CN113698346A - Preparation method of impurity B in blonanserin process - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 30
- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229950002871 blonanserin Drugs 0.000 title claims abstract description 22
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 21
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims abstract description 12
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000010410 layer Substances 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 3
- 239000012320 chlorinating reagent Substances 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims 1
- 238000006561 solvent free reaction Methods 0.000 claims 1
- WAWSKWGQLMPXQY-UHFFFAOYSA-N cyclooctane;pyridine Chemical compound C1=CC=NC=C1.C1CCCCCCC1 WAWSKWGQLMPXQY-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- -1 4-ethyl-1-piperazinyl Chemical group 0.000 description 1
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
Abstract
The invention relates to a preparation method of impurity B in blonanserin process, which comprises the steps of reacting 4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula III) with a chloro reagent phenyl phosphoryl dichloride to obtain 2-chloro-4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula II), and reacting the formula II with N-ethylpiperazine under the catalysis of potassium iodide to obtain impurity B in blonanserin process (formula I), wherein the process is simple, the operation is convenient, the chromatographic purity is more than 99.0%, and the yield is high.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of impurity B in a blonanserin process of an antipsychotic drug.
Background
Impurity B (formula (I)) compound of blonanserin process refers to 2- (4-ethyl-1-piperazinyl) -4- (4-phenyl) -5,6,7,8,9, 10-hexahydrocyclooctane pyridine, and the compound is one of main impurities in blonanserin (atypical antipsychotic). The intermediate contains 2 aromatic molecular structures of chloropyridine and fluorobenzene, F and CI are same group atoms, and an intermediate state of defluorination can be formed after the intermediate is activated by iodine element, so the intermediate becomes one of main process impurities generated in the blonanserin synthesis process, and is also one of necessary impurities in the blonanserin quality standard.
The structure is shown as the following formula:
blonanserin is a new generation of atypical anti-schizophrenia drug, belongs to 5-hydroxytryptamine receptor antagonist, has a main action mechanism with strong blocking effect on dopamine D2 receptor and 5-hydroxytryptamine receptor, and is mainly used for treating schizophrenia in clinic. The medicine is developed by Sumitomo pharmaceutical corporation of Japan and is marketed in Japan in 1 month of 2008, the main dosage form is tablet, the clinical application is 2mg and 4mg, and the medicine is approved to be marketed as an imported subpackaged variety in China at present.
For the synthesis of impurity B in the blonanserin process, no special synthesis report is found, so that the synthesis can only be carried out by referring to an analogue method in US 5021421.
Disclosure of Invention
The invention aims to provide a method for synthesizing impurity B of blonanserin, which has strong selectivity, simple process and environmental protection.
The invention takes 4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula III) as a starting material, and reacts with a chloro reagent phenyl phosphoryl dichloride to obtain 2-chloro-4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula II), and the formula II reacts with N-ethylpiperazine under the catalysis of potassium iodide to obtain blonanserin process impurity B (formula (I)). Simple process, convenient operation, high chromatographic purity up to 99.0% and high yield.
The process of the invention is described in more detail below:
a preparation method of impurity B in blonanserin process comprises the following chemical reaction equations:
formula (III), formula (II), formula (I)
The method specifically comprises the following steps:
adding phenyl phosphoryl dichloride into 4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula III) in a reactor under stirring, reacting at a proper temperature, detecting the completion of a reaction by HPLC, cooling a reaction liquid, adding an organic solvent and water, continuously cooling, adding ammonia water to adjust the pH value to 9-10, stirring and crystallizing at a controlled temperature, filtering, washing and drying to obtain a gray solid; can be directly put into the next reaction without refining or refining;
adding 2-chloro-4- (4-phenyl) -5,6,7,8,9, 10-hexahydro cyclooctane pyridine (formula II) into a certain amount of N-ethyl piperazine under stirring, adding a catalyst, reacting at a proper temperature, monitoring the reaction completion by HPLC, sequentially adding methyl tert-butyl ether and saturated saline into the reaction solution at a low temperature, and standing for layering. And adding a hydrochloric acid solution into the organic layer for extraction, layering, adding a potassium carbonate solution into the acid water layer under the condition of cooling to adjust the pH value to 9-10, adding methyl tert-butyl ether to dissolve the oily substance, fully stirring, layering, and concentrating the organic layer to be dry to obtain a gray solid. Refining with isopropanol to obtain yellowish impurity B (formula (I)) of blonanserin.
The method has the advantage of no solvent reaction.
The molar ratio of the compound of the formula (III) to the phenyl phosphoryl dichloride serving as a chlorination reagent is 1-3, preferably 1-2.
The method comprises the step of reacting a compound of formula (III) with a chlorinated reagent, namely phenyl phosphoryl dichloride, at 160-170 ℃, preferably 160-165 ℃.
The method comprises the steps of cooling to 80 ℃ after the reaction is completed, adding ethanol, continuously cooling to 60 ℃, adding water, cooling to 20 ℃, adjusting the pH value to 9-10 with ammonia water, carrying out temperature control stirring crystallization, filtering, washing and drying to obtain a gray solid.
The method comprises the step that the molar ratio of the Chinese (II) to the N-ethylpiperazine is 1-5, preferably 3-4.
The method comprises the step of enabling the molar ratio of the Chinese formula (II) to the catalyst potassium iodide to be 0.1-1, preferably 0.3-0.5.
The reaction temperature of the method is 160-170 ℃, and preferably 160-165 ℃.
After the reaction, the solvent for dissolving the materials can be methyl tert-butyl ether, ethyl acetate, cyclohexane, n-butanol and the like, and preferably methyl tert-butyl ether and ethyl acetate.
The refined solvent of the crude compound of the formula (I) can be selected from methanol, ethanol, isopropanol, n-hexane, ethyl acetate, acetonitrile and the like, and the isopropanol is preferred.
The compound of formula (iii) was confirmed by mass spectrometry: excimer peak M/z, 254[ M + H ]]+. The compound of formula (ii) was confirmed by mass spectrometry: excimer ion peak M/z, [ 272M + H ]]+、274[M+2+H]+。
The structure and purity of the blonanserin impurity B (formula (I)) compound are determined by nuclear magnetic resonance1H NMR), mass spectrometry and liquid chromatography detection. MS: peak of excimer ion M/z, 350[ M + H ]]+。1H-NMR（400MHz，DMSO-d 6）：
δ1.02（3H，t，J=7.2Hz），1.30（4H，m），1.38（2H，m），1.68（2H，m），2.34（2H，q，J=7.2Hz），2.42（4H，t，J=4.8Hz），2.53（2H，m），2.80（2H，m），3.42（4H，t，J=4.8Hz），6.36（1H，s），7.26（2H，dd，J=8.0,1.2Hz），7.38（1H，td，J=8.0,1.2Hz），7.38（2H，td，J=8.0,1.2Hz）
HPLC:≥99.0%。
Detailed Description
The following examples are intended to illustrate the invention without limiting it.
Example 1.
Adding 7.8g of a compound shown in formula (III) and 12.0g of phenyl phosphoryl dichloride (IV) into a 100mL three-necked bottle, stirring, heating to (165 +/-5) DEG C, reacting for 1.5 h-2.5 h, detecting the reaction process by HPLC, cooling to (80 +/-5) DEG C after the reaction is finished, adding 80mL of dichloromethane, cooling to (20 +/-5) DEG C, adding 40mL of water, dropwise adding 10mL of ammonia water, adjusting the pH value of a water phase to 8-9, stirring for 30min, standing for layering, extracting a water layer by using dichloromethane for 3 times, using 20mL of dichloromethane each time, combining organic layers, drying for 1h by anhydrous magnesium sulfate, filtering, leaching by using 10mL of dichloromethane, and concentrating the filtrate (40 +/-5) DEG C under reduced pressure to dryness to obtain an off-white solid; adding 75ml of ethanol, stirring, heating to reflux and dissolve, dripping 10ml of purified water, cooling to 20 +/-5 ℃, crystallizing for 2 hours, filtering, washing and drying to obtain 6.52g of a white solid, namely the compound of the formula (II), wherein the yield is 78 percent and the purity is 99.9 percent.
Example 2.
Adding 7.8g of a compound of a formula (III) and 12.0g of phenyl phosphoryl dichloride (IV) into a 100mL three-necked flask, stirring, heating to 160-165 ℃ for reaction for 1.5h, detecting the reaction process by HPLC, cooling to (80 +/-5 ℃) after the reaction is finished, adding 48mL of ethanol, cooling to 60 ℃, adding 24mL of water, cooling to 20 ℃, dropwise adding 12mL of ammonia water to adjust the pH value to 8-9, stirring for crystallization for 60min, filtering, washing and drying to obtain 7.9g of gray solid, namely the compound of the formula (II), wherein the yield is 94.55%, and the purity is 99.67%.
Example 3.
Adding 4.0g of a compound shown as a formula (II), 2.1g of potassium iodide and 5.0g of N-ethylpiperazine into a 100mL three-necked flask, introducing nitrogen, stirring, heating to (165 +/-5) DEG C, controlling the temperature to react for 24 hours, detecting the reaction progress by PHLC, stopping heating after the reaction is finished, cooling to (90 +/-5) DEG C, adding 50mL of tert-butyl methyl ether, stirring, adding 20mL of saturated sodium chloride solution for washing 3 times, standing, separating, adding 5mol/L of hydrochloric acid solution into an organic phase to adjust the pH to 1, stirring for 30 minutes, standing, separating, washing an aqueous layer for 2 times by using tert-butyl methyl ether, using 50mL each time, standing for separating, adjusting the pH of an aqueous phase to 8-9 by using saturated potassium carbonate solution, adding 100mL of tert-butyl methyl ether, stirring for 1 hour, standing for separating, drying an organic phase for 1 hour by using anhydrous magnesium sulfate, filtering, leaching a filter cake by using 20mL of tert-butyl methyl ether, (40 + -5) deg.C, and vacuum concentrating to dryness to obtain 3.2g off-white solid, i.e. blonanserin impurity B (formula (I)) compound, with yield of 68% and purity of 99.5%.
Example 4.
Adding 5.0g of a compound shown as a formula (II), 1.5g of potassium iodide and 7.2g N-ethylpiperazine into a 100mL three-necked flask, introducing nitrogen, stirring, heating to 160-165 ℃, reacting for 24 hours under controlled temperature, detecting the reaction process by HPLC, stopping heating after the reaction is finished, cooling to (90 +/-5) ° C, adding 150mL of tert-butyl methyl ether, stirring, adding 30mL of saturated sodium chloride solution for washing 3 times, standing, separating, adding 5mol/L of hydrochloric acid solution into an organic phase to adjust the pH to 1, stirring for 30 minutes, standing, separating, washing an aqueous layer for 2 times by using 50mL of tert-butyl methyl ether each time, standing for separating, adjusting the pH of an aqueous phase to 8-9 by using saturated potassium carbonate solution, adding 150mL of tert-butyl methyl ether, stirring for 1 hour, standing for separating, drying an organic phase for 1 hour by anhydrous magnesium sulfate, filtering, leaching a filter cake by using 20mL of tert-butyl methyl ether, concentrating under reduced pressure at 40 + -5 deg.C to dryness to obtain gray solid. Adding 15ml of isopropanol, heating to reflux and dissolve, slowly dripping 20ml of water, cooling to 25 ℃ after dripping, crystallizing, filtering and drying to obtain 5.08g of off-white solid, namely the blonanserin impurity B (formula (I)) compound, wherein the yield is 78.89% and the purity is 99.74%.
Example 5.
Adding 5.0g of a compound shown as a formula (II), 1.5g of potassium iodide and 7.2g N-ethylpiperazine into a 100mL three-necked flask, introducing nitrogen, stirring, heating to 160-165 ℃, reacting for 24 hours under controlled temperature, detecting the reaction process by HPLC, stopping heating after the reaction is finished, cooling to (90 +/-5) ° C, adding 150mL of ethyl acetate, stirring, adding a saturated sodium chloride solution, washing for 3 times, using 30mL of sodium chloride solution each time, standing, separating, adding 5mol/L of hydrochloric acid solution into an organic phase to adjust the pH to 1, stirring for 30min, standing, separating, washing an aqueous layer for 2 times, using 50mL of ethyl acetate each time, standing, separating, adjusting the pH of an aqueous phase to 8-9 by using a saturated potassium carbonate solution, adding 150mL of ethyl acetate, stirring for 1 hour, standing, drying the organic phase for 1 hour by anhydrous magnesium sulfate, filtering, leaching a filter cake by 20mL of ethyl acetate, (40 +/-5) ° C, concentrating under reduced pressure to dryness, 4.08g of a white-like solid, i.e. the blonanserin impurity B (formula (I)) compound, was obtained in a yield of 63.36% and a purity of 99.48%.
Claims (10)
1. A preparation method of impurity B in blonanserin process is characterized by comprising the following steps:
1) reacting the compound of the formula (III) with a chlorinated reagent, namely phenyl phosphoryl dichloride at a higher temperature to obtain a compound of a formula (II);
2) condensing the compound of the formula (II) and N-ethylpiperazine to obtain a high-purity blonanserin process impurity B (formula (I)) compound;
2. the method according to claim 1, wherein step 1) is a solvent-free reaction.
3. The process according to claim 1, wherein the molar ratio of the compound of formula (III) in step 1) to the chlorinating reagent phenylphosphoryldichloride is 1 to 3, preferably 1 to 2.
4. The process according to claim 1, wherein the reaction of step 1) of the compound of formula (III) with the chlorinating reagent phenylphosphoryl dichloride is carried out at 160-170 ℃, preferably 160-165 ℃.
5. The preparation method according to claim 1, characterized in that in the step 1), after the reaction is finished, ethanol and water are sequentially added into the reaction solution at a lower temperature, the temperature is continuously reduced to be below 20 ℃, ammonia water is slowly added to adjust the pH value to 9-10, the temperature is controlled, stirring is carried out, crystallization is carried out, filtering, washing and drying are carried out, and a gray solid is obtained.
6. The preparation method according to claim 1, wherein the molar ratio of the compound of formula (II) in step 2) to N-ethylpiperazine is 1:2 to 5, preferably 1:3 to 4.
7. The molar ratio of the compound of formula (II) to potassium iodide is 1: 0.2-1, preferably 1: 0.2-0.5.
8. The process according to claim 1, wherein the reaction of step 2) of the compound of formula (II) with N-ethylpiperazine is carried out at a temperature of 150 to 170 ℃, preferably 160 to 165 ℃.
9. The preparation method according to claim 1, wherein in the step 2), after the reaction is completed, methyl tert-butyl ether and saturated brine are sequentially added into the reaction solution at a lower temperature, and the mixture is allowed to stand for layering; and adding a hydrochloric acid solution into the organic layer for extraction, layering, adding a potassium carbonate solution into the acid water layer under the condition of cooling to adjust the pH value to 9-10, adding methyl tert-butyl ether to dissolve the oily substance, fully stirring, layering, and concentrating the organic layer to be dry to obtain a gray solid.
10. Refining with isopropanol to obtain yellowish impurity B (formula (I)) of blonanserin.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021421A (en) * | 1989-03-03 | 1991-06-04 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
-
2020
- 2020-05-22 CN CN202010442954.3A patent/CN113698346A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021421A (en) * | 1989-03-03 | 1991-06-04 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
Non-Patent Citations (1)
| Title |
|---|
| K. SUDARSHAN RAO等: "An Investigation into Formation of Impurities During Synthesis of Blonanserin", 《ASIAN JOURNAL OF CHEMISTRY》 * |
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