CN114181172B - Efficient preparation method of quetiapine fumarate - Google Patents
Efficient preparation method of quetiapine fumarate Download PDFInfo
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- CN114181172B CN114181172B CN202111608959.XA CN202111608959A CN114181172B CN 114181172 B CN114181172 B CN 114181172B CN 202111608959 A CN202111608959 A CN 202111608959A CN 114181172 B CN114181172 B CN 114181172B
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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 41
- 229960005197 quetiapine fumarate Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims abstract description 65
- 229960004431 quetiapine Drugs 0.000 claims abstract description 64
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 54
- 239000003513 alkali Substances 0.000 claims abstract description 47
- 239000001530 fumaric acid Substances 0.000 claims abstract description 27
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 27
- 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 17
- 150000002576 ketones Chemical class 0.000 claims abstract description 17
- 239000007800 oxidant agent Substances 0.000 claims abstract description 14
- 239000005749 Copper compound Substances 0.000 claims abstract description 11
- 150000001880 copper compounds Chemical class 0.000 claims abstract description 11
- 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
- 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
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 and after separation Substances 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 43
- 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 19
- 230000001590 oxidative effect Effects 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 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 5
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 description 137
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 132
- 238000003756 stirring Methods 0.000 description 105
- 238000001816 cooling Methods 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000010438 heat treatment Methods 0.000 description 42
- 238000000605 extraction Methods 0.000 description 41
- 238000009413 insulation Methods 0.000 description 39
- 101000738734 Drosophila melanogaster Tyrosine-protein phosphatase 69D Proteins 0.000 description 24
- 239000003651 drinking water Substances 0.000 description 21
- 235000020188 drinking water Nutrition 0.000 description 21
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- 238000004321 preservation Methods 0.000 description 17
- 238000001035 drying Methods 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 16
- 238000005660 chlorination reaction Methods 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 4
- 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 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 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
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012535 impurity 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
- 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
- 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 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 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
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 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
- 150000001875 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
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 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
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- QAMFBRUWYYMMGJ-UHFFFAOYSA-N hexafluoroacetylacetone Chemical compound FC(F)(F)C(=O)CC(=O)C(F)(F)F QAMFBRUWYYMMGJ-UHFFFAOYSA-N 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
- 239000000126 substance Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a high-efficiency preparation method of quetiapine fumarate. The efficient preparation method of quetiapine fumarate comprises the following steps: the dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxy ethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst for 6-16 hours at 80-120 ℃ to obtain quetiapine free alkali, and after separation, fumaric acid is added to form salt to obtain quetiapine fumarate; the copper catalyst includes a copper compound and an oxidizing agent.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a high-efficiency preparation method of quetiapine fumarate.
Background
Quetiapine fumarate is a new generation of atypical psychosis, first marketed in the united kingdom by Zeneca corporation in 1997, month 11, and clinically used as a first line drug for schizophrenia. Quetiapine fumarate is known as 11- [4- [2- (2-hydroxyethoxy) ethyl ] -1-piperazinyl ] dibenzo [ b, f ] [1,4] thiazepine hemi-fumarate and is prepared by salifying quetiapine with fumaric acid and has the following chemical structural formula:
the literature reports that a number of synthetic routes can be made:
1. european patent EP282236 reports that dibenzo [ b, f ] [1,4] thiazepin-11- (10H) ketone is chlorinated with phosphorus oxychloride and then condensed with piperazine to obtain an intermediate 11-piperazinyl-dibenzo [ b, f ] [1,4] thiazepin, and 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 phosphorus oxychloride (the use amount is 148 mole times of dibenzo [ b, f ] [1,4] thiazepin-11- (10H) ketone) is used in a large amount, so that a large amount of phosphorus-containing wastewater is generated, and great pressure is caused to environmental management; in addition, the yield is relatively low due to the longer procedure.
2. The route reported in EP240228 is likewise dibenzo [ b, f ] [1,4] thiazepin-11- (10H) one and phosphorus oxychloride are chlorinated to give the intermediate 11-chloro-dibenzo [ b, f ] [1,4] thiazepin, which, unlike the route of EP282236, is condensed directly with the side chain 1- (2-hydroxyethoxy) ethylpiperazine to give quetiapine, the steps being reduced to a certain extent, but the overall route being still longer; the route also requires chlorination reaction and a large amount of phosphorus oxychloride; the ether and the methylene dichloride which are extremely flammable and explosive low-boiling solvents are used in the route, so that the potential safety hazard in production is high.
3. The route reported in patent W02005014590 is that dibenzo [ b, f ] [1,4] thiazepin-11- (10H) ketone is chlorinated to give 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 chloroethanol compound with protected hydroxy and removing the protecting group under acidic condition to obtain quetiapine, wherein the route step is longer due to the need of removing the protecting group, and the total yield is reduced; the traditional chlorination reagent is still adopted in the route, so that dangerous chlorination reaction is carried out; the mixed solvent of toluene, methanol, butanone, methanol and the like is used for multiple times in the route, so that the manufacturing cost and the environmental treatment cost are increased.
4, the route reported in patent CN101619047 is dibenzo [ b, f ] [1,4] thiazepin-11- (10H) ketone, which is chloridized by triphosgene to obtain intermediate 11-chloro-dibenzo [ b, f ] [1,4] thiazepin, which is then condensed directly with side chain 1- (2-hydroxyethoxy) ethylpiperazine to obtain quetiapine, the route is shorter than that of patent EP282236, EP240228 and W02005014590, the yield is high, triphosgene is used as chloride to carry out chloridization reaction, and no pollution is generated to environment during post treatment. However, 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 generates phosgene after being heated, is a highly toxic product and has potential safety hazard.
In the prior art for industrially synthesizing quetiapine fumarate, at least two steps of chlorination and condensation are needed from dibenzo [ b, f ] [1,4] thiazepine-11- (10H) ketone to quetiapine fumarate, 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 a high-efficiency preparation method of quetiapine fumarate.
Disclosure of Invention
The invention aims to provide a high-efficiency preparation method of quetiapine fumarate, which aims to solve the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the efficient preparation method of quetiapine fumarate comprises the following steps: the dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxy ethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst for 6-16 hours at 80-120 ℃ to obtain quetiapine free alkali, 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, copper iodide, copper chloride and copper iodide.
Preferably, the copper compound is copper acetylacetonate or copper acetate.
Preferably, the oxidizing agent is one or two of di-tert-butyl peroxide and tert-butyl hydroperoxide.
Preferably, the oxidizing agent is di-t-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 ] ketone to the N, N-dimethylformamide is 1:6-10.
Preferably, the weight ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone to the N, N-dimethylformamide is 1:8.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a high-efficiency preparation method of quetiapine fumarate, which uses a copper catalyst to carry out one-step condensation reaction on DPTP and heel to obtain quetiapine fumarate, so that the reaction steps are reduced, and the synthesis efficiency of quetiapine fumarate is greatly improved;
(2) The invention provides a high-efficiency preparation method of quetiapine fumarate, which avoids the chlorination reaction in the traditional synthesis process, does not need to use chlorides such as phosphorus oxychloride, thionyl chloride, triphosgene, oxalyl chloride and the like, greatly reduces the process danger and simultaneously eliminates the environmental pollution caused by post-treatment of the 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 some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Adding 1g of copper acetylacetonate and 160g (170 ml) of N, N-Dimethylformamide (DMF) into a reaction bottle, starting stirring, slowly dripping 51.5g of di-tert-butyl peroxide (DTBP), stirring for 30min at room temperature after dripping, sequentially adding 20g of dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone (DPTP) and 16g of 1- [2 (2-hydroxyethoxy) ethyl ] piperazine (heel) into the reaction bottle, heating to 80-90 ℃, preserving heat for reaction for 10H, cooling to 20-30 ℃, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, extracting a toluene layer, concentrating an upper toluene layer solution to dryness to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating and stirring until the quetiapine is dissolved, adding 5g of fumaric acid into the reaction bottle, stirring for 1H, cooling to 0-5 ℃ for crystallization, cooling to 1H, cooling to 1-30 ℃, preserving heat, crystallizing, preserving heat, filtering, and drying to obtain quetiapine free alkali after crystallization, and preserving heat for 3g.
Example 2
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 90-100 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 30.8g of quetiapine.
Example 3
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 35.4g of quetiapine.
Example 4
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 110-120 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 35.5g of quetiapine fumarate.
Example 5
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 6h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 27.9g of quetiapine.
Example 6
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out heat preservation reaction for 8h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out heat preservation stirring for 1h, cooling to 0-5 ℃, carrying out heat preservation crystallization for 1h, carrying out heat preservation, and carrying out suction filtration to obtain 32.1g of quetiapine.
Example 7
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 12h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain quetiapine fumarate 35.9.
Example 8
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 14h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain quetiapine fumarate 35.7.
Example 9
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 16h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain quetiapine fumarate 35.5.
Example 10
Adding 1g of copper acetylacetonate and 160g (170 ml) 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, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out heat preservation reaction for 10h, cooling to 20-30 ℃, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating and stirring until the quetiapine free alkali is dissolved, adding 5g of fumaric acid into the reaction bottle, carrying out heat preservation and stirring for 1h, cooling to 0-5 ℃ after heat preservation, crystallizing the fumaric acid for 1h after heat preservation, carrying out suction filtration, and obtaining 34.8g of quetiapine.
Example 11
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, stirring, slowly dripping 51.5g of tert-butyl hydroperoxide (TBHP), stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, reacting for 10h under heat preservation, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating the upper toluene layer solution to dryness to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into quetiapine free alkali, heating and stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, stirring for 1h under heat preservation, cooling to 0-5 ℃ under heat preservation, crystallizing for 1h under heat preservation, filtering under heat preservation, and obtaining 28g of quetiapine fumarate.
Example 12
Adding 1g of cuprous chloride and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, separating the extraction, concentrating the upper toluene layer solution to dryness to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating and stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, preserving heat and filtering to obtain 23.7g of quetiapine.
Example 13
Adding 1g of cuprous iodide and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 26.9g of quetiapine.
Example 14
Adding 1g of copper chloride and 160g (170 ml) of DMF into a reaction bottle, stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, separating the extraction, concentrating the upper toluene layer solution to dryness to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating and stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, preserving heat and stirring for 1h, cooling to 0-5 ℃, preserving heat and crystallizing for 1h, preserving heat and filtering to obtain 31.6g of quetiapine.
Example 15
Adding 1g of copper iodide and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 32.2g of quetiapine.
Example 16
Adding 1g of copper acetate and 160g (170 ml) of DMF into a reaction bottle, stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, preserving heat for reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution to dryness to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, preserving heat for stirring for 1h, cooling to 0-5 ℃, preserving heat for crystallization for 1h, preserving heat for filtering to obtain 34g of quetiapine fumarate.
Example 17
Adding 1g of bis (hexafluoroacetylacetone) copper (II) and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out heat preservation reaction for 10h, cooling to 20-30 ℃, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating and stirring to dissolve, adding 5g of fumaric acid into the reaction bottle, carrying out heat preservation and stirring for 1h, cooling to 0-5 ℃ after heat preservation, crystallizing for 1h after heat preservation, carrying out suction filtration, and drying to obtain 31.4g of quetiapine.
Example 18
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 25.8g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 31g of quetiapine fumarate.
Example 19
Adding 1g of copper acetylacetonate and 160g (170 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 77.3g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 35.6g of quetiapine.
Example 20
Adding 1g of copper acetylacetonate and 120g (128 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain quetiapine fumarate 35.4.
Example 21
Adding 1g of copper acetylacetonate and 200g (213 ml) of DMF into a reaction bottle, starting stirring, slowly dripping 51.5g of DTBP, stirring for 30min at room temperature after dripping, sequentially adding 20g of DPTP and 16gheep into the reaction bottle, heating to 100-110 ℃, carrying out thermal insulation reaction for 10h, cooling to 20-30 ℃ after reaction, adding 80g (80 ml) of drinking water into the reaction bottle, stirring for 30min, adding 100g (115 ml) of toluene for extraction, layering after extraction, concentrating an upper toluene layer solution, drying to obtain quetiapine free alkali, adding 110g (140 ml) of 95% ethanol into the quetiapine free alkali, heating, stirring until dissolving, adding 5g of fumaric acid into the reaction bottle, carrying out thermal insulation stirring for 1h, cooling to 0-5 ℃, carrying out thermal insulation crystallization for 1h, carrying out suction filtration to obtain 35.7g of quetiapine.
Summarizing data:
table 1: summary of data for the synthesis of quetiapine fumarate in examples 1-4
As can be seen from table 1: under 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 lower when the reaction temperature is insufficient, the impurities are increased when the reaction temperature is too high, and the purity is reduced.
Table 2: summary of data for the synthesis of quetiapine fumarate in example 3, examples 5-9
As can be seen from table 2: under 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 impurities are increased and the purity is reduced when the reaction time is prolonged.
Table 3: summary of data for the synthesis of quetiapine fumarate in example 3, example 10
As can be seen from table 3: under certain other conditions, the solvent is replaced by DEF, and the whole yield and purity are not greatly different and can be used.
Table 4: summary of data for the synthesis of quetiapine fumarate in example 3, example 11
As can be seen from table 4: under other conditions, the oxidant is replaced by DTHP, the overall yield is greatly reduced, and the purity difference is small.
Table 5: summary of data for the Synthesis of quetiapine fumarate in example 3, examples 12-17
As can be seen from table 5: under the condition of certain other conditions, the influence of various copper compounds on the reaction is verified, and the comparison of the yield and the purity shows that the effect of the copper acetylacetonate and the copper acetate is optimal.
Table 6: summary of data for the Synthesis of quetiapine fumarate in example 3, examples 18-19
As can be seen from table 6: under other conditions, the influence of different amounts of the oxidizing agent DTBP on the reaction is verified, and the comparison of the yield and the purity proves that when the amount of the oxidizing agent DTBP is more than 4 times of the equivalent of DPTP, the reaction is basically completed, so that 4 times of the equivalent of the DTBP is most suitable.
Table 7: summary of data for the Synthesis of quetiapine fumarate in example 3, examples 20-21
As can be seen from table 7: under other conditions, the influence of the DMF solvents with different dosages on the reaction is verified, and the comparison of the yield and the purity shows that when the DMF dosage is 8 times or more of DPTP, the purity of the obtained product is better, so that the solvent dosage of 8 times is most suitable.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. The efficient preparation method of quetiapine fumarate is characterized by comprising the following steps of: the dibenzo [ b, f ] [1,4] thiazepine-11- [10H ] ketone and 1- [2 (2-hydroxy ethoxy) ethyl ] piperazine are subjected to catalytic reaction in a solvent through a copper catalyst for 6-16 hours at 80-120 ℃ to obtain quetiapine free alkali, and after separation, fumaric acid is added to form salt to obtain quetiapine fumarate; the copper catalyst comprises a copper compound and an oxidant; 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; the copper compound is copper acetylacetonate or copper acetate; the oxidant is one or two of di-tert-butyl peroxide and tert-butyl hydroperoxide
2. The efficient preparation method of quetiapine fumarate according to claim 1, wherein the method comprises the following steps: the oxidant is di-tert-butyl peroxide.
3. The efficient preparation method of quetiapine fumarate according to claim 1, wherein the method comprises the following steps: the solvent is N, N-dimethylformamide or N, N-diethylformamide.
4. The efficient preparation method of quetiapine fumarate according to claim 1, wherein the method comprises the following steps: 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.
5. a process for the efficient preparation of quetiapine fumarate according to claim 3, 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.
6. The efficient preparation method of quetiapine fumarate according to claim 5, wherein: the weight ratio of the dibenzo [ b, f ] [1,4] thiazepin-11- [10H ] ketone to the N, N-dimethylformamide is 1:8.
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| JP2007505864A (en) * | 2003-09-23 | 2007-03-15 | フェルミオン オサケ ユキチュア | Manufacture of quetiapine |
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