CN104803947A - Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate - Google Patents
Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate Download PDFInfo
- Publication number
- CN104803947A CN104803947A CN201510109955.5A CN201510109955A CN104803947A CN 104803947 A CN104803947 A CN 104803947A CN 201510109955 A CN201510109955 A CN 201510109955A CN 104803947 A CN104803947 A CN 104803947A
- Authority
- CN
- China
- Prior art keywords
- piperazinyl
- dibenzo
- reaction
- nitrae
- isosorbide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate. The preparation method comprises steps as follows: 2-(2-nitro-thiophenyl)-benzoic acid(I) has a chlorination reaction firstly to generate 2-(2-nitro-thiophenyl)-benzoyl chloride (II); the compound II reacts with piperazine in the presence of an acid binding agent to generate piperazinyl-[2-(2-nitro) thiophenyl] benzophenone(III); the nitro group of the compound III is reduced to an amino group through a hydrogenation reaction, and piperazinyl-[2-(2-amino)-thiophenyl]-benzophenone(IV) is obtained; in xylene, tetraisopropyl titanate is taken as a condensation agent, the compound IV has a cyclization reaction to generate 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine; 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine and fumaric acid have a salt forming reaction to obtain 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate. The preparation method has the benefits as follows: phosphorus reagents are not used, column chromatography purification is not required, the purity of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate is higher than 99.0%, and quetiapine can be obtained through a one-step reaction.
Description
Technical field
The present invention relates to chemosynthesis technical field, especially 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate.
Background technology
Quetiapine (Quetiapine) chemistry 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-1-piperazinyl] dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine by name
, use with the form of quetiapine fumarate clinically, be a kind of atypical antipsychotic agnets, be used for the treatment of schizophrenia, have interaction to various neurotransmitters acceptor.Clinical trial shows, Quetiapine fumarate tablet to treatment the schizoid positive and negative symptoms all effective, it is the only atypical antipsychotic being used for the treatment of emotion dependency bipolar affective disorder got permission at present, also be the medicine that the only license of current European Union is used for the treatment of bipolar affective disorder, Quetiapine chemical structural formula is as follows:
In the Quetiapine synthetic route of existing bibliographical information, the overwhelming majority all will use the phosphorus reagent such as Vanadium Pentoxide in FLAKES, phosphorus oxychloride, and the use of phosphorus reagent can bring larger pressure to sewage disposal.
The technique that Chinese patent CN101891707 introduces can avoid the use of phosphorus reagent, and reaction formula is as follows:
There is following problem in the technique that patent CN101891707 introduces: by 2-(2-Nitro-phenvlsulfansl)-Benzoyl chloride <2> and 1-, ["-NH " in 2-(2-hydroxyl-oxethyl) piperazine reacts in generation amide compound process, inevitably [there is side reaction and generate ester in "-OH " in 2-(2-hydroxyl-oxethyl) piperazine with 1-, and this by product need adopt the mode of column chromatography to be removed, be not suitable for suitability for industrialized production; In the process being prepared Quetiapine <5> by compound L EssT.LTssT.LT4>, titanium isopropylate is condensing agent and solvent, consumption is excessive, trouble is brought to last handling process, the Quetiapine obtained need carry out column chromatography and carry out purifying, more difficultly applies in suitability for industrialized production.
Different from the technique of existing bibliographical information, patent of the present invention provides 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation technology of fumarate, 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
fumarate after desalting treatment directly and 2-(2-chloroethoxy) ethanol synthesis can obtain Quetiapine, do not need through column chromatography purification.Preparation 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the chemical equation of fumarate is as follows:
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides a kind of 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate.
The present invention solves the technical scheme that its technical problem adopts: a kind of 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, comprises the following steps:
(1) 2-(2-Nitro-phenvlsulfansl)-phenylformic acid (I) generates 2-(2-Nitro-phenvlsulfansl)-Benzoyl chloride (II) through chlorination reaction;
(2) compound ii reacts with excessive piperazine and generates piperazinyl-[2-(2-nitro) thiophenyl] benzophenone (III) under acid binding agent existent condition;
(3) by hydrogenation, the nitroreduction of compound III is become amino, obtain piperazinyl-[2-(2-is amino) thiophenyl] benzophenone (IV);
(4) in dimethylbenzene, take titanium isopropylate as condensing agent, compounds Ⅳ generation ring-closure reaction generates 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
;
(5) 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine is obtained with fumaric acid salt-forming reaction
fumarate (V).
Further, in step (1), chlorination reagent is sulfur oxychloride and oxalyl chloride, preferred sulfur oxychloride; Chlorination reaction solvent is toluene, dimethylbenzene, methylene dichloride, preferred toluene; Chlorination reaction catalyzer is dimethyl formamide when chlorination reagent is sulfur oxychloride, is triethylamine when chlorination reagent is oxalyl chloride; Chlorination reaction temperature, when chlorination reagent is sulfur oxychloride is 60 ~ 90 DEG C, preferably 70 ~ 80 DEG C; Be-5 DEG C ~ 10 DEG C when chlorination reagent is oxalyl chloride, preferably 0 ~ 5 DEG C; The chlorination reaction time is 5 ~ 7 hours when chlorination reagent is sulfur oxychloride, preferably 6 hours, is 0.5 ~ 1.5 hour when chlorination reagent is oxalyl chloride, preferably 1 hour.
Further, the amount of chlorination reagent in step (1), when chlorination reagent is sulfur oxychloride, be (4 ~ 6) with the mol ratio of chemical compounds I: 1, preferred 5:1, when chlorination reagent is oxalyl chloride, be (1.3 ~ 1.7) with the mol ratio of chemical compounds I: 1, preferred 1.5:1; The amount of chlorination reaction catalyzer, when chlorination reagent is sulfur oxychloride, dimethyl formamide consumption is 0.3 ~ 0.5% of chemical compounds I weight, and when chlorination reagent is oxalyl chloride, triethylamine consumption is 2 times of oxalyl chloride molar weight.
Further, in step (2), acid binding agent is the organic amines such as triethylamine, Diisopropylamine, diisopropylethylamine, preferred triethylamine; Reaction solvent is methylene dichloride, ethyl acetate, toluene, preferred methylene dichloride; Temperature of reaction is 15 ~ 30 DEG C, preferably 20 ~ 25 DEG C; Reaction times is 4 ~ 6 hours, preferably 5 hours.
Further, in step (2), the amount of acid binding agent is 1.5 ~ 2.5 times of the molar weight of chemical compounds I, and preferably 2 times, the mol ratio of piperazine and chemical compounds I is (3 ~ 4): 1, preferred 3.5:1.
Further, in step (3), hydrogenation solvent is methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF), ethyl acetate; Hydrogenation catalyst is palladium carbon, Raney's nickel, preferably the palladium carbon of 5%; Hydrogenation temperature is 20 ~ 40 DEG C, preferably 25 ~ 35 DEG C.
Further, the amount of hydrogenation catalyst in step (3), when catalyzer is palladium carbon, consumption is 3 ~ 5% of compound III weight, preferably 4%, when catalyzer is Raney's nickel, consumption is 30 ~ 50% of compound III weight, preferably 40%.
Further, in step (4), ring-closure reaction temperature is back flow reaction, desolventizes the Virahol that the mode adding dimethylbenzene removes by-product in reaction process by steaming; The ring-closure reaction time is 20 ~ 28 hours, preferably 24 hours.
Further, to go out reaction with shrend in step (4), then filter out the solid in system, filtrate phase-splitting, organic phase and mixed in hydrochloric acid, stirred at ambient temperature 1 ~ 2 hour, used salt acid concentration is 1 ~ 3%, preferably 2%, and churning time preferably 1.5 hours; Separate sour water phase, adjust pH=9 ~ 10 with sodium hydroxide solution, then use dichloromethane extraction, extracting solution merges, and drying processed, then concentrates, and obtains 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
.
Further, in step (4), the mol ratio of titanium isopropylate and compound III is (3 ~ 5): 1, preferred 4:1.
Further, in step (5), salt-forming reaction solvent is acetone, butanone, Virahol, preferred acetone; Salt-forming reaction temperature is the reflux temperature of solvent for use; The salt-forming reaction time is 20 ~ 40 minutes, preferably 30 minutes; The Tc of salt-forming reaction is 15 ~ 30 DEG C, preferably 20 ~ 25 DEG C, crystallization time 1 ~ 3 hour, preferably 2 hours.
Further, the amount of fumaric acid is 30 ~ 50% of compound III weight in step (5), preferably 40%.
The invention has the beneficial effects as follows: this preparation method does not use phosphorus reagent, does not need column chromatography purification, 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
fumarate purity reaches more than 99.0%, can obtain Quetiapine through single step reaction.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
Chemical compounds I 27.5g, toluene 110ml and 0.1ml dimethyl formamide is dropped in reaction flask, be heated between 70 ~ 80 DEG C, drip sulfur oxychloride 60g, drip and finish, insulation reaction 6 hours between 70 ~ 80 DEG C, then concentrating under reduced pressure obtains compound ii, for next step reaction after dissolving with 50ml methylene dichloride.
Methylene dichloride 150ml, piperazine 35g, triethylamine 20g is added in reaction flask, the dichloromethane solution of compound ii is dripped under stirring at room temperature, drip and finish, 20 ~ 25 DEG C are continued stirring reaction 5 hours, then use water 200ml washing reaction liquid 2 times, gained dichloromethane solution anhydrous sodium sulfate drying dewaters, concentrating under reduced pressure, the acetone crystallization of gained residue, obtains compound III and is about 27g.
In 1000ml autoclave, drop into 270ml ethyl acetate and 27g compound III, add the palladium carbon 1g of 5% after stirring and dissolving, after nitrogen replacement air, pass into hydrogen, maintenance hydrogen pressure is 0.12 ~ 0.18MPa, 25 ~ 35 DEG C of insulation reaction, and TLC follows the tracks of reaction to compound III spot and disappears.After reaction terminates, filter out palladium carbon, filtrate concentrates, and obtains oily compound IV about 30g.
With 300ml xylene soluble compounds Ⅳ, mix with 90g titanium isopropylate, be warming up to backflow, keeping back flow reaction 24 hours, when reacting to 6 hours, 12 hours and 18 hours nodes, changeing back stream for distillation, steam about 100ml solution, then the dimethylbenzene adding respective numbers continues back flow reaction.After insulation terminates, be cooled between 80 ~ 90 DEG C, add water 200ml, stir insulation 1 hour, filter, filtrate phase-splitting, aqueous phase discards, the mixed in hydrochloric acid of organic phase and 300ml 2%, stirred at ambient temperature 1.5 hours, separate sour water phase, the sodium hydroxide solution with 10% adjusts pH=9 ~ 10, then uses 300ml dichloromethane extraction, extracting solution merges, and through anhydrous sodium sulfate drying processed, then concentrates, obtain oily 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
about 17.5g.
11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine is dissolved with acetone 80ml
, then add fumaric acid 10g, back flow reaction 30 minutes, is cooled to 20 ~ 25 DEG C, stirred crystallization 2 hours, suction filtration, and filter cake decompression drying obtains compound V about 20.5g, purity (HPLC) more than 99.0%.
Embodiment 2
Compound III is prepared by embodiment 1 step.
In 1000ml autoclave, drop into 270ml tetrahydrofuran (THF) and 27g compound III, stir molten clear after add Raney's nickel 10g, after nitrogen replacement air, pass into hydrogen, keep hydrogen pressure 0.12 ~ 0.18MPa, 25 ~ 35 DEG C of vigorous stirring insulation reaction, TLC follows the tracks of reaction to compound III spot and disappears.After reaction terminates, filter out Raney's nickel, filtrate concentrates, and obtains oily compound IV about 30g.
Then compound V about 19.5g is prepared by embodiment 1 remaining steps, purity (HPLC) more than 99.0%.
Embodiment 3
Chemical compounds I 27.5g, methylene dichloride 165ml and oxalyl chloride 19g is dropped in reaction flask, be cooled between 0 ~ 5 DEG C, drip triethylamine 30g, drip and finish, insulation reaction 1 hour between 0 ~ 5 DEG C, filter out the solid in system, then concentrating under reduced pressure obtains compound ii, for next step reaction after dissolving with 50ml methylene dichloride.
Then compound V about 20.0g is prepared by embodiment 1 remaining steps, purity (HPLC) more than 99.0%.
Claims (12)
1. 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: comprise the following steps:
(1) 2-(2-Nitro-phenvlsulfansl)-phenylformic acid (I) generates 2-(2-Nitro-phenvlsulfansl)-Benzoyl chloride (II) through chlorination reaction;
(2) compound ii reacts with excessive piperazine and generates piperazinyl-[2-(2-nitro) thiophenyl] benzophenone (III) under acid binding agent existent condition;
(3) by hydrogenation, the nitroreduction of compound III is become amino, obtain piperazinyl-[2-(2-is amino) thiophenyl] benzophenone (IV);
(4) in dimethylbenzene, take titanium isopropylate as condensing agent, compounds Ⅳ generation ring-closure reaction generates 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
;
(5) 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine is obtained with fumaric acid salt-forming reaction
fumarate (V).
2. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (1), chlorination reagent is sulfur oxychloride and oxalyl chloride, preferred sulfur oxychloride; Chlorination reaction solvent is toluene, dimethylbenzene, methylene dichloride, preferred toluene; Chlorination reaction catalyzer is dimethyl formamide when chlorination reagent is sulfur oxychloride, is triethylamine when chlorination reagent is oxalyl chloride; Chlorination reaction temperature, when chlorination reagent is sulfur oxychloride is 60 ~ 90 DEG C, preferably 70 ~ 80 DEG C; Be-5 DEG C ~ 10 DEG C when chlorination reagent is oxalyl chloride, preferably 0 ~ 5 DEG C; The chlorination reaction time is 5 ~ 7 hours when chlorination reagent is sulfur oxychloride, preferably 6 hours, is 0.5 ~ 1.5 hour when chlorination reagent is oxalyl chloride, preferably 1 hour.
3. 11-according to claim 1 and 2 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, it is characterized in that: the amount of chlorination reagent in described step (1), when chlorination reagent is sulfur oxychloride, be (4 ~ 6) with the mol ratio of chemical compounds I: 1, preferred 5:1, when chlorination reagent is oxalyl chloride, be (1.3 ~ 1.7) with the mol ratio of chemical compounds I: 1, preferred 1.5:1; The amount of chlorination reaction catalyzer, when chlorination reagent is sulfur oxychloride, dimethyl formamide consumption is 0.3 ~ 0.5% of chemical compounds I weight, and when chlorination reagent is oxalyl chloride, triethylamine consumption is 2 times of oxalyl chloride molar weight.
4. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (2), acid binding agent is the organic amines such as triethylamine, Diisopropylamine, diisopropylethylamine, preferred triethylamine; Reaction solvent is methylene dichloride, ethyl acetate, toluene, preferred methylene dichloride; Temperature of reaction is 15 ~ 30 DEG C, preferably 20 ~ 25 DEG C; Reaction times is 4 ~ 6 hours, preferably 5 hours.
5. 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine according to claim 1 or 4
the preparation method of fumarate, is characterized in that: in described step (2), the amount of acid binding agent is 1.5 ~ 2.5 times of the molar weight of chemical compounds I, and preferably 2 times, the mol ratio of piperazine and chemical compounds I is (3 ~ 4): 1, preferred 3.5:1.
6. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (3), hydrogenation solvent is methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF), ethyl acetate; Hydrogenation catalyst is palladium carbon, Raney's nickel, preferably the palladium carbon of 5%; Hydrogenation temperature is 20 ~ 40 DEG C, preferably 25 ~ 35 DEG C.
7. 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine according to claim 1 or 6
the preparation method of fumarate, it is characterized in that: the amount of hydrogenation catalyst in described step (3), when catalyzer is palladium carbon, consumption is 3 ~ 5% of compound III weight, preferably 4%, when catalyzer is Raney's nickel, consumption is 30 ~ 50% of compound III weight, preferably 40%.
8. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (4), ring-closure reaction temperature is back flow reaction, desolventizes the Virahol that the mode adding dimethylbenzene removes by-product in reaction process by steaming; The ring-closure reaction time is 20 ~ 28 hours, preferably 24 hours.
9. 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine according to claim 1 or 8
the preparation method of fumarate, it is characterized in that: to go out reaction with shrend in described step (4), then the solid in system is filtered out, filtrate phase-splitting, organic phase and mixed in hydrochloric acid, stirred at ambient temperature 1 ~ 2 hour, used salt acid concentration is 1 ~ 3%, preferably 2%, churning time preferably 1.5 hours; Separate sour water phase, adjust pH=9 ~ 10 with sodium hydroxide solution, then use dichloromethane extraction, extracting solution merges, and drying processed, then concentrates, and obtains 11-(1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
.
10. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (4), the mol ratio of titanium isopropylate and compound III is (3 ~ 5): 1, preferred 4:1.
11. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: in described step (5), salt-forming reaction solvent is acetone, butanone, Virahol, preferred acetone; Salt-forming reaction temperature is the reflux temperature of solvent for use; The salt-forming reaction time is 20 ~ 40 minutes, preferably 30 minutes; The Tc of salt-forming reaction is 15 ~ 30 DEG C, preferably 20 ~ 25 DEG C, crystallization time 1 ~ 3 hour, preferably 2 hours.
12. 11-according to claim 1 (1-piperazinyl) dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
the preparation method of fumarate, is characterized in that: the amount of fumaric acid is 30 ~ 50% of compound III weight in described step (5), preferably 40%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510109955.5A CN104803947A (en) | 2015-03-12 | 2015-03-12 | Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510109955.5A CN104803947A (en) | 2015-03-12 | 2015-03-12 | Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104803947A true CN104803947A (en) | 2015-07-29 |
Family
ID=53689186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510109955.5A Pending CN104803947A (en) | 2015-03-12 | 2015-03-12 | Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104803947A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553591A (en) * | 2019-01-15 | 2019-04-02 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of quetiapine fumarate intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1664007B1 (en) * | 2003-09-23 | 2009-12-23 | Fermion Oy | Preparation of quetiapine |
| EP1856073B1 (en) * | 2005-03-07 | 2010-05-12 | Union Quimico-Farmaceutica, S.A. | A PROCESS FOR THE PREPARATION OF AN 11-(4-SUBSTITUTED-I-PIPERAZINYL)DIBENZO[b,f][1,4]THIAZEPINE DERIVATIVE |
| CN101891707A (en) * | 2010-07-29 | 2010-11-24 | 浙江海正药业股份有限公司 | Method for preparing Quetiapine or pharmaceutically acceptable fumarate thereof |
| US20110237568A1 (en) * | 2005-11-18 | 2011-09-29 | Black Simon N | Crystalline forms |
| CN103664822A (en) * | 2012-09-18 | 2014-03-26 | 四川大学华西医院 | Compound used as anesthetic |
-
2015
- 2015-03-12 CN CN201510109955.5A patent/CN104803947A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1664007B1 (en) * | 2003-09-23 | 2009-12-23 | Fermion Oy | Preparation of quetiapine |
| EP1856073B1 (en) * | 2005-03-07 | 2010-05-12 | Union Quimico-Farmaceutica, S.A. | A PROCESS FOR THE PREPARATION OF AN 11-(4-SUBSTITUTED-I-PIPERAZINYL)DIBENZO[b,f][1,4]THIAZEPINE DERIVATIVE |
| US20110237568A1 (en) * | 2005-11-18 | 2011-09-29 | Black Simon N | Crystalline forms |
| CN101891707A (en) * | 2010-07-29 | 2010-11-24 | 浙江海正药业股份有限公司 | Method for preparing Quetiapine or pharmaceutically acceptable fumarate thereof |
| CN103664822A (en) * | 2012-09-18 | 2014-03-26 | 四川大学华西医院 | Compound used as anesthetic |
Non-Patent Citations (1)
| Title |
|---|
| A.KUCSMAN ET AL.: "intramolecular sulphur(Ⅱ)-oxygen interaction in sulphides and disulphides with 2-methoxycarbonylphenyl and 2-nitrophenyl groups:an x-ray study", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553591A (en) * | 2019-01-15 | 2019-04-02 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of quetiapine fumarate intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105330582B (en) | (R) preparation method of-Esomeprazole | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN104341333B (en) | A kind of preparation method of pramiracetam sulfate | |
| CN105130926B (en) | A kind of preparation method of methylene blue | |
| US20060173178A1 (en) | Process for preparing dibenzothiazepine derivatives | |
| CN101891707B (en) | Method for preparing Quetiapine or pharmaceutically acceptable fumarate thereof | |
| CN104803947A (en) | Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate | |
| CN105859653A (en) | Quetiapine synthesizing method | |
| CN100427460C (en) | Method for synthesis of L-norvaline | |
| JP2009527458A (en) | Method for producing dibenzothiazepine compounds | |
| CN108164423A (en) | A kind of preparation method of naftifine hydrochloride | |
| CN101531634B (en) | High-purity blonanserin and preparation method thereof | |
| CN103012264B (en) | The method for splitting of 3 substituted-amino hexahydro 1H azepans | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride | |
| CN101613349B (en) | Preparation method of S-3-aminoquinuclidine dihydrochloride | |
| CN105061359B (en) | Refining method of quetiapine hemifumarate | |
| CN113045524B (en) | Synthesis method of ramelteon intermediate | |
| CN113651800B (en) | Preparation method of oxitinib mesylate | |
| JP2011126887A (en) | Method for producing dibenzothiazepine derivative | |
| CN107652269A (en) | Methanesulfonic acid fluorine imatinib purification of intermediate method | |
| JP3865096B2 (en) | Method for producing dibenzothiazepine derivative | |
| CN103772319A (en) | Synthetic method of thiazepine compound | |
| CN104003977B (en) | The preparation method of N-(2-chloromethyl-1-methyl isophthalic acid H-benzoglyoxaline-5-acyl group)-N-(pyridine-2-base)-3-alanine ethyl ester | |
| CN107353314A (en) | A kind of synthetic method of 5- deoxidations-L-arabinose | |
| CN1872846B (en) | Method of preparing 2-benzothiazepines derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 213105 Changzhou, Wujin District, Luoyang City, Dai Dai Street Applicant after: Kang Li (Changzhou) Medicine Pharmaceutical Co. Ltd. Address before: 213105 Changzhou, Wujin District, Luoyang City, Dai Dai Street Applicant before: Changzhou Kangli Pharmaceutical Co., Ltd. |
|
| COR | Change of bibliographic data | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150729 |
|
| RJ01 | Rejection of invention patent application after publication |