CN115894434A - Preparation method of 4-piperazinyl benzothiophene hydrochloride - Google Patents
Preparation method of 4-piperazinyl benzothiophene hydrochloride Download PDFInfo
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- CN115894434A CN115894434A CN202211420141.XA CN202211420141A CN115894434A CN 115894434 A CN115894434 A CN 115894434A CN 202211420141 A CN202211420141 A CN 202211420141A CN 115894434 A CN115894434 A CN 115894434A
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- XDUUWPNOUUQXBX-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine;hydrochloride Chemical compound Cl.C1CNCCN1C1=CC=CC2=C1C=CS2 XDUUWPNOUUQXBX-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 31
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 229930192474 thiophene Natural products 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011630 iodine Substances 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 238000005576 amination reaction Methods 0.000 claims abstract description 5
- 238000005899 aromatization reaction Methods 0.000 claims abstract description 5
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 claims abstract description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 116
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 24
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 238000012544 monitoring process Methods 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- ADLMRIHGWPIQHH-UHFFFAOYSA-N 1-(1-benzothiophen-7-yl)piperazine hydrochloride Chemical compound C1CN(CCN1)C2=CC=CC3=C2SC=C3.Cl ADLMRIHGWPIQHH-UHFFFAOYSA-N 0.000 claims description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000007806 chemical reaction intermediate Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 239000002002 slurry Substances 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- 239000012265 solid product Substances 0.000 claims description 4
- 229940014800 succinic anhydride Drugs 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- -1 aromatic amine compound Chemical class 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- HEMZNEGKTOHOHW-UHFFFAOYSA-N n,2-dichloro-n-(2-chloroethyl)ethanamine Chemical compound ClCCN(Cl)CCCl HEMZNEGKTOHOHW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- 239000012071 phase Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 23
- 238000003786 synthesis reaction Methods 0.000 abstract description 23
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003245 coal Substances 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 238000006146 oximation reaction Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract 2
- ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical compound CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- IRMXPESEXLQKHG-UHFFFAOYSA-N 1-benzothiophen-4-amine Chemical compound NC1=CC=CC2=C1C=CS2 IRMXPESEXLQKHG-UHFFFAOYSA-N 0.000 description 4
- VYTXLSQVYGNWLV-UHFFFAOYSA-N 4-(2-thienyl)butyric acid Chemical compound OC(=O)CCCC1=CC=CS1 VYTXLSQVYGNWLV-UHFFFAOYSA-N 0.000 description 4
- ULJMYWHLMLRYSO-UHFFFAOYSA-N 4-oxo-4-(2-thienyl)butyric acid Chemical compound OC(=O)CCC(=O)C1=CC=CS1 ULJMYWHLMLRYSO-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 229960001210 brexpiprazole Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- YGYUMNQONHLLNC-UHFFFAOYSA-N 4-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1C=CS2 YGYUMNQONHLLNC-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000002894 chemical waste Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- QPBSEYFVZDMBFW-UHFFFAOYSA-N 4-bromo-1-benzothiophene Chemical compound BrC1=CC=CC2=C1C=CS2 QPBSEYFVZDMBFW-UHFFFAOYSA-N 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 206010001540 Akathisia Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229940011389 rexulti Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
A preparation method of 4-piperazinyl benzothiophene hydrochloride, belonging to the technical field of pharmaceutical and chemical drug synthesis. The method uses thiophene with low price and easy obtainment as a starting raw material to construct a compound (I) through Acrylation, huang Minlon reduction, cyclization, oximation, aromatization amination and nucleophilic substitution, wherein the aromatization amination reaction mainly adopts an iodine source with low price and easy obtainment as a catalyst to realize 4-aminobenzene [ b ] b]High-efficiency synthesis of thiophene, and effectively solves the problem of expensive compound 4-aminobenzo [ b]The problem of the random modeling production of thiophene. The method can prepare the 4-piperazinyl benzothiophene hydrochloride with high yield, high purity and easy operation, and has industrial application value. In addition, the invention can effectively solve the problem of thiophene waste generated in coal chemical industry, and changes waste into valuable.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical and chemical drug synthesis, and particularly relates to a synthesis method of an important intermediate 4-piperazinyl benzothiophene hydrochloride of brexpiprazole.
Background
Brexpiprazole is an anti-mental drug co-developed by danailing north and tsukamur medicine company in japan, and is mainly used as an auxiliary drug for treating patients with adult severe depression. Compared with aripiprazole, the affinity of the epiprazole with 5-HT receptor is increased, the activity of the epiprazole on D2 receptor is reduced, the tolerance performance is better, the incidence rate of side reaction of akathisia is lower, and the curative effect on the negative symptoms and cognitive function of schizophrenia tends to be better. The drug was approved by the U.S. FDA for marketing at 7 months 2015 under the trade name Rexulti, having the structure of formula (II) and the chemical name 7- [4- (4-benzo [ b ] thiophen-4-yl-piperazin-1-yl) butoxy ] -1H-quinolin-2-one.
Wherein 4-piperazinyl benzothiophene hydrochloride is one of key intermediates for preparing the epipiprazole, and the reported synthetic method comprises the following steps:
the tsukamur medicine of original research corporation in patent CN 101155804B discloses that 4-bromobenzo [ B ] thiophene is used as a starting material to prepare an intermediate shown in formula (i) through a coupling reaction with piperazine under the action of a palladium catalyst, and the synthetic route is as follows:
the method adopts noble metal palladium as a catalyst, increases the cost of the synthesis process and the complexity of post treatment, and is not easy for industrialized production. Meanwhile, the Buchwald-Hartwig coupling reaction is adopted, so that double coupling impurities are easily generated.
A preparation process similar to that of the original company is disclosed in patent WO 2013/015456, starting from 4-chlorobenzothiophene, which effectively reduces the palladium catalyst and the phosphine ligand. However, the method for obtaining 4-chlorobenzothiophene requires a complex synthetic method, decarboxylation reaction is required in the method under high temperature conditions, the conditions are not suitable for industrial production, and the synthetic process route is as follows:
patent CN 105461703B discloses 4-aminobenzene [ B ] thiophene as a starting material to react with bis (2-chloroethyl) amine hydrochloride to prepare a compound of formula (I), and the synthetic route is as follows.
The method effectively avoids the use of a heavy metal palladium catalyst, but the starting material 4-aminobenzene [ b ] thiophene adopted by the route has higher production cost and is not produced on a large scale in the market, so that the industrial application of the route is limited.
Based on the problems of the preparation method of the formula (I) reported in the patent, the invention designs and develops a synthetic route with high yield by using thiophene as a starting material, and the method has important significance for the industrial production of the ipiprazole medicine.
Disclosure of Invention
The invention designs and develops a new synthesis process for preparing the intermediate compound shown in the formula (I), overcomes the problems of the existing synthesis process route, and provides a new synthesis strategy for the synthesis process of the drug intermediate of the brexpiprazole.
The main technical scheme of the invention is as follows: a preparation method of 4-piperazinyl benzothiophene hydrochloride is characterized by comprising the following steps: a synthetic route to 4-piperazinyl benzothiophene hydrochloride, a compound of formula (I):
the method comprises the following specific steps:
(1) Preparing a compound (B) by a clarke acylation reaction of thiophene (A) and succinic anhydride under the catalysis of Lewis acid;
(2) Reducing carbonyl into methylene by the compound (B) and hydrazine hydrate through Huang Minlon reduction under alkaline condition to form a compound (C);
(3) The compound (C) is combined to form a six-membered cyclohexanone ring under the action of trifluoroacetic anhydride and trifluoroacetic acid to construct a compound (D);
(4) The compound (D) and hydroxylamine hydrochloride are reacted with sodium acetate to construct a compound (E);
(5) The compound (E) is subjected to aromatization amination under the catalysis of an iodine source reagent to construct a compound (F);
(6) Finally, compound (F) is reacted with bis (chloroethyl) amino hydrochloride via nucleophilic substitution to form compound (I).
In the step (1), lewis acid is used as a catalyst, and the Lewis acid is selected from AlCl 3 、SnCl 4 、FeCl 3 、AlBr 3 And SbCl 5 Wherein AlCl is preferred 3 And the equivalence ratio is 1 to 2equiv, preferably 1.6equiv; the solvent used in the reaction is one of dichloromethane, tetrahydrofuran and acetonitrile; the reaction temperature is room temperature; after the reaction is completed, dropwise adding an aqueous hydrochloric acid solution into the reaction system, stirring for a period of time after the dropwise adding is completed, separating liquid after stirring, collecting an organic phase, extracting the aqueous phase once by using dichloromethane, combining the organic phases, concentrating the organic phase, adding petroleum ether, stirring, carrying out suction filtration on the obtained slurry after stirring, collecting a filter cake, and drying to obtain a light yellow solid.
Reacting with hydrazine hydrate in the step (2) under an alkaline condition, wherein the hydrazine hydrate is hydrazine hydrate solution with the content of 80%, and the alkali is one or more selected from potassium hydroxide, sodium hydroxide and lithium hydroxide, wherein potassium hydroxide is preferred; the solvent used in the reaction is one of diethylene glycol and triethylene glycol, and the reaction temperature is 160-190 ℃. The method specifically comprises the following steps: weighing a compound (B), dissolving the compound (B) in a solvent, stirring at room temperature until the compound (B) is completely dissolved, then respectively adding alkali and hydrazine hydrate into a reaction system, heating to 165 ℃ for reaction, monitoring the reaction process by HPLC, connecting a water separator for continuous reaction after the raw materials are completely consumed, removing excessive hydrazine hydrate and water generated by the reaction, then heating the temperature to 190 ℃ for reaction, monitoring the reaction by HPLC, and cooling the system to room temperature after all reaction intermediates are converted into products; after cooling, the reaction mixture was dispersed in water, made acidic with hydrochloric acid, extracted 2 times with ethyl acetate, the organic phases were combined and the solvent was removed under reduced pressure to give a yellow oily liquid.
Reacting under the action of trifluoroacetic acid and trifluoroacetic anhydride in the step (3), wherein the trifluoroacetic acid is used as a catalyst and a reaction solvent, the equivalent of the trifluoroacetic anhydride is 1.5-2.5 equiv, and the reaction temperature is 25 ℃. The method specifically comprises the following steps: weighing a compound (C) and dissolving the compound in trifluoroacetic acid, adding trifluoroacetic anhydride, reacting at room temperature, monitoring the reaction by HPLC (high performance liquid chromatography), slowly dropwise adding a reaction system into a sodium hydroxide solution when the raw materials are completely consumed, stirring while dropwise adding, extracting the system twice by using ethyl acetate after dropwise adding is finished, collecting an organic phase, and removing the solvent under reduced pressure to obtain a brown solid.
Reacting with hydroxylamine hydrochloride in the step (4), wherein the equivalent ratio of the hydroxylamine hydrochloride is 1.5-2.3 equiv, preferably 2equiv; the reaction solvent is selected from one mixed solvent of methanol-water, isopropanol-water, acetonitrile-water and ethanol-water, wherein ethanol-water is preferably used as the reaction solvent, and the proportion of the ethanol-water mixed solvent is 1:1 to 8:1; the pulping and purifying solvent ethanol and water must be 1:6. the method specifically comprises the following steps: adding a reaction solvent into a reaction bottle, sequentially adding a compound (D), sodium acetate (the mol number is 2equiv of the compound D) and hydroxylamine hydrochloride (the mol number is 1.5equiv of the compound D), heating to reflux reaction, carrying out HPLC detection reaction, after the reaction is completed, carrying out reduced pressure distillation to remove the organic solvent in the reaction system, then adding a mixed solution of water and ethanol, pulping, purifying, after stirring, filtering and drying to obtain a white solid product (E).
In the step (5), an arylamine compound is formed under the action of an iodine catalyst, wherein the catalyst is selected from elementary iodine, N-iodosuccinimide, sodium iodide and potassium iodide; the solvent used in the reaction is ethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile and 1, 4-dioxane, preferably ethylene glycol dimethyl ether; the reaction temperature is 75-90 ℃, and specifically comprises the following steps: adding a solvent, a compound (E) and an iodine source catalyst into a reaction bottle in sequence, heating to a reaction temperature for reaction, detecting the reaction by HPLC, cooling to room temperature after the reaction is completed, adding a sodium thiosulfate solution, stirring for reaction for a period of time, extracting the reaction system by using ethyl acetate, combining organic phases, distilling under reduced pressure to remove the solvent, and purifying to obtain a compound (F).
In the step (6), 4-piperazinyl benzothiophene hydrochloride is prepared by reacting under the condition that alkali is used as a deacidification agent, wherein the alkali is inorganic alkali or organic alkali, the inorganic alkali is selected from one or more of potassium carbonate, sodium bicarbonate and potassium bicarbonate, the organic alkali is selected from triethylamine, diisopropylamine, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine, and a reaction solvent is N-butanol and isopropanol; the method comprises the following specific steps: and (3) sequentially adding the compound (F), bis (2-chloroethyl) amine hydrochloride and alkali into a reaction bottle to dissolve in a solvent, heating to reflux reaction, cooling to room temperature after complete reaction, separating out a white solid, filtering and drying to obtain the product 1- (benzo [ b ] thiophene-7-yl) piperazine hydrochloride.
The novel synthesis method of the compound shown in the formula (I) firstly uses low-cost coal chemical waste thiophene as a starting raw material, and an important intermediate 4-piperazinyl benzothiophene hydrochloride of an epipiprazole medicine is constructed through Friedel-crafts acylation, huang Minlon reduction, cyclization, oximation, aromatization amination and nucleophilic substitution cyclization reactions. Compared with the existing method for preparing the formula (I) by taking the 4-aminobenzothiophene as the starting material, the method can be used for preparing the 4-aminobenzothiophene on a large scale by taking the low-cost coal chemical waste thiophene as the starting material, effectively solves the problem of large-scale synthesis of the 4-aminobenzothiophene compound, and can be applied to the industrial production of the ipiprazole medicine.
The synthesis process route designed by the invention has the advantages of easily available raw materials, simple operation, high yield, low total cost and the like, overcomes the defects of the use of a metal palladium catalyst and the generation of related impurities in the existing synthesis process route, and provides a new research route for the industrial production of the ipiprazole medicine.
Drawings
FIG. 1 is an HPLC chromatogram of a compound of formula (I)
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Synthesis of Compound (B)
Methylene chloride (450 g) was added to a reaction flask, succinic anhydride (53 g) was added thereto, and the mixture was stirred at room temperature until it was completely dissolved, and then aluminum trichloride was weighed and added to the reaction system in portions. A solution of thiophene (45 g) in methylene chloride was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 9 hours. After the reaction is completed, 6mol/L hydrochloric acid aqueous solution is dropwise added into the reaction system, and after the dropwise addition is completed, the mixture is stirred for 2 hours. After stirring, liquid separation was carried out, and the organic phase was collected. The aqueous phase was extracted once with dichloromethane (300 mL) and the organic phases were combined. Concentrating the organic phase, adding petroleum ether, stirring for 10min, performing suction filtration on the obtained slurry after stirring, collecting a filter cake, and drying to obtain light yellow solid 4-oxo-4- (thiophene-2-yl) butyric acid, wherein the yield is as follows: 96 percent.
Synthesis of Compound (C)
Weighing 4-oxo-4- (thiophene-2-yl) butyric acid (61 g) and dissolving in diethylene glycol (671 g), stirring at room temperature until the materials are completely dissolved, respectively adding potassium hydroxide (65 g) and 80% hydrazine hydrate (48 g) into a reaction system, reacting at 165 ℃ for 3h, monitoring the reaction process by HPLC (high performance liquid chromatography), connecting a water separator to continue reacting for 0.5h after the raw materials are completely consumed, and removing excessive hydrazine hydrate and water generated by the reaction. After 0.5h, the temperature is increased to 190 ℃ for reaction for 5h, the reaction is monitored by HPLC, and after all reaction intermediates are converted into products, the system is cooled to room temperature. After cooling, the reaction mixture was dispersed in water and adjusted to pH =1 with 4mol/L hydrochloric acid. Extraction was performed 2 times with ethyl acetate (300 mL), the organic phases were combined, and the solvent was removed under reduced pressure to give a yellow oily liquid, yield: 90 percent.
Synthesis of Compound (D)
The compound 4- (thien-2-yl) butyric acid (48 g) was weighed out and dissolved in trifluoroacetic acid (357 g), and trifluoroacetic anhydride (118 g) was added to the system and reacted at room temperature for 3 hours. Monitoring the reaction by HPLC, and slowly dropwise adding the reaction system into 3mol/L sodium hydroxide solution (1L) while stirring when the raw material 4- (thiophene-2-yl) butyric acid is completely consumed. After the end of the dropwise addition, the system was extracted twice with ethyl acetate (260 kg), the organic phases were collected and the solvent was removed under reduced pressure to give a brown solid, yield: 95 percent.
Synthesis of Compound (E)
Adding ethanol (400 mL and water (200 mL), sequentially adding 6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketone (40 g), sodium acetate (43 g) and hydroxylamine hydrochloride (36 g), heating to reflux reaction for 3H, detecting by HPLC, after the reaction is completed, removing an ethanol solvent in a reaction system by reduced pressure distillation, adding a mixed solution of water and ethanol, stirring for 30min, filtering and drying after the stirring is finished to obtain a white solid product (E) -6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketoxime, wherein the yield is 97%.
Synthesis of Compound (F)
Ethylene glycol dimethyl ether (400 mL), 6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketoxime (44 g) and iodine (100 g) are sequentially added into a reaction bottle, the temperature is raised to 90 ℃ for reaction, and the reaction is detected by HPLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and a sodium thiosulfate solution (280 mL) was added thereto to stir the reaction mixture for 30min. Extracting the reaction system by using ethyl acetate (220X 2), combining organic phases, distilling under reduced pressure to remove the solvent, and purifying to obtain a product with the yield: 88 percent.
Synthesis of Compound (I)
4-aminobenzothiophene (32 g), bis (2-chloroethyl) amine hydrochloride (38 g) and potassium carbonate (58 g) are added into a reaction bottle in sequence and dissolved in n-butanol (200 mL), and the temperature is increased to reflux reaction for 5h. After the reaction is completed, cooling to room temperature, separating out white solid, filtering and drying to obtain the product 1- (benzo [ b ] thiophene-7-yl) piperazine hydrochloride, wherein the yield is as follows: 89 percent.
Example 2
Synthesis of Compound (B)
Methylene chloride (450 g) was added to a reaction flask, succinic anhydride (53 g) was added thereto, and the mixture was stirred at room temperature until it was completely dissolved, and then aluminum trichloride was weighed and added to the reaction system in portions. A solution of thiophene (45 g) in methylene chloride was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 9 hours. After the reaction is completed, 6mol/L hydrochloric acid aqueous solution is dropwise added into the reaction system, and after the dropwise addition is completed, stirring is carried out for 2 hours. After stirring, liquid separation was carried out, and the organic phase was collected. The aqueous phase was extracted once with dichloromethane (300 mL) and the organic phases were combined. Concentrating the organic phase, adding petroleum ether, stirring for 10min, performing suction filtration on the obtained slurry after stirring, collecting a filter cake, and drying to obtain light yellow solid 4-oxo-4- (thiophene-2-yl) butyric acid, wherein the yield is as follows: 98 percent.
Synthesis of Compound (C)
Weighing 4-oxo-4- (thiophene-2-yl) butyric acid (61 g) and dissolving in diethylene glycol (671 g), stirring at room temperature until the materials are completely dissolved, respectively adding potassium hydroxide (65 g) and 80% hydrazine hydrate (48 g) into a reaction system, reacting at 165 ℃ for 3h, monitoring the reaction process by HPLC (high performance liquid chromatography), connecting a water separator to continue reacting for 0.5h after the raw materials are completely consumed, and removing excessive hydrazine hydrate and water generated by the reaction. After 0.5h, the temperature is increased to 190 ℃ for reaction for 5h, the reaction is monitored by HPLC, and after all reaction intermediates are converted into products, the system is cooled to room temperature. After cooling, the reaction mixture was dispersed in water and adjusted to pH =1 with 4mol/L hydrochloric acid. Extraction was performed 2 times with ethyl acetate (300 mL), the organic phases were combined, and the solvent was removed under reduced pressure to give a yellow oily liquid, yield: 92 percent.
Synthesis of Compound (D)
The compound 4- (thien-2-yl) butyric acid (48 g) was weighed out and dissolved in trifluoroacetic acid (357 g), and trifluoroacetic anhydride (118 g) was added to the system and reacted at room temperature for 3 hours. Monitoring the reaction by HPLC, and slowly dropwise adding the reaction system into 3mol/L sodium hydroxide solution (1L) while stirring when the raw material 4- (thiophene-2-yl) butyric acid is completely consumed. After the end of the dropwise addition, the system was extracted twice with ethyl acetate (260 kg), the organic phases were collected and the solvent was removed under reduced pressure to give a brown solid, yield: 93 percent.
Synthesis of Compound (E)
Adding ethanol (400 mL and water (200 mL), sequentially adding 6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketone (40 g), sodium acetate (43 g) and hydroxylamine hydrochloride (36 g), heating to reflux reaction for 3H, detecting by HPLC, after the reaction is completed, removing an ethanol solvent in a reaction system by reduced pressure distillation, adding a mixed solution of water and ethanol, stirring for 30min, filtering and drying after the stirring is finished to obtain a white solid product (E) -6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketoxime, wherein the yield is 95%.
Synthesis of Compound (F)
Ethylene glycol dimethyl ether (400 mL), 6, 7-dihydrobenzo [ b ] thiophene-4 (5H) -ketoxime (44 g) and sodium iodide (65 g) were added in this order to a reaction flask, and the reaction was carried out at a temperature of 90 ℃ and then detected by HPLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and a sodium thiosulfate solution (280 mL) was added thereto to stir the reaction mixture for 30min. Extracting the reaction system by using ethyl acetate (220 multiplied by 2), combining organic phases, distilling under reduced pressure to remove the solvent, and purifying to obtain the product with the yield: 89 percent.
Synthesis of Compound (I)
4-aminobenzothiophene (32 g), bis (2-chloroethyl) amine hydrochloride (38 g) and potassium carbonate (58 g) are added into a reaction bottle in sequence and dissolved in n-butanol (200 mL), and the temperature is increased to reflux reaction for 5h. After the reaction is completed, cooling to room temperature, separating out white solid, filtering and drying to obtain the product 1- (benzo [ b ] thiophene-7-yl) piperazine hydrochloride, wherein the yield is as follows: 89 percent.
Claims (7)
1. A preparation method of 4-piperazinyl benzothiophene hydrochloride is characterized by comprising the following steps: a synthetic route to 4-piperazinyl benzothiophene hydrochloride, a compound of formula (I):
the method comprises the following specific steps:
(1) Preparing a compound (B) by a clarke acylation reaction of thiophene (A) and succinic anhydride under the catalysis of Lewis acid;
(2) Reducing carbonyl into methylene by the compound (B) and hydrazine hydrate through Huang Minlon reduction under alkaline condition to form a compound (C);
(3) The compound (C) is combined to form a six-membered cyclohexanone ring under the action of trifluoroacetic anhydride and trifluoroacetic acid to construct a compound (D);
(4) The compound (D) and hydroxylamine hydrochloride are reacted with sodium acetate to construct a compound (E);
(5) The compound (E) is subjected to aromatization amination under the catalysis of an iodine source reagent to construct a compound (F);
(6) Finally, compound (F) is reacted with bis (chloroethyl) amino hydrochloride via nucleophilic substitution to form compound (I).
2. The process according to claim 1, wherein a Lewis acid selected from AlCl is used as a catalyst in step (1) 3 、SnCl 4 、FeCl 3 、AlBr 3 And SbCl 5 Wherein AlCl is preferred 3 And the equivalence ratio is 1-2 equiv, preferably 1.6equiv; the solvent used in the reaction is one of dichloromethane, tetrahydrofuran and acetonitrile; the reaction temperature is room temperature; after the reaction is completed, dropwise adding hydrochloric acid aqueous solution into the reaction system, stirring for a period of time after dropwise adding, separating liquid after stirring, and collectingAnd (3) collecting organic phases, extracting the water phase once by using dichloromethane, combining the organic phases, concentrating the organic phases, adding petroleum ether, stirring, carrying out suction filtration on the obtained slurry after stirring, collecting a filter cake, and drying to obtain a light yellow solid.
3. The method according to claim 1, wherein the reaction with hydrazine hydrate in step (2) is carried out under alkaline conditions, the hydrazine hydrate is a hydrazine hydrate solution with the content of 80%, and the alkali is one or more selected from potassium hydroxide, sodium hydroxide and lithium hydroxide, wherein potassium hydroxide is preferred; the solvent used in the reaction is one of diethylene glycol and triethylene glycol, and the reaction temperature is 160-190 ℃; the method specifically comprises the following steps: weighing a compound (B), dissolving the compound (B) in a solvent, stirring at room temperature until the compound (B) is completely dissolved, then respectively adding alkali and hydrazine hydrate into a reaction system, heating to 165 ℃ for reaction, monitoring the reaction process by HPLC, connecting a water separator for continuous reaction after the raw materials are completely consumed, removing excessive hydrazine hydrate and water generated by the reaction, then heating the temperature to 190 ℃ for reaction, monitoring the reaction by HPLC, and cooling the system to room temperature after all reaction intermediates are converted into products; after cooling, the reaction mixture was dispersed in water, made acidic with hydrochloric acid, extracted with ethyl acetate, the organic phases were combined and the solvent was removed under reduced pressure to give a yellow oily liquid.
4. The process according to claim 1, wherein in the step (3), trifluoroacetic acid and trifluoroacetic anhydride are reacted with each other, trifluoroacetic anhydride is used as a catalyst and a reaction solvent, the equivalent of trifluoroacetic anhydride is 1.5 to 2.5equiv, and the reaction temperature is 25 ℃; the method specifically comprises the following steps: weighing a compound (C), dissolving the compound in trifluoroacetic acid, adding trifluoroacetic anhydride, reacting at room temperature, monitoring the reaction by HPLC, slowly dropwise adding a reaction system into a sodium hydroxide solution when the raw materials are completely consumed, stirring while dropwise adding, extracting the system with ethyl acetate after dropwise adding is finished, collecting an organic phase, and removing the solvent under reduced pressure to obtain a brown solid.
5. The method according to claim 1, wherein the reaction with hydroxylamine hydrochloride in the step (4) is carried out at an equivalent ratio of hydroxylamine hydrochloride of 1.5 to 2.3equiv, preferably 2equiv; the reaction solvent is selected from one mixed solvent of methanol-water, isopropanol-water, acetonitrile-water and ethanol-water, wherein ethanol-water is preferably used as the reaction solvent, and the proportion of the ethanol-water mixed solvent is 1:1 to 8:1; the pulping purification solvent ethanol and water must be 1:6; the method specifically comprises the following steps: adding a reaction solvent into a reaction bottle, sequentially adding a compound (D), sodium acetate (2 equiv) and hydroxylamine hydrochloride (1.5 equiv), heating to reflux reaction, detecting reaction by HPLC, after the reaction is completed, removing the organic solvent in the reaction system by reduced pressure distillation, adding a mixed solution of water and ethanol, pulping, purifying, after stirring, filtering and drying to obtain a white solid product (E).
6. The method according to claim 1, wherein the aromatic amine compound is formed in step (5) under the action of an iodine-based catalyst selected from the group consisting of elemental iodine, N-iodosuccinimide, sodium iodide, potassium iodide; the solvent used in the reaction is ethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile and 1, 4-dioxane, preferably ethylene glycol dimethyl ether; the reaction temperature is 75-90 ℃, and specifically comprises the following steps: adding a solvent, a compound (E) and an iodine source catalyst into a reaction bottle in sequence, heating to a reaction temperature for reaction, detecting the reaction by HPLC, cooling to room temperature after the reaction is completed, adding a sodium thiosulfate solution, stirring for reaction for a period of time, extracting the reaction system by using ethyl acetate, combining organic phases, distilling under reduced pressure to remove the solvent, and purifying to obtain a compound (F).
7. The method according to claim 1, wherein the 4-piperazinyl benzothiophene hydrochloride is prepared in the step (6) by reacting under the condition of taking a base as a deacidification agent, wherein the base is an inorganic base or an organic base, the inorganic base is one or more selected from potassium carbonate, sodium bicarbonate and potassium bicarbonate, the organic base is triethylamine, diisopropylamine, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine, and the reaction solvent is N-butanol and isopropanol; the method specifically comprises the following steps: and (3) sequentially adding the compound (F), bis (2-chloroethyl) amine hydrochloride and alkali into a reaction bottle to dissolve in a solvent, heating to reflux reaction, cooling to room temperature after complete reaction, separating out a white solid, filtering and drying to obtain the product 1- (benzo [ b ] thiophene-7-yl) piperazine hydrochloride.
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