CN105859653B - A kind of synthetic method of Quetiapine - Google Patents
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- 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
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Abstract
The invention discloses a kind of synthetic methods of Quetiapine to react using cheap 0-chloro-benzoic acid as starting material with benzenethiol, and then cyclization obtains thioxanthone.It resets to obtain key intermediate dibenzo [b through hydroxylamination, Beckmann, f] [1,4] sulphur azatropylidene -11- (10H) ketone, chlorination, then it reacts to obtain Quetiapine in the presence of acid binding agent with 1- (2- hydroxy ethoxy) ethyl piperazidine, obtains product at salt with fumaric acid in dehydrated alcohol system.The raw material of the synthetic method of the Quetiapine is cheap and easy to get, and step is less, and operation is easy, and can be effectively reduced cost.The Quetiapine of the available high-purity of this method, the half quetiapine fumarate liquid phase purity obtained after at salt can be applied to field of medicaments 99% or more.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of synthetic method of Quetiapine.
Background technique
11- { 4- [2- (2- (hydroxy ethoxy) ethyl -1- piperazine] } dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine(structure such as formula
(I) shown in), also known as Quetiapine is sold generally in the form of hemifumarate.It is by Britain AstraZeneca UK
A kind of antipsychotics of limited (AstraZeneca drugmaker) research and development, in November, 1997 list in Britain for the first time, use
To treat schizophrenia, there is stronger antipsycholic action and cause less Extra Pyramidal Syndrome.In 2000, state
It produces after Quetiapine completes I, II clinical trial phase and goes through to list, import Quetiapine also completed registration in the same year and in 2001
It lists at home.
Synthetic method in relation to half quetiapine fumarate, has more document report, and principal synthetic routes have several following.
Route 1: using 2- diaminodiphenyl sulfide as starting material, 2- phenyl is then generated in the presence of a base with phenyl chloroformate
Thio-phenyl phenyl carbamate, then molecule inner ring condensation is carried out by polyphosphoric acids, generate dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine
Zhuo -11- (10H) ketone, uses POCl3Chlorination obtains 11- chlorodiphenyl simultaneously [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene, then reacts with Piperazine anhydrous,
It is further condensed under alkaline condition with 2- (2 '-chloroethoxy) ethyl alcohol up to Quetiapine, Quetiapine is in anhydrous ethanol solvent body
With half fumaric acid at salt getting the product in system.The subsequent improvement to the technique mainly first synthesizes side chain 1- (2- hydroxy ethoxy)
Ethyl piperazidine segment, then simultaneously [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene reacts (WO028458) with 11- chlorodiphenyl.The technique is lacked there are some
Fall into: first is that acylation process uses phenyl chloroformate as acylating reagent, atom utilization is lower；Second is that 2- aminodiphenyl thiophenol is simultaneously
The not common raw material of industry needs to prepare using halogenated nitrobenzene and thiophenol as starting material by condensation, reduction two-step reaction,
Higher cost.
Route 2: the first step first synthesizes 2- phenylthiophenyl phenyl carbamate, is not then direct with above
By cyclizing agent cyclization, but first then intermediate sulphur azepine is obtained by PPA cyclization with side chain N- (2- hydroxyethyl) piperazine condensation
Zhuo, back flow reaction obtains quinoline sulphur under alkaline condition with ethylene glycol after phosphorus oxychloride is to the hydroxy chloride on its side-chain structure
It is flat, product (WO055125) is obtained at salt with half fumaric acid equally in dehydrated alcohol system.But the disadvantage is that the molecule of third step
Interior ring-closure reaction is more difficult, it may be possible to due to first connecing side chain (2- hydroxyethyl) piperazinyl and increase steric hindrance.
Tan Yun etc. proposed route 3 in 2007: using thiosalicylic acid and o-fluoronitrobenzene as raw material, 2- nitro-is made
2 '-carboxyl diphenyl sulfides are restored to obtain 2- amino -2 '-carboxyl diphenyl sulfide with ferrous sulfate, are then dehydrated under effect of sulfuric acid
Cyclization obtains amide, takes off a molecule hydrogen chloride through phosphorus oxychloride chlorination after-condensation and obtains half fumaric acid quinoline at salt with fumaric acid
Sulphur puts down (Chinese Journal of New Drugs 2007,16,867-868).There are two obvious disadvantages for the route: first is that starting material thiosalicylic
Acid and o-fluoronitrobenzene price are higher, improve production cost；Second is that a large amount of iron content waste liquid is had after restoring nitro with iron, it is difficult
With processing.
It can be seen that mainly heptatomic ring key intermediate dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azepine from process above route
The synthesis of Zhuo -11- (10H) ketone, prior art are to use polyphosphoric acids cyclization, or restore nitro with iron mostly, do not meet country
Requirement to environmental protection.
Summary of the invention
The present invention provides a kind of synthetic method of Quetiapine, raw material used in the synthetic method is cheap and easy to get, and
The waste liquid generated in reaction process significantly reduces, to more environment-friendly.
A kind of synthetic method of Quetiapine, comprising the following steps:
(1) under the action of copper catalyst, coupling reaction occurs for 0-chloro-benzoic acid and benzenethiol, obtains 2- carboxyl diphenyl sulfide
Ether；
Shown in the structure such as formula (II) of the 2- carboxyl diphenyl sulfide:
(2) under the action of acid catalyst, it is anti-that intramolecular cyclization occurs for the 2- carboxyl diphenyl sulfide for obtaining step (1)
It answers, obtains thioxanthone；
Shown in the structure of the thioxanthone such as formula (III):
(3) thioxanthone for obtaining step (2) and azanol carry out condensation reaction, obtain thioxanthene ketoxime；
Shown in the structure such as formula (IV) of the thioxanthene ketoxime:
(4) rearrangement reaction is carried out under the conditions of by thioxanthene ketoxime that step (3) obtains existing for the acid, obtains 10,11- bis-
Diphenyl hydrogen [b, f] [1,4] oxygen azatropylidene -11- ketone；
Shown in the structure such as formula (V) of described bis- diphenyl hydrogen of 10,11- [b, f] [1,4] oxygen azatropylidene -11- ketone:
(5) under chlorination reagent effect, 10,11-, bis- diphenyl hydrogen [b, f] [Isosorbide-5-Nitrae] oxygen azatropylidene -11- that step (4) obtains
Ketone carries out chlorination, obtains the chloro- dibenzo of 11- [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene.
Shown in the structure such as formula (VI) of the chloro- dibenzo of the 11- [b, f] [1,4] sulphur azatropylidene:
(6) in the presence of a base, the chloro- dibenzo of the 11- obtained [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene and 2- (2- hydroxyl-oxethyl)
Ethyl piperazidine is reacted, and Quetiapine is obtained；
Shown in the structure such as formula (VII) of described 2- (2- hydroxyl-oxethyl) ethyl piperazidine:
Shown in the structure of the Quetiapine such as formula (VIII):
(7) Quetiapine that step (6) obtains is obtained into the half fumaric acid quinoline sulphur at salt with fumaric acid in alcoholic solvent
It is flat；
Shown in the structure such as formula (I) of half quetiapine fumarate:
The reaction route of the synthetic method is as follows:
Synthetic method of the invention uses cheap and easily-available 0-chloro-benzoic acid as starting material, makees in the copper of catalytic amount
It under, is reacted with benzenethiol, obtains 2- carboxyl diphenyl sulfide, then cyclization obtains thioxanthone under the action of acid catalyst,
Then oxime is obtained with azanol reaction, then using Beckmann reset as committed step obtain key intermediate dibenzo [b,
F] [Isosorbide-5-Nitrae] sulphur azatropylidene -11- (10H) ketone, then chloro, reacts to obtain with raw material of industry 1- (2- hydroxy ethoxy) ethyl piperazidine
Quetiapine, finally and fumaric acid at salt obtains half quetiapine fumarate.The synthesis step of this synthetic method is less, operation
It is easy, therefore the cost of production can be effectively reduced.
In step (1), the type of copper catalyst can generate large effect to reaction yield, and the copper catalyst is copper
Powder, stannous chloride or copper chloride, at this point, the yield of reaction is higher.
In step (1), reaction carries out in a solvent, and the solvent is preferably naphthane.
In step (1), reaction carries out in the presence of alkali, and the alkali is preferably sodium hydroxide.
In step (1), the temperature of reaction is 110~130 DEG C, and reaction temperature is 6~24 hours.
In step (2), the acid catalyst is at least one of the concentrated sulfuric acid and concentrated phosphoric acid.
In step (2), the Intra-molecular condensation carries out in a solvent, and the solvent is benzene, toluene and diformazan
At least one of benzene.
In step (2), the temperature of the Intra-molecular condensation is 80~100 DEG C, and the reaction time is 1~3 hour.
In step (3), the condensation reaction carries out in a solvent, and the solvent is in methanol, ethyl alcohol and isopropanol
At least one.
In step (3), the temperature of the condensation reaction is 70~100 DEG C, and the reaction time is 3~10 hours.
In step (4), the acid is p-methyl benzenesulfonic acid, sulfuric acid or phosphoric acid, most preferably p-methyl benzenesulfonic acid, using pair
Reaction yield highest when toluenesulfonic acid.
In step (4), the rearrangement reaction carries out in a solvent, and the solvent is in benzene, toluene and dimethylbenzene
It is at least one.
In step (4), the temperature of the rearrangement reaction is 100~130 DEG C, and the reaction time is 12~24 hours.
In step (5), the chlorination reagent is phosphorus oxychloride or thionyl chloride, and reaction temperature is solvent refluxing temperature
Degree.
The product that step (5) obtains is adopted be extracted with ethyl acetate after, organic phase, which is not concentrated, to be directly added into alkali and is reacted.
In step (6), the alkali is triethylamine, sodium carbonate or potassium carbonate.
In step (7), the alcoholic solvent is methanol, ethyl alcohol or isopropanol.
The Quetiapine that the present invention obtains obtains half quetiapine fumarate after fumaric acid is acidified into salt, and liquid phase purity is 99%
More than, it can be applied to field of medicaments.
Compared with the existing technology, the beneficial effects of the present invention are embodied in:
(1) starting material used in is cheap and easy to get, is suitble to large-scale production, and it is cheap and easily-available to reduce preparation cost raw material,
0-chloro-benzoic acid price is 1.25W/ tons, and other route starting material o-fluoronitrobenzene prices are greater than 10W/ tons, cost of material
It is reduced to only 1/8；
(2) reaction condition is fairly simple, easily operated, intractable iron content waste liquid is not generated in reaction process, to environment
It is friendly；
(3) the Quetiapine purity is high obtained, can be applied to field of medicaments.
Specific embodiment
The preparation of 1 2- carboxyl diphenyl sulfide (compound II) of embodiment
150mL naphthane, 0-chloro-benzoic acid (15.6g, 0.1mol), copper powder (0.32g, 0.005mol) are added to reaction
In bottle, when system is down to 0 DEG C or so, sequentially added under stirring sodium hydroxide (6.0g, 0.15mol), benzenethiol (11.1g,
0.1mol), 130 DEG C are warming up to after finishing to react 6 hours (TLC is monitored in reaction process), end of reaction is cooling, add water 100mL,
It filters and removes copper powder, a large amount of white solids are precipitated in filtrate layered, water phase salt acid for adjusting pH to 2-3, and 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 2 thioxanthone of embodiment (III)
2- carboxyl diphenyl sulfide (23g, 0.1mol, compound II) is added in reaction flask, it is molten that 100mL toluene is added
When ice bath is cooled to 0 DEG C or so, the 20mL concentrated sulfuric acid is added dropwise in solution, and 80 DEG C are warming up to after finishing and continues to be stirred to react 1h, TLC monitoring
Reactant is poured into water by the degree that reaction carries out after completion of the reaction, and liquid separation, organic phase is washed to neutrality, dry, removes first
Benzene obtains faint yellow crude product 16g, yield: 75.5% with ethyl alcohol recrystallization.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；It is molten
Point: 207.5 DEG C -209.1 DEG C.
The preparation of 3 thioxanthene ketoxime (compound VI) of embodiment
Thioxanthone (21.2g, 0.1mol, compound III) is added in reaction flask, the dissolution of 100mL ethyl alcohol is added, so
Hydroxylamine hydrochloride (7.65g, 0.11mol, CAS:5470-11-1) is added afterwards, return stirring reaction 3h, TLC prison is warming up to after finishing
The degree that reaction carries out is surveyed, after completion of the reaction, rotation is precipitated crystal except most of 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 added in reaction flask, it is molten that 100mL dry toluene is added
Then p-methyl benzenesulfonic acid (0.95g, 0.005mol, CAS:104-15-4) is added in solution, return stirring reaction is warming up to after finishing
Overnight, the degree that TLC monitoring reaction carries out, after completion of the reaction, rotation are precipitated crystal except most of solvent, cooling, and suction filtration obtains white
Color 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 added in reaction flask, it is molten that 100mL dimethylbenzene is added
Then glacial acetic acid (0.3g, 0.005mol) is added in solution, return stirring reaction is warming up to after finishing overnight, and TLC monitoring reaction carries out
Degree, after completion of the reaction, rotation is precipitated crystal except most of solvent, cooling, 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 added in reaction flask, it is molten that 100mL mesitylene is added
Then solution is added p-methyl benzene sulfonic chloride (0.95g, 0.005mol, CAS:98-59-9), it is anti-to be warming up to return stirring after finishing
It should stay overnight, the degree that TLC monitoring reaction carries out, after completion of the reaction, rotation is precipitated crystal except most of 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+)。
The chloro- dibenzo of 7 11- of embodiment [b, f] [1,4] sulphur azatropylidene (compound VI) and Quetiapine (compound
VIII preparation)
Dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene -11- (10H) ketone (11.4g, 50mmol, compound V) is added to reaction
It in bottle, is added phosphorus oxychloride (40g, 260mmol), is warming up to the degree that return stirring reaction 4h, TLC monitoring reaction carries out, instead
After answering, rotation removes solvent, cooling, and ethyl acetate and ice water 150mL, liquid separation is added.Organic phase is dry, it is transferred to reaction flask
In, be added potassium carbonate (2.76g, 0.2mol), be added dropwise under ice-water bath N- piperazine ethoxy ethanol (9.63g, 55mmol, CAS:
13349-82-1), room temperature reaction is stayed overnight.Adding water 60mL, liquid separation, organic phase is 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 8 quetiapine hemifumarate (compound I) of embodiment
Quetiapine (7.66g, 20mmol) is dissolved in ethyl alcohol (40mL), addition fumaric acid (1.16g, 10mmol, CAS:
110-17-8), 8h is stirred at room temperature, filters, vacuum drying obtains white solid 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 DEG C -175.1 DEG C.
Claims (7)
1. a kind of synthetic method of Quetiapine, which comprises the following steps:
(1) under the action of copper catalyst, coupling reaction occurs for 0-chloro-benzoic acid and benzenethiol, obtains 2- carboxyl diphenyl sulfide；
Shown in the structure such as formula (II) of the 2- carboxyl diphenyl sulfide:
(2) under the action of acid catalyst, Intra-molecular condensation occurs for the 2- carboxyl diphenyl sulfide that step (1) obtains, and obtains
Thioxanthone；
Shown in the structure of the thioxanthone such as formula (III):
(3) thioxanthone for obtaining step (2) and azanol carry out condensation reaction, obtain thioxanthene ketoxime；
Shown in the structure such as formula (IV) of the thioxanthene ketoxime:
(4) rearrangement reaction is carried out under the conditions of by thioxanthene ketoxime that step (3) obtains existing for the acid, obtains 10,11- dihydro two
Benzene [b, f] [1,4] oxygen azatropylidene -11- ketone；
Shown in the structure such as formula (V) of described bis- diphenyl hydrogen of 10,11- [b, f] [1,4] oxygen azatropylidene -11- ketone:
In step (4), the acid is p-methyl benzenesulfonic acid；
(5) under chlorination reagent effect, 10,11-, bis- diphenyl hydrogen [b, f] [Isosorbide-5-Nitrae] oxygen azatropylidene -11- ketone that step (4) obtains into
Row chlorination obtains the chloro- dibenzo of 11- [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene；
Shown in the structure such as formula (VI) of the chloro- dibenzo of the 11- [b, f] [1,4] sulphur azatropylidene:
(6) in the presence of a base, the chloro- dibenzo of the 11- obtained [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene and 2- (2- hydroxyl-oxethyl) ethyl
Piperazine is reacted, and Quetiapine is obtained；
Shown in the structure such as formula (VII) of described 2- (2- hydroxyl-oxethyl) ethyl piperazidine:
Shown in the structure of the Quetiapine such as formula (VIII):
(7) Quetiapine that step (6) obtains is obtained into half quetiapine fumarate at salt with fumaric acid in alcoholic solvent；
Shown in the structure such as formula (I) of half quetiapine fumarate:
2. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (1), the copper catalyst
For copper powder, stannous chloride or copper chloride.
3. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (2), the acid catalyst
For at least one of the concentrated sulfuric acid and concentrated phosphoric acid.
4. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (3), the azanol is salt
Sour azanol or free azanol.
5. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (5), the chlorination reagent
For phosphorus oxychloride or thionyl chloride.
6. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (6), the alkali is three second
Amine, sodium carbonate or potassium carbonate.
7. the synthetic method of Quetiapine according to claim 1, which is characterized in that in step (7), the alcoholic solvent is
Methanol, ethyl alcohol or isopropanol.
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| 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 |
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