CN114181172A - Efficient preparation method of quetiapine fumarate - Google Patents
Efficient preparation method of quetiapine fumarate Download PDFInfo
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- CN114181172A CN114181172A CN202111608959.XA CN202111608959A CN114181172A CN 114181172 A CN114181172 A CN 114181172A CN 202111608959 A CN202111608959 A CN 202111608959A CN 114181172 A CN114181172 A CN 114181172A
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- Prior art keywords
- stirring
- quetiapine
- quetiapine fumarate
- preserving heat
- copper
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- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 title claims abstract description 60
- 229960005197 quetiapine fumarate Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 52
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960004431 quetiapine Drugs 0.000 claims abstract description 49
- 239000001530 fumaric acid Substances 0.000 claims abstract description 26
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 26
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000002576 ketones Chemical class 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 14
- 239000005749 Copper compound Substances 0.000 claims abstract description 12
- 150000001880 copper compounds Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 and after separation Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229910052802 copper Inorganic materials 0.000 claims abstract description 7
- 239000010949 copper Substances 0.000 claims abstract description 7
- 239000012458 free base Substances 0.000 claims abstract description 7
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 52
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 28
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 claims description 20
- 230000001590 oxidative effect Effects 0.000 claims description 10
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 6
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 4
- RTERDTBXBYNZIS-UHFFFAOYSA-N 5h-benzo[b][1,4]benzothiazepin-6-one Chemical compound O=C1NC2=CC=CC=C2SC2=CC=CC=C12 RTERDTBXBYNZIS-UHFFFAOYSA-N 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- QAMFBRUWYYMMGJ-UHFFFAOYSA-N hexafluoroacetylacetone Chemical compound FC(F)(F)C(=O)CC(=O)C(F)(F)F QAMFBRUWYYMMGJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 129
- 238000006243 chemical reaction Methods 0.000 description 119
- 238000003756 stirring Methods 0.000 description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000001816 cooling Methods 0.000 description 42
- 238000010438 heat treatment Methods 0.000 description 42
- 238000000605 extraction Methods 0.000 description 40
- 239000003513 alkali Substances 0.000 description 38
- 101000738734 Drosophila melanogaster Tyrosine-protein phosphatase 69D Proteins 0.000 description 24
- 238000001035 drying Methods 0.000 description 22
- 239000003651 drinking water Substances 0.000 description 21
- 235000020188 drinking water Nutrition 0.000 description 21
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 238000005660 chlorination reaction Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 230000001376 precipitating effect Effects 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 9
- 238000004321 preservation Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZFOZNNFYECYUQB-UHFFFAOYSA-N 6-chlorobenzo[b][1,4]benzothiazepine Chemical compound ClC1=NC2=CC=CC=C2SC2=CC=CC=C12 ZFOZNNFYECYUQB-UHFFFAOYSA-N 0.000 description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- PFCBGPOWBVNNMA-UHFFFAOYSA-N 2-(1-piperazin-1-ylethoxy)ethanol Chemical compound OCCOC(C)N1CCNCC1 PFCBGPOWBVNNMA-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HUTXVUPGARJNHM-UHFFFAOYSA-N 1-(2-chloroethoxy)ethanol Chemical compound CC(O)OCCCl HUTXVUPGARJNHM-UHFFFAOYSA-N 0.000 description 1
- OFLMIXVKBNAUIB-UHFFFAOYSA-N 2-(4-benzo[b][1,4]benzothiazepin-6-ylpiperazin-1-yl)ethanol Chemical compound C1CN(CCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 OFLMIXVKBNAUIB-UHFFFAOYSA-N 0.000 description 1
- KFGFVPMRLOQXNB-UHFFFAOYSA-N 3,5,5-trimethylhexanoyl 3,5,5-trimethylhexaneperoxoate Chemical compound CC(C)(C)CC(C)CC(=O)OOC(=O)CC(C)CC(C)(C)C KFGFVPMRLOQXNB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLOAJISUHPIQOX-UHFFFAOYSA-N Norquetiapine Chemical compound C1CNCCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 JLOAJISUHPIQOX-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to an efficient preparation method of quetiapine fumarate. A high-efficiency preparation method of quetiapine fumarate comprises the following steps: dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxyethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst at 80-120 ℃ for 6-16H to directly condense to obtain quetiapine free base, and after separation, fumaric acid is added to form salt to obtain quetiapine fumarate; the copper catalyst comprises a copper compound and an oxidizing agent.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an efficient preparation method of quetiapine fumarate.
Background
Quetiapine fumarate is a new generation of atypical antipsychotic drug, first marketed in the uk by Zeneca corporation in 1997 in 11 months, and is used clinically as the first line drug for schizophrenia. The chemical name of the quetiapine fumarate is 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1,4] thiazepine hemifumarate, the quetiapine fumarate is prepared by salifying quetiapine and fumaric acid, and the chemical structural formula is as follows:
the literature reports that a plurality of synthetic routes can be used for preparing the quetiapine fumarate:
1. european patent EP282236 reports that dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone is chlorinated with phosphorus oxychloride and then condensed with piperazine to obtain an intermediate 11-piperazinyl-dibenzo [ b, f ] [1,4] thiazepine, which is finally condensed with 2-chloroethoxyethanol and salified with fumaric acid to obtain quetiapine fumarate. The chlorination reaction in the route is a typical dangerous reaction, and a large amount of phosphorus oxychloride (the using amount is 148 molar times of dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone) is used, so that a large amount of phosphorus-containing wastewater is generated, and great pressure is caused for environmental treatment; in addition, the yield is low due to the long procedure.
2. The European patent EP240228 also reports that the route is dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone chlorinated with phosphorus oxychloride to obtain an intermediate product 11-chloro-dibenzo [ b, f ] [1,4] thiazepine, and different from the EP282236 route, the intermediate product 11-chloro-dibenzo [ b, f ] [1,4] thiazepine of the chlorination reaction is directly condensed with side chain 1- (2-hydroxyethoxy) ethylpiperazine to obtain quetiapine, steps are reduced to a certain extent, but the whole route is still longer; the route also requires chlorination and uses a large amount of phosphorus oxychloride; the method uses low boiling point solvents such as diethyl ether and dichloromethane which are extremely flammable and explosive, and has great potential safety hazard in production.
3. The route reported in patent W02005014590 is dibenzo [ b, f ] [1,4] thiazepin-11- (10H) ketone chlorinated to give the intermediate 11-chloro-dibenzo [ b, f ] [1,4] thiazepin. Condensing the intermediate with 1- (2-hydroxy) ethylpiperazine to obtain 11- [4- (2-hydroxyethyl) -1-piperazinyl ] dibenzo [ b, f ] [1,4] thiazepine, condensing with a chlorohydrin compound protected by hydroxy, and removing a protecting group under an acidic condition to obtain quetiapine, wherein the protecting group is removed in the route, so that the steps of the route are longer, and the total yield is reduced; the traditional chlorination reagent is still adopted in the route, and dangerous chlorination reaction is carried out; the mixed solvent of toluene and methanol, butanone and methanol, etc. is used in the route for many times, which increases the manufacturing cost and the environmental management cost.
4, the route reported in patent CN101619047 is dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone chlorinated by triphosgene to obtain intermediate 11-chloro-dibenzo [ b, f ] [1,4] thiazepine, and the intermediate is directly condensed with side chain 1- (2-hydroxyethoxy) ethylpiperazine to obtain quetiapine, which is shorter in route and higher in yield than the above patents EP282236, EP240228, and W02005014590, and triphosgene is used as chloride for chlorination reaction, so that no pollution is caused to the environment during post-treatment. But the route still carries out chlorination reaction, and the danger of the chlorination process cannot be relieved; triphosgene is used in the route, and the compound can generate phosgene after being heated, so that the compound is a highly toxic product and has potential personal safety hazards.
In the existing industrial synthesis process of quetiapine fumarate, at least two steps of chlorination and condensation are needed for synthesizing quetiapine fumarate from dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone, the chlorination reaction is high in risk, and certain pressure is caused to the environment after post-treatment. Based on the defects of the prior art scheme, the invention hopes to provide an efficient preparation method of quetiapine fumarate.
Disclosure of Invention
The invention aims to provide a method for efficiently preparing quetiapine fumarate, so as to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a high-efficiency preparation method of quetiapine fumarate comprises the following steps: dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxyethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst at 80-120 ℃ for 6-16H to directly condense to obtain quetiapine free base, and after separation, fumaric acid is added to form salt to obtain quetiapine fumarate; the copper catalyst comprises a copper compound and an oxidant;
preferably, the copper compound is one or more of copper acetylacetonate, copper (II) bis (hexafluoroacetylacetonate), copper acetate, copper chloride, ketone iodide, cuprous chloride and cuprous iodide.
Preferably, the copper compound is copper acetylacetonate or copper acetate.
Preferably, the oxidant is one or two of di-tert-butyl peroxide and tert-butyl hydroperoxide.
Preferably, the oxidizing agent is di-tert-butyl peroxide.
Preferably, the solvent is N, N-dimethylformamide or N, N-diethylformamide.
Preferably, the molar ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone, the copper compound and the oxidant is 1: 0.05: 2-6.
Preferably, the molar ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone, the copper compound and the oxidant is 1: 0.05: 4.
preferably, the weight ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] one to the N, N-dimethylformamide is 1: 6-10.
Preferably, the weight ratio of dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] one to N, N-dimethylformamide is 1: 8.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides an efficient preparation method of quetiapine fumarate, which is characterized in that DPTP and hepe are subjected to one-step condensation reaction by using a copper catalyst to obtain quetiapine fumarate, so that reaction steps are reduced, and the synthesis efficiency of quetiapine fumarate is greatly improved;
(2) the invention provides an efficient preparation method of quetiapine fumarate, which avoids chlorination reaction in the traditional synthesis process, does not need chlorides such as phosphorus oxychloride, thionyl chloride, triphosgene, oxalyl chloride and the like, greatly reduces process risk and eliminates environmental pollution caused by post-treatment of chlorination reaction.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding 1g of copper acetylacetonate and 160g (170ml) of N, N-Dimethylformamide (DMF) into a reaction bottle, starting stirring, slowly dropwise adding 51.5g of di-tert-butyl peroxide (DTBP), stirring for 30min at room temperature after dropwise adding, sequentially adding 20g of dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone (DPTP) and 16g of 1- [2 (2-hydroxyethoxy) ethyl ] piperazine (heep) into the reaction bottle, heating to 80-90 ℃, carrying out heat preservation reaction for 10H, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting layers after extraction, concentrating and drying the upper layer toluene layer solution to obtain quetiapine free base, adding 110g (140ml) of 95% ethanol into the quetiapine free base, heating and stirring to be clear, adding 5g of fumaric acid into a reaction bottle, keeping the temperature and stirring for 1h, keeping the temperature, cooling to 0-5 ℃, keeping the temperature and crystallizing for 1h, keeping the temperature, performing suction filtration and drying to obtain 24.3g of quetiapine fumarate.
Example 2
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 90-100 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 30.8g of quetiapine fumarate.
Example 3
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 35.4g of quetiapine fumarate.
Example 4
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 110-120 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 35.5g of quetiapine fumarate.
Example 5
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 6h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 27.9g of quetiapine fumarate.
Example 6
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reacting for 8h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free base, adding 110g (140ml) of 95% ethanol into the quetiapine free base, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 32.1g of quetiapine fumarate.
Example 7
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 12h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain quetiapine fumarate 35.9.
Example 8
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 14h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain quetiapine fumarate 35.7.
Example 9
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 16h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain quetiapine fumarate 35.5.
Example 10
Adding 1g of copper acetylacetonate and 160g (170ml) of N, N-Dimethylacetamide (DEF) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃ after reaction is finished, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, separating layers after extraction is finished, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, carrying out suction filtration after heat preservation, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, preserving heat and obtaining 34.8g of quetiapine fumarate.
Example 11
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of tert-butyl hydroperoxide (TBHP), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, carrying out heat preservation reaction for 10h, cooling to 20-30 ℃ after the reaction is finished, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene, extracting, layering after extraction is finished, concentrating and drying an upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to be clear, adding 5g of fumaric acid into the reaction bottle, carrying out heat preservation stirring for 1h, carrying out heat preservation and suction filtration, cooling to 0-5 ℃, carrying out heat preservation crystallization for 1h, and carrying out heat preservation to obtain 28g of quetiapine fumarate.
Example 12
Adding 1g of cuprous chloride and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-bis-tert-butyl-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, and carrying out suction filtration to obtain 23.7g of quetiapine fumarate.
Example 13
Adding 1g of cuprous iodide and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-bis-tert-butyl-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, and carrying out suction filtration to obtain 26.9g of quetiapine fumarate.
Example 14
Adding 1g of copper chloride and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-dimethyl-terephthalate), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, and carrying out suction filtration to obtain 31.6g of quetiapine fumarate.
Example 15
Adding 1g of copper iodide and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-bis-tert-butyl-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, and carrying out suction filtration to obtain 32.2g of quetiapine fumarate.
Example 16
Adding 1g of copper acetate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-bis-tert-butyl-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting, layering after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, and carrying out suction filtration to obtain 34g of quetiapine fumarate.
Example 17
Adding 1g of bis (hexafluoroacetylacetone) copper (II) and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl sulfoxide), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃ after reaction is finished, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting a separated layer after extraction, concentrating and drying an upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, carrying out suction filtration after heat preservation, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, preserving heat, obtaining 31.4g of quetiapine fumarate.
Example 18
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 25.8g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 31g of quetiapine fumarate.
Example 19
Adding 1g of copper acetylacetonate and 160g (170ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 77.3g of DTBP (dimethyl disulfide-bis-tert-butyl-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 35.6g of quetiapine fumarate.
Example 20
Adding 1g of copper acetylacetonate and 120g (128ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping is finished, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain quetiapine fumarate 35.4.
Example 21
Adding 1g of copper acetylacetonate and 200g (213ml) of DMF (dimethyl formamide) into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP (dimethyl disulfide-N), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16g of heep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃, adding 80g (80ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115ml) of toluene for extraction, extracting the separated layer after extraction, concentrating and drying the upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to clear, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, preserving heat, cooling to 0-5 ℃, preserving heat and precipitating crystals for 1h, and preserving heat to obtain 35.7g of quetiapine fumarate.
Data summarization:
table 1: data summary of the Quetiapine fumarate Synthesis in examples 1-4
As can be seen from Table 1: under the condition of certain other conditions, the influence of different reaction temperatures on the reaction is verified, the reaction is best when the reaction temperature is 100-110 ℃, the yield is low when the temperature is insufficient, impurities are increased when the temperature is too high, and the purity is reduced.
Table 2: data summary for the synthesis of quetiapine fumarate in examples 3, 5-9
As can be seen from Table 2: under the condition of certain other conditions, the influence of different reaction time lengths on the reaction is verified, the reaction time length is 10-12 h after the reaction is finished, and if the reaction time is continuously prolonged, the impurities are increased, and the purity is reduced.
Table 3: data summary of quetiapine fumarate synthesis in examples 3 and 10
As can be seen from Table 3: under other conditions, the solvent was replaced with DEF, and the product could be used without any significant difference in overall yield and purity.
Table 4: data summary of quetiapine fumarate synthesis in examples 3 and 11
As can be seen from Table 4: under other conditions, the oxidant is replaced by the DTHP, so that the overall yield is greatly reduced, and the purity difference is not large.
Table 5: data summary for the synthesis of quetiapine fumarate in examples 3, 12-17
As can be seen from Table 5: under other conditions, the effect of various copper compounds on the reaction was verified, and the best effect of copper acetylacetonate and copper acetate was obtained by comparing the yield and purity.
Table 6: data summary for the synthesis of quetiapine fumarate in examples 3, 18-19
As can be seen from Table 6: under other conditions, the effect of different amounts of the oxidizing agent DTBP on the reaction was verified, and it was found from the comparison of the yield and the purity that the reaction was almost completed when the amount of the oxidizing agent DTBP was 4 times or more equivalent of DPTP, and therefore, it was most appropriate to select 4 times equivalent of DTBP.
Table 7: data summary of the synthesis of quetiapine fumarate in example 3, examples 20-21
As can be seen from Table 7: under other conditions, the influence of different amounts of solvent DMF on the reaction is verified, and the comparison of yield and purity shows that when the amount of DMF is 8 times or more of DPTP, the purity of the obtained product is better, so that the amount of DMF is most suitable for selecting 8 times of solvent.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A high-efficiency preparation method of quetiapine fumarate is characterized by comprising the following steps: dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxyethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst at 80-120 ℃ for 6-16H to directly condense to obtain quetiapine free base, and after separation, fumaric acid is added to form salt to obtain quetiapine fumarate; the copper catalyst comprises a copper compound and an oxidant;
2. the efficient preparation method of quetiapine fumarate according to claim 1, which is characterized in that: the copper compound is one or more of copper acetylacetonate, bis (hexafluoroacetylacetone) copper (II), copper acetate, copper chloride, ketone iodide, cuprous chloride and cuprous iodide.
3. The efficient preparation method of quetiapine fumarate according to claim 2, which is characterized in that: the copper compound is copper acetylacetonate or copper acetate.
4. The efficient preparation method of quetiapine fumarate according to claim 1, which is characterized in that: the oxidant is one or two of di-tert-butyl peroxide and tert-butyl hydroperoxide.
5. The efficient preparation method of quetiapine fumarate according to claim 4, which is characterized in that: the oxidant is di-tert-butyl peroxide.
6. The efficient preparation method of quetiapine fumarate according to claim 1, which is characterized in that: the solvent is N, N-dimethylformamide or N, N-diethylformamide.
7. The efficient preparation method of quetiapine fumarate according to claim 1, which is characterized in that: the molar ratio of the dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone, the copper compound and the oxidant is 1: 0.05: 2-6.
8. The efficient preparation method of quetiapine fumarate according to claim 7, which is characterized in that: the molar ratio of the dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone, the copper compound and the oxidant is 1: 0.05: 4.
9. the efficient preparation method of quetiapine fumarate according to claim 6, which is characterized in that: the weight ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone to the N, N-dimethylformamide is 1: 6-10.
10. The efficient preparation method of quetiapine fumarate according to claim 9, which is characterized in that: the weight ratio of dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] one to N, N-dimethylformamide is 1: 8.
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