CN105859653A - Quetiapine synthesizing method - Google Patents
Quetiapine synthesizing method Download PDFInfo
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- CN105859653A CN105859653A CN201610282040.9A CN201610282040A CN105859653A CN 105859653 A CN105859653 A CN 105859653A CN 201610282040 A CN201610282040 A CN 201610282040A CN 105859653 A CN105859653 A CN 105859653A
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- 0 C[C@@](C1)N(CCO)CCCN1C(*C(CSc1ccccc1)=CC=CC=C)=O Chemical compound C[C@@](C1)N(CCO)CCCN1C(*C(CSc1ccccc1)=CC=CC=C)=O 0.000 description 2
- UYBXGTHDRYRWFD-UHFFFAOYSA-N CC(Nc1ccccc1Sc1ccccc1)=O Chemical compound CC(Nc1ccccc1Sc1ccccc1)=O UYBXGTHDRYRWFD-UHFFFAOYSA-N 0.000 description 1
- XCLJBDAATRCAQW-UHFFFAOYSA-N CC12C(Cl)=Nc(cccc3)c3SC1C=CC=C2 Chemical compound CC12C(Cl)=Nc(cccc3)c3SC1C=CC=C2 XCLJBDAATRCAQW-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N OCCN1CCNCC1 Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
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- 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
Abstract
The invention discloses a quetiapine synthesizing method. O-chlorobenzoic acid with the low price is adopted as a starting material to react with thiophenol, and then ring closure is performed to obtain thioxanthone. Hydroxyl amination and Beckmann rearrangement are performed to obtain a key intermediate dibenzo[b,f][1,4]thiazepines-11-(10H)one, chlorination is performed, then, a reaction is performed on 1-(2-hydroxyethoxy)ethylpiperazine with the existence of acid-binding agent to obtain quetiapine, and the quetiapine and fumaric acid form a salt in an absolute ethyl alcohol system to obtain a product. According to the quetiapine synthesizing method, raw materials are low in price and easy to obtain, the steps are simple, operation is easy, and the cost can be effectively lowered. According to the method, the high-purity quetiapine can be obtained, the liquid phase purity of the obtained semi-fumaric acid quetiapine obtained through salt forming is 99% or above, and the quetiapine synthesizing method can be applied to the field of medicine.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the synthetic method of a kind of Quetiapine.
Background technology
11-{4-[2-(2-(hydroxy ethoxy) ethyl-1-piperazine] } dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
(shown in structure such as formula (I)), is also called Quetiapine, typically sells with the form of hemifumarate.
It is the anti-essence of one researched and developed by Britain AstraZeneca UK limited (AstraZeneca drugmaker)
God's medicine, in November, 1997, lists in Britain first, is used for treating schizophrenia, has
Stronger antipsycholic action and cause less Extra Pyramidal Syndrome.In 2000, domestic quinoline
Sulphur puts down the listing that goes through after completing I, II clinical trial phase, and import Quetiapine also completes note the same year
Volume also lists at home in calendar year 2001.
About the synthetic method of half quetiapine fumarate, existing more document report, principal synthetic routes
There are following several.
Route 1: with 2-diaminodiphenyl sulfide as initiation material, then exists at alkali with phenyl chloroformate
Lower generation 2-phenylthiophenyl phenyl carbamate, then carry out molecule inner ring condensation by polyphosphoric acids,
Generate dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene-11-(10H) ketone, use POCl3Chlorination obtains 11-chlorodiphenyl
And [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene, then react with Piperazine anhydrous, further with 2-(2 '-chloroethoxy) ethanol
Be condensed in the basic conditions and i.e. obtain Quetiapine, Quetiapine in anhydrous ethanol solvent system with half fumaric acid
Salt is become i.e. to obtain product.The follow-up improvement to this technique the most first synthesis side chain 1-(2-hydroxy ethoxy)
Ethyl piperazidine fragment, then react (WO028458) with 11-chlorodiphenyl also [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene.
There are some defects in this technique: one is that acylation process uses phenyl chloroformate as acylating reagent, atom
Utilization rate is relatively low;Two be 2-ADP thiophenol be not the common raw material of industry, need with halo nitre
Base benzene and thiophenol are that initiation material is prepared by condensation, reduction two-step reaction, relatively costly.
Route 2: the first step, with the most the same, first synthesizes 2-phenylthiophenyl phenyl carbamate,
It not the most directly by cyclizing agent cyclization, but first and side chain N-(2-hydroxyethyl) piperazine condensation,
Intermediate sulphur azatropylidene is obtained again, through POCl3 to the hydroxy chloride on its side-chain structure by PPA cyclization
Quetiapine is obtained, equally in absolute ethyl alcohol system with ethylene glycol back flow reaction in the basic conditions after change
Become salt to obtain product (WO055125) with half fumaric acid.But shortcoming is that the intramolecular ring closure of the 3rd step is anti-
Should be more difficult, it may be possible to owing to first connecing the reason that side chain (2-hydroxyethyl) piperazinyl makes steric hindrance increase.
Tan Yun etc. proposed route 3 in 2007: with thiosalicylic acid and o-fluoronitrobenzene as raw material,
Prepare 2-nitro-2 '-carboxyl diphenyl sulfide, obtain 2-amino-2 with ferrous sulfate reduction '-carboxyl diphenyl sulfide
Ether, is then dehydrated cyclization under effect of sulfuric acid and obtains acid amides, take off one through POCl3 chlorination after-condensation
Molecule hydrogen chloride and become with fumaric acid salt obtain half quetiapine fumarate (Chinese Journal of New Drugs 2007,16,
867-868).This route has two obvious shortcomings: one is initiation material thiosalicylic acid and adjacent fluorine nitre
Base benzene price is higher, improves production cost;Two is useless with having substantial amounts of iron content after iron reduction nitro
Liquid, it is difficult to process.
From process above route it can be seen that mainly heptatomic ring key intermediate dibenzo [b, f] [Isosorbide-5-Nitrae]
The synthesis of sulphur azatropylidene-11-(10H) ketone, existing technique is to use polyphosphoric acids cyclization mostly, or uses iron
Reduction nitro, does not meets the requirement of Environmental protection.
Summary of the invention
The invention provides the synthetic method of a kind of Quetiapine, the raw material that this synthetic method is used is inexpensive
It is easy to get, and the waste liquid produced in course of reaction significantly reduces, to more environment-friendly.
The synthetic method of a kind of Quetiapine, comprises the following steps:
(1) under the effect of copper catalyst, 0-chloro-benzoic acid and benzenethiol generation coupling reaction,
To 2-carboxyl diphenyl sulfide;
Shown in the structure such as formula (II) of described 2-carboxyl diphenyl sulfide:
(2) under the effect of acid catalyst, the 2-carboxyl diphenyl sulfide making step (1) obtain occurs
Intra-molecular condensation, obtains thioxanthone;
Shown in the structure of described thioxanthone such as formula (III):
(3) thioxanthone step (2) obtained and azanol carry out condensation reaction, obtain thioxanthene
Ketoxime;
Shown in the structure such as formula (IV) of described thioxanthene ketoxime:
(4) thioxanthene ketoxime step (3) obtained carries out rearrangement reaction under conditions of acid exists,
Obtain 10,11-bis-diphenyl hydrogen [b, f] [1,4] oxygen azatropylidene-11-ketone;
Shown in the structure such as formula (V) of described 10,11-bis-diphenyl hydrogen [b, f] [1,4] oxygen azatropylidene-11-ketone:
(5) under chlorination reagent effect, step (4) obtain 10,11-bis-diphenyl hydrogen [b, f] [Isosorbide-5-Nitrae]
Oxygen azatropylidene-11-ketone carries out chlorination, obtains 11-chloro-dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene.
Shown in the structure such as formula (VI) of described 11-chloro-dibenzo [b, f] [1,4] sulphur azatropylidene:
(6) 11-chloro-dibenzo [b, f] [Isosorbide-5-Nitrae] the sulphur azatropylidene in the presence of a base, obtained and 2-(2-hydroxyl
Base oxethyl) ethyl piperazidine reacts, and obtains Quetiapine;
Shown in the structure such as formula (VII) of described 2-(2-hydroxyl-oxethyl) ethyl piperazidine:
Shown in the structure of described Quetiapine such as formula (VIII):
(7) salt is become to obtain with fumaric acid in alcoholic solvent the Quetiapine that step (6) obtains described
Half quetiapine fumarate;
Shown in the structure such as formula (I) of half described quetiapine fumarate:
The reaction scheme of this synthetic method is as follows:
The synthetic method of the present invention uses cheap and easily-available 0-chloro-benzoic acid as initiation material, is being catalyzed
Under the copper effect of dosage, react with benzenethiol, obtain 2-carboxyl diphenyl sulfide, then at acid catalyst
Effect under cyclization obtain thioxanthone, then obtain oxime with azanol reaction, then utilize Beckmann
Reset and obtain key intermediate dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene-11-(10H) ketone as committed step,
Then chloro, reacts obtain Quetiapine with raw material of industry 1-(2-hydroxy ethoxy) ethyl piperazidine, last with
Fumaric acid becomes salt to obtain half described quetiapine fumarate.The synthesis step of this synthetic method is less, behaviour
Make easily, to be therefore effectively reduced the cost of production.
In step (1), the kind of copper catalyst can produce large effect to reaction yield, described
Copper catalyst be copper powder, stannous chloride or copper chloride, now, the yield of reaction is higher.
In step (1), reaction is carried out in a solvent, and described solvent is preferably naphthane.
In step (1), reaction is carried out under the effect of alkali, and described alkali is preferably NaOH.
In step (1), the temperature of reaction is 110~130 DEG C, and reaction temperature is 6~24 hours.
In step (2), described acid catalyst is at least one in the concentrated sulfuric acid and SPA.
In step (2), described Intra-molecular condensation is carried out in a solvent, and described solvent is
At least one in benzene, toluene and dimethylbenzene.
In step (2), the temperature of described Intra-molecular condensation is 80~100 DEG C, the reaction time
It it is 1~3 hour.
In step (3), described condensation reaction is carried out in a solvent, described solvent be methyl alcohol,
At least one in ethanol and isopropanol.
In step (3), the temperature of described condensation reaction is 70~100 DEG C, and the reaction time is 3~10
Hour.
In step (4), described acid is p-methyl benzenesulfonic acid, sulfuric acid or phosphoric acid, the most right
Toluenesulfonic acid, when using p-methyl benzenesulfonic acid, reaction yield is the highest.
In step (4), described rearrangement reaction is carried out in a solvent, and described solvent is benzene, first
At least one in benzene and dimethylbenzene.
In step (4), the temperature of described rearrangement reaction is 100~130 DEG C, and the reaction time is 12~24
Hour.
In step (5), described chlorination reagent is POCl3 or thionyl chloride, reaction temperature
For solvent reflux temperature.
The product that step (5) obtains is adopted after being extracted with ethyl acetate, and organic phase does not concentrate and directly adds
Enter alkali to react.
In step (6), described alkali is triethylamine, sodium carbonate or potassium carbonate.
In step (7), described alcoholic solvent is methyl alcohol, ethanol or isopropanol.
The Quetiapine that the present invention obtains obtains half quetiapine fumarate, liquid phase after fumaric acid is acidified into salt
Purity, more than 99%, can apply to field of medicaments.
Compared with the existing technology, beneficial effects of the present invention is embodied in:
(1) initiation material used by is cheap and easy to get, is suitable for large-scale production, decreases preparation cost
Raw material is cheap and easily-available, and 0-chloro-benzoic acid price is 1.25W/ ton, and other route initiation material neighbour's fluorine nitre
Base benzene price is more than 10W/ ton, and cost of material is reduced to only 1/8;
(2) reaction condition is fairly simple, it is easy to operation, does not produce intractable containing in course of reaction
Iron waste liquid, environmentally friendly;
(3) the Quetiapine purity obtained is high, can apply to field of medicaments.
Detailed description of the invention
The preparation of embodiment 1 2-carboxyl diphenyl sulfide (compound II)
By 150mL naphthane, 0-chloro-benzoic acid (15.6g, 0.1mol), copper powder (0.32g, 0.005
Mol) join in reaction bulb, when system is down to about 0 DEG C, under stirring, be sequentially added into hydroxide
Sodium (6.0g, 0.15mol), benzenethiol (11.1g, 0.1mol), it is warming up to 130 DEG C after finishing
Reacting 6 hours (TLC monitoring in course of reaction), react complete cooling, add water 100mL, suction filtration
Removing copper powder, filtrate is layered, and aqueous phase to 2-3, separates out a large amount of white solid with salt acid for adjusting pH,
Suction filtration obtains crude product 20.5g, yield 89%, purity (HPLC): 97.8%.
Molecular formula: C13H10O2S;Molecular weight: 230.0;MS (m/z): 231.0 (M++H)。
The preparation of embodiment 2 thioxanthone (III)
2-carboxyl diphenyl sulfide (23g, 0.1mol, compound II) is joined in reaction bulb, adds
Enter 100mL toluene to dissolve, when ice bath is cooled to about 0 DEG C, drips the 20mL concentrated sulfuric acid, finish
After be warming up to 80 DEG C and continue stirring reaction 1h, the TLC monitoring degree that carries out of reaction, after completion of the reaction,
Being poured into water by reactant, separatory, organic phase is washed to neutrality, is dried, and removes toluene, uses ethanol
It is recrystallized to give faint yellow crude product 16g, yield: 75.5%.Purity (GC): 98.2%.
Molecular formula: C13H8OS;Molecular weight: 212.0;MS (m/z): 213.0 (M+)。
1H NMR(400MHz,CDCl3) δ 8.52 (d, J=8.0Hz, 2H), 7.52-7.43 (m, 4H),
7.37 (t, J=7.6Hz, 2H);13C NMR(100MHz,CDCl3) δ 179.2,137.1,132.1,
129.6,129.0,126.1,125.7;Fusing point: 207.5 DEG C-209.1 DEG C.
The preparation of embodiment 3 thioxanthene ketoxime (compound VI)
Thioxanthone (21.2g, 0.1mol, compound III) is joined in reaction bulb, adds 100
ML ethanol dissolves, and is subsequently adding hydroxylamine hydrochloride (7.65g, 0.11mol, CAS:5470-11-1),
Return stirring reaction 3h, the TLC monitoring degree that carries out of reaction it is warming up to after finishing, after completion of the reaction,
Rotation separates out crystal except major part solvent, cooling, and suction filtration obtains white solid 21.1g, yield: 93%.
Purity (HPLC): 99.1%.
Molecular formula: C13H9NOS;Molecular weight: 227.0;MS (m/z): 228.0 (M+)。
The preparation of embodiment 4 dibenzo [b, f] [1,4] sulphur azatropylidene-11-(10H) ketone (compound V)
Thioxanthene ketoxime (22.7g, 0.1mol, compound IV) is joined in reaction bulb, adds
100mL dry toluene dissolve, be subsequently adding p-methyl benzenesulfonic acid (0.95g, 0.005mol, CAS:
104-15-4), it is warming up to return stirring after finishing and reacts overnight, the degree that TLC monitoring reaction is carried out,
After completion of the reaction, rotation separates out crystal except major part solvent, cooling, and suction filtration obtains white solid 18.5g,
Yield: 81.5%.Purity (HPLC): 97.0%.
Molecular formula: C13H9NOS;Molecular weight: 227.0;MS (m/z): 228.0 (M+)。
The preparation of embodiment 5 dibenzo [b, f] [1,4] sulphur azatropylidene-11-(10H) ketone (compound V)
Thioxanthene ketoxime (22.7g, 0.1mol, compound IV) is joined in reaction bulb, adds
100mL xylene soluble, is subsequently adding glacial acetic acid (0.3g, 0.005mol), is warming up to after finishing
Return stirring reacts overnight, and the degree that TLC monitoring reaction is carried out, after completion of the reaction, rotation is except major part
Solvent, cooling separates out crystal, and suction filtration obtains white solid 17.7g, yield: 78.0%.Purity (HPLC):
95.1%.
Molecular formula: C13H9NOS;Molecular weight: 227.0;MS (m/z): 228.0 (M+)。
The preparation of embodiment 6 dibenzo [b, f] [1,4] sulphur azatropylidene-11-(10H) ketone (compound V)
Thioxanthene ketoxime (22.7g, 0.1mol, compound IV) is joined in reaction bulb, adds
100mL mesitylene dissolve, be subsequently adding p-methyl benzene sulfonic chloride (0.95g, 0.005mol, CAS:
98-59-9), it is warming up to return stirring after finishing and reacts overnight, the degree that TLC monitoring reaction is carried out,
After completion of the reaction, rotation separates out crystal except major part solvent, cooling, and suction filtration obtains white solid 15.2g,
Yield: 67%.Purity (HPLC): 94%.
Molecular formula: C13H9NOS;Molecular weight: 227.0;MS (m/z): 228.0 (M+)。
Embodiment 7 11-chloro-dibenzo [b, f] [1,4] sulphur azatropylidene (compound VI) and Quetiapine (chemical combination
Thing VIII) preparation
By dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene-11-(10H) ketone (11.4g, 50mmol, compound V)
Join in reaction bulb, add POCl3 (40g, 260mmol), be warming up to return stirring anti-
Answering the degree that 4h, TLC monitoring reaction is carried out, after completion of the reaction, rotation, except solvent, cooling, adds
Ethyl acetate and frozen water 150mL, separatory.Organic phase is dried, transfers in reaction bulb, add
Potassium carbonate (2.76g, 0.2mol), under ice-water bath drip N-piperazine ethoxy ethanol (9.63g, 55
Mmol, CAS:13349-82-1), room temperature reaction is overnight.Add water 60mL, separatory, organic relevant
Dry, it is spin-dried for obtaining grease 14.94g, yield: 78%.Purity (HPLC): 96.8%.
Molecular formula: C21H25N3O2S;Molecular weight: 384.2.0;MS (m/z): 385.2 (M+)。
The preparation of embodiment 8 quetiapine hemifumarate (compound I)
Quetiapine (7.66g, 20mmol) is dissolved in ethanol (40mL), adds fumaric acid (1.16
G, 10mmol, CAS:110-17-8), 8h is stirred at room temperature, filters, it is solid that vacuum drying obtains white
Body 8.29g, yield 94%.Purity (HPLC): 99%.
1H NMR(400MHz,DMSO-d6) δ 8.53-8.33 (br, 1H), 7.49-7.27 (m, 5H),
7.16 (m, 2H), 6.98 (dd, J=8.0,1.2Hz, 2H), 6.83 (dd, J=7.6,1.2Hz, 2H), 6.58
(s, 1H), 3.50-3.32 (m, 10H), 2.57-2.44 (m, 6H);13C NMR(100MHz,
DMSO-d6) δ 165.9,159.5,148.0,138.1,133.6,132.9,131.6,131.5,130.7,
128.8,128.5,128.3,126.6,124.6,122.0,71.7,67.2,59.8,56.6,52.2;Fusing point:
173.8℃-175.1℃。
Claims (8)
1. the synthetic method of a Quetiapine, it is characterised in that comprise the following steps:
(1) under the effect of copper catalyst, 0-chloro-benzoic acid and benzenethiol generation coupling reaction,
To 2-carboxyl diphenyl sulfide;
Shown in the structure such as formula (II) of described 2-carboxyl diphenyl sulfide:
(2) under the effect of acid catalyst, the 2-carboxyl diphenyl sulfide that step (1) obtains occurs to divide
Ring closure reaction in son, obtains thioxanthone;
Shown in the structure of described thioxanthone such as formula (III):
(3) thioxanthone step (2) obtained and azanol carry out condensation reaction, obtain thioxanthene
Ketoxime;
Shown in the structure such as formula (IV) of described thioxanthene ketoxime:
(4) thioxanthene ketoxime step (3) obtained carries out rearrangement reaction under conditions of acid exists,
Obtain 10,11-bis-diphenyl hydrogen [b, f] [1,4] oxygen azatropylidene-11-ketone;
Shown in the structure such as formula (V) of described 10,11-bis-diphenyl hydrogen [b, f] [1,4] oxygen azatropylidene-11-ketone:
(5) under chlorination reagent effect, step (4) obtain 10,11-bis-diphenyl hydrogen [b, f] [Isosorbide-5-Nitrae]
Oxygen azatropylidene-11-ketone carries out chlorination, obtains 11-chloro-dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene;
Shown in the structure such as formula (VI) of described 11-chloro-dibenzo [b, f] [1,4] sulphur azatropylidene:
(6) 11-chloro-dibenzo [b, f] [Isosorbide-5-Nitrae] the sulphur azatropylidene in the presence of a base, obtained and 2-(2-hydroxyl
Base oxethyl) ethyl piperazidine reacts, and obtains Quetiapine;
Shown in the structure such as formula (VII) of described 2-(2-hydroxyl-oxethyl) ethyl piperazidine:
Shown in the structure of described Quetiapine such as formula (VIII):
(7) salt is become to obtain with fumaric acid in alcoholic solvent the Quetiapine that step (6) obtains described
Half quetiapine fumarate;
Shown in the structure such as formula (I) of half described quetiapine fumarate:
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (1)
In, described copper catalyst is copper powder, stannous chloride or copper chloride.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (2)
In, described acid catalyst is at least one in the concentrated sulfuric acid and SPA.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (3)
In, described azanol is hydroxylamine hydrochloride or free azanol.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (4)
In, described acid is p-methyl benzenesulfonic acid, sulfuric acid or phosphoric acid.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (5)
In, described chlorination reagent is POCl3 or thionyl chloride.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (6)
In, described alkali is triethylamine, sodium carbonate or potassium carbonate.
The synthetic method of Quetiapine the most according to claim 1, it is characterised in that step (7)
In, described alcoholic solvent is methyl alcohol, ethanol or isopropanol.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109705056A (en) * | 2019-02-25 | 2019-05-03 | 福安药业集团重庆博圣制药有限公司 | A kind of preparation method of half quetiapine fumarate of high-purity |
CN112939892A (en) * | 2021-03-23 | 2021-06-11 | 浙江工业大学 | Preparation method of quetiapine |
CN114149384A (en) * | 2021-02-05 | 2022-03-08 | 南宁师范大学 | Synthetic method of quetiapine |
CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101525333A (en) * | 2009-04-07 | 2009-09-09 | 华东师范大学 | Synthesis method of metixene hydrochloride |
CN101830887A (en) * | 2010-05-25 | 2010-09-15 | 江苏双勤民生冶化设备制造有限公司 | Production process of 2-isopropyl thioxanthone |
-
2016
- 2016-04-29 CN CN201610282040.9A patent/CN105859653B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101525333A (en) * | 2009-04-07 | 2009-09-09 | 华东师范大学 | Synthesis method of metixene hydrochloride |
CN101830887A (en) * | 2010-05-25 | 2010-09-15 | 江苏双勤民生冶化设备制造有限公司 | Production process of 2-isopropyl thioxanthone |
Non-Patent Citations (3)
Title |
---|
JIH RU HWU ET AL.: "Indian Journal of Chemistry", 《BIOCONJUGATE CHEM》 * |
K. NAFARAJAN ET AL.: "Condensed Heterotricycles: Beckmann Rearrangement of Xanthone and Thioxanthone Oximes as a Route to Dibenz[b,f][r,4]-oxazepines and thiazepines", 《INDIAN JOURNAL OF CHEMISTRY》 * |
谭云等: "喹硫平的合成改进研究", 《中国新药杂志》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109705056A (en) * | 2019-02-25 | 2019-05-03 | 福安药业集团重庆博圣制药有限公司 | A kind of preparation method of half quetiapine fumarate of high-purity |
CN114149384A (en) * | 2021-02-05 | 2022-03-08 | 南宁师范大学 | Synthetic method of quetiapine |
CN112939892A (en) * | 2021-03-23 | 2021-06-11 | 浙江工业大学 | Preparation method of quetiapine |
CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
CN114181172B (en) * | 2021-12-27 | 2023-12-22 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
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