity; can produce functional excitation effect on the middle cerebral cortex channel, and can improve negative symptoms and cognitive impairment caused by D2 hypofunction. Brexpiprazole (brexpiprazole) jointly developed by Lingbei pharmacy (license) and Tsukamur pharmacy (original research) is an experimental serotonin-dopamine activity regulator (SDAM), is a novel multi-target action mechanism therapeutic drug for mental disorder diseases, mainly has partial agonism of a dopamine D2 receptor, partial agonism of a D3 receptor, partial agonism of a 5-HT1A receptor and partial antagonism of a 5-HT2A receptor, and is a novel drug which is developed aiming at multiple targets of monoamine neurotransmitters and has the effects of resisting schizophrenia and depression. The medicine is approved to be on the market and can be used for the adjuvant treatment of schizophrenia and major depression.
The research on impurities is an important content in the research and development process of the medicine, is directly related to the quality control and the medication safety of the medicine, and can ensure the quality and the safety of the product by controlling the impurities in the medicine product. The impurities of the drug mainly originate from the by-products in the synthesis process and the degradation of the drug. At present, related process impurities and degradation impurities are rarely reported, but the invention aims at the impurities which are generated in the processes of synthesis, storage and use of the ipiprazole and can influence the product quality, and has important significance for controlling the product quality.
Disclosure of Invention
The invention provides an impurity compound of brexpiprazole and a preparation method thereof, wherein the impurity compound is a compound shown in a formula I, and X in the compound shown in the formula I is chlorine, bromine or iodine.
These impurity compounds are generated during the preparation, storage and use of the brexpiprazole.
The compound of formula I has the chemical name 4- (benzo [ b ] thiophen-4-yl) -1, 1-bis (4- ((2-oxo-1, 2-dihydroquinolin-7-oxy) butoxy) piperazin-1-yl ammonium halide (where halogen X is chlorine, bromine, or iodine).
The invention provides the following technical scheme for preparing the impurity compound, and the method comprises the following step of carrying out substitution reaction on a compound shown in a formula 1 and a compound shown in a formula 2 or hydrochloride thereof in a solvent under the action of a catalyst under the alkaline condition to obtain a compound shown in a formula I.
Wherein X in the compounds of formula 1 and formula I is chlorine, bromine or iodine.
The reaction solvent used is preferably selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, or 1, 4-dioxane. The reaction equivalent number of the compound in the formula 1 is 1.2 eq-4.0 eq. The reaction temperature range is preferably 60 to 140 degrees. The alkali is: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or cesium carbonate. The catalyst is as follows: potassium iodide, sodium iodide, potassium bromide, or sodium bromide.
Purifying by a recrystallization mode, wherein a purification solvent is as follows: dichloromethane, N-dimethylformamide.
Drawings
FIG. 1 is a drawing of a compound of formula I1H-NMR spectrum.
FIG. 2 is a drawing of a compound of formula I13C-NMR spectrum.
Detailed Description
The following examples are intended to illustrate the present invention, and it is noted that the following descriptions are merely illustrative of the features and advantages of the present invention, and do not limit the scope of the claims of the present invention.
Example 1. 20.0g of 4-piperazinylbenzo [ B ] thiophene and 20.7g of 7- (4-chlorobutoxy) quinolin-2 (1H) -one were added to 300m L of acetonitrile, 14.6g of sodium carbonate and 5.7g of potassium iodide were added, the mixture was heated to 80 ℃ to react for 20 hours, after the reaction was completed, the system was cooled to room temperature of 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 200m L of water and heated to 65 ℃ and stirred for 2 hours, the wet product was filtered to obtain a wet product, the wet product was transferred to 400m L of dichloromethane and heated to 39 ℃ and stirred for 2 hours, the system was cooled to room temperature of 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 100m L N, N-dimethylformamide and heated to 100 ℃ and stirred to clear, the system was cooled to room temperature of 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 100m L of water and stirred for 2 hours, the wet product was dried under vacuum at 60 ℃ to obtain 4- (benzob) -1-oxobis [ 1-7-oxoquinoline-1-7- (0.47-dihydroquinoline-1H) -piperazine.
Example 2.10.0 g of 4-piperazinylbenzo [ B ] thiophene and 18.3g of 7- (4-bromobutoxy) quinolin-2 (1H) -one were added to 150m of L of N, N-dimethylformamide, 14.4g of potassium carbonate and 4.2g of potassium iodide were added, and the mixture was heated to 100 ℃ for 20 hours, after the completion of the reaction, 100m of L water was slowly dropped, the system was cooled to 65 ℃ and filtered to obtain a wet product, the wet product was transferred to 200m of L of dichloromethane, heated to 39 ℃ and stirred for 2 hours, the system was cooled to room temperature of 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 50m of L N, N-dimethylformamide, heated to 100 ℃ and stirred to dissolve, the system was cooled to room temperature of 15 to 30 ℃, filtered to obtain a wet product, the wet product was transferred to 50m of L of water, stirred at room temperature for 2 hours, and the wet product was dried under vacuum at 60 ℃ to obtain 4- (benzo [ B ] thiophen-4-yl) -1, 1-bis (2-oxoquinolyl-1H) -1, and 4- (dihydroquinolyl) ammonium bromide was obtained in a yield of 70.23 hours.
Example 3 4-Piperazinylbenzo [ B ] thiophene 10.0g and 7- (4-iodobutyloxy) quinolin-2 (1H) -one 56.4g were added to 1, 4-dioxane 150m L, sodium carbonate 18.3g and sodium iodide 5.0g were added, and the mixture was heated to 80 ℃ for 20 hours, after the reaction was completed, the system was cooled to 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 100m L water and heated to 65 ℃ for stirring for 2 hours, the wet product was obtained by heat filtration, the wet product was transferred to 200m L dichloromethane and heated to 39 ℃ for stirring for 2 hours, the system was cooled to 15 to 30 ℃ and filtered to obtain a wet product, the wet product was transferred to 50m L water and stirred for 2 hours, the wet product was transferred to 50m L N, N-dimethylformamide, heated to 100 ℃ and stirred to dissolve, the system was cooled to room temperature for 15 to 30 ℃ and filtered to obtain a wet product, and the wet product was dried in vacuum to obtain bis [ 4- (4-phenylbutoxy) -1-2- (1-2-oxo) piperazino-2- ((1.76) ammonium iodide yield).
1H-NMR(d6-DMSO)(ppm):11.623(2H,s),7.706-7.789(3H,m),7.711-7.731(1H,d), 7.510-7.545(3H,m),7.305-7.344(1H,t),7.003-7.022(1H,d),6.768-6.782(4H,m),6.278-6.306(2H,dd),4.054-4.067(4H,m),3.727(4H,br),3.597(4H,br),3.458(4H,br),1.860(8H,br)。
13C-NMR(d6-DMSO)(ppm):162.711,160.591,146.534,140.994,140.438,133.769, 129.714,127.082,125.324,122.153,119.021,118.334,113.837,113.497,111.137,99.033, 67.248,58.629,45.201,25.750,18.186。
Claims (8)
2. The process for preparing the epipiprazole impurity compound according to claim 1, which comprises the steps of dissolving the compound of formula 1 and the compound of formula 2 or hydrochloride thereof in a solvent, adding a catalyst, and carrying out a substitution reaction under an alkaline condition to obtain the compound of formula I.
3. The method of claim 2 wherein X in the compound of formula 1 is chlorine, bromine or iodine.
4. The method of claim 2: the reaction solvent used is preferably selected from N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile or 1, 4-dioxane.
5. The method of claim 2: the reaction equivalent number of the compound in the formula 1 is 1.2 eq-4.0 eq.
6. The reaction temperature range of the process according to claim 2 is preferably 60-140 degrees.
7. The base of claim 2 is: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or cesium carbonate.
8. The catalyst of claim 2 being: potassium iodide, sodium iodide, potassium bromide, or sodium bromide.
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CN111624263A (en) * | 2019-02-27 | 2020-09-04 | 上海科胜药物研发有限公司 | Determination and analysis method for IMP17 content in brexpiprazole |
CN115108981A (en) * | 2022-08-29 | 2022-09-27 | 天津辰欣药物研究有限公司 | Synthesis method of brexpiprazole impurity |
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CN106892909A (en) * | 2015-12-18 | 2017-06-27 | 重庆医药工业研究院有限责任公司 | One kind is according to piperazine azoles impurity compound and preparation method thereof |
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CN106892909A (en) * | 2015-12-18 | 2017-06-27 | 重庆医药工业研究院有限责任公司 | One kind is according to piperazine azoles impurity compound and preparation method thereof |
Cited By (2)
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CN111624263A (en) * | 2019-02-27 | 2020-09-04 | 上海科胜药物研发有限公司 | Determination and analysis method for IMP17 content in brexpiprazole |
CN115108981A (en) * | 2022-08-29 | 2022-09-27 | 天津辰欣药物研究有限公司 | Synthesis method of brexpiprazole impurity |
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