CN104710383A - Quetiapine fumarate related substance, preparation method and applications thereof - Google Patents
Quetiapine fumarate related substance, preparation method and applications thereof Download PDFInfo
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- CN104710383A CN104710383A CN201310674510.2A CN201310674510A CN104710383A CN 104710383 A CN104710383 A CN 104710383A CN 201310674510 A CN201310674510 A CN 201310674510A CN 104710383 A CN104710383 A CN 104710383A
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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 fumarate related substance, a preparation method and applications thereof. The structural formula of the substance is represented by the formula I.
Description
Technical field
The present invention relates to the related substances of medicine, particularly relate to a kind of quetiapine fumarate related substance and its production and use.
Background technology
Quetiapine fumarate (Quetiapine Fumarate) (structure is such as formula II Suo Shi), chemical name is 11-[4-[2-(2-hydroxyl-oxethyl)-ethyl]-1-piperazinyl] dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene hemifumarate.Molecular formula C
21h
25n
3o
2s1/2C
4h
4o
4, commodity are called Serouel (Seroquel).Quetiapine fumarate belongs to s-generation atypical antipsychotic agnets, and being the tall and erect class medicine of dibenzothiazepine, is 5HT
2and dopamine D
2receptor antagonist.Be mainly used in clinically treating schizophrenia.
The synthetic route of Quetiapine can be: with dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene (V) is raw material, generates muriate (VI) through phosphorus oxychloride chlorination, VI react generation IV, IV and 2-chloroethoxyethanol with piperazine reacts and generates Quetiapine (II).Wherein VI directly and 2-[2-(1-piperazinyl) oxyethyl group] ethanol synthesis also can obtain Quetiapine.
The Quetiapine meeting generated and intermediate IV reacting generating compound I further, becomes the related substance of Quetiapine.
The existence of related substance is directly connected to quality and the security of medicine, therefore need to carry out the restriction of isolation identification, source analysis, safety research and impurity to determine, complete the work of these complexity, first need to obtain related substance, therefore structure synthesized such as formula the related substance shown in I and as impurity reference substance, the quality control of finished product had great significance.
Therefore, this area is in the urgent need to providing a kind of method that is easy, syntheticcompoundofformulaⅰ effectively.
Summary of the invention
The present invention aims to provide related substance related in quetiapine fumarate synthesis and its production and use.
In a first aspect of the present invention, provide a kind of structure such as formula the compound shown in I,
In a second aspect of the present invention, provide a kind of structure such as formula the compound shown in III,
In a third aspect of the present invention, provide the preparation method of a kind of structure as above such as formula the compound shown in I, described method comprises step: structure reacted in a solvent such as formula the compound shown in IV such as formula the compound shown in III and structure, obtains structure such as formula the compound shown in I; Described reaction is carried out at alkaline condition with under 50 DEG C to the condition of solvent reflux temperature;
In another preference, described alkaline condition has selected N, N-xylidene(s) or triethylamine; More preferably triethylamine.
In another preference, described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; More preferably toluene.
In another preference, described reaction is carried out at 90-120 DEG C; More preferably carry out at 110-115 DEG C.
In another preference, described formula III compound is that structure is obtained such as formula the compound shown in II and the reaction of 2-chloroacetyl chloride; Described reaction is carried out at alkaline condition with under the condition of subzero 5-20 DEG C; Described alkaline condition has selected N, N-xylidene(s) or triethylamine; Preferred triethylamine; Described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; Preferred toluene; Described reaction is carried out at subzero 5-20 DEG C; Preferably carry out at 0-10 DEG C.
In a fourth aspect of the present invention, provide the preparation method of a kind of structure such as formula the compound shown in I, described method comprises step:
(1) structure is reacted such as formula the compound shown in II and 2-chloroacetyl chloride, obtain structure such as formula the compound shown in III; With
(2) structure is reacted such as formula the compound shown in IV such as formula the compound shown in III and structure, obtain structure such as formula the compound shown in I.
In another preference, step (1) is carried out under the condition of subzero 5-20 DEG C; More preferably at 0-10 DEG C; Reaction in step (2) is carried out under the condition of 90-120 DEG C; More preferably at 110-115 DEG C.
In another preference, described alkaline condition has selected N, N-xylidene(s) or triethylamine; More preferably triethylamine.
In another preference, described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; More preferably toluene.
In a fifth aspect of the present invention, provide a kind of if structure is such as formula the purposes of the compound shown in I, for the quality control of structure such as formula compound shown in II; And/or structure such as formula when raw materials of compound shown in II and/or preparation Related substances separation as impurity reference substance.
In a sixth aspect of the present invention, provide a kind of pharmaceutical composition, wherein containing structure such as formula the compound shown in II and structure such as formula the compound shown in I.
In another preference, with the total weight of described pharmaceutical composition, wherein structure is less than or equal to 1% such as formula the content of the compound shown in I; More preferably content is less than or equal to 0.1%.
Accordingly, the invention provides a kind of method that is easy, syntheticcompoundofformulaⅰ effectively.
Embodiment
Contriver through extensive and deep research, easy to use first and effectively method synthesized the related substance related in quetiapine fumarate synthesis technique.On this basis, the present invention is completed.
As used herein, " chemical compounds I ", " type I compound " and " structure is such as formula the compound shown in I " can exchange use, all refer to following compound:
The rest may be inferred, and other compounds using Roman character to represent also are such implications.
The compound that the present invention relates to is listed as follows:
As used herein, " related substance " refers to starting raw material, intermediate, polymer, the side reaction product brought in drug production process, and the degraded product etc. in storage.
Compound and preparation method thereof
The invention provides the related substance related in a kind of quetiapine fumarate synthesis technique, i.e. type I compound, and provide a kind of preparation method of this compound, namely using formula III compound as initiator, in alkaline condition and related solvents, react with formula IV compound and obtain type I compound.
Particularly, the preparation method of type I compound comprises the steps: structure to mix such as formula the compound shown in IV, organic bases and organic solvent such as formula the compound shown in III, structure, and reacting by heating, obtains structure such as formula the compound shown in I.
The organic bases related in above-mentioned preparation method is selected from N, N-xylidene(s) or triethylamine; Preferred triethylamine.The organic solvent related in above-mentioned preparation method is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; Preferred toluene.Temperature of reaction in above-mentioned preparation method is at 50 DEG C of reflux temperatures to organic solvent; Preferably at 90-120 DEG C; More preferably at 110-115 DEG C.Reaction times in above-mentioned preparation method is 12-36 hour; Be preferably 20-30 hour.Further, the reaction solution obtained after above-mentioned preparation method's reacting by heating terminates washes with water, dry, filter, filtrate (oil reservoir) concentrates evaporate to dryness, carries out column chromatography, in one embodiment of the invention, use silica gel column chromatography, such as but not limited to, 200 ~ 300 order silica gel mixed samples, dry method loading, methyl alcohol: chloroform=1:9 is eluent etc., obtains the type I compound that purity is high.
Above-mentioned structure can be obtained by following step such as formula the compound shown in III: after being mixed with organic bases by the solution containing quetiapine fumarate free alkali and organic solvent, adds 2-chloroacetyl chloride and reacts, and obtains structure such as formula the compound shown in III.
The organic solvent related in above-mentioned preparation method is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; Preferred toluene.The organic bases related in above-mentioned preparation method is selected from N, N-xylidene(s) or triethylamine; Preferred triethylamine.The 2-chloroacetyl chloride related in above-mentioned preparation method adds reaction system by the mode dripped, and dropping temperature is 0-10 DEG C, and the reaction times is 1-5 hour.The solution containing quetiapine fumarate free alkali and organic solvent related in above-mentioned preparation method obtains in the following way: after structure is free such as formula the saturated inorganic alkali solution of the compound shown in II, the organic solvent layer obtained with organic solvent extraction; Described mineral alkali is selected from sodium bicarbonate.
The present invention also provides a kind of structure such as formula the preparation method of the compound shown in I, comprises step:
The first step, after being mixed by the solution containing quetiapine fumarate free alkali and organic solvent, adds 2-chloroacetyl chloride and reacts, obtain structure such as formula the compound shown in III with organic bases;
Second step, structure mixed such as formula the compound shown in IV, organic bases and organic solvent such as formula the compound shown in III, structure, reacting by heating, obtains structure such as formula the compound shown in I.
The organic solvent related in above-mentioned two steps can be the same or different, and its Application Range can be described above.
The organic bases related in above-mentioned two steps can be the same or different, and its Application Range can be described above.
Other reaction conditions related in above-mentioned two steps can be described above.
The reaction solution saturated sodium bicarbonate solution obtained in the above-mentioned the first step is washed, dry, filters.Filtrate concentrates evaporate to dryness, directly casts single step reaction.
Purposes
Structure provided by the invention can as impurity reference substance in the bulk drug of quetiapine fumarate and/or preparation are produced such as formula the compound shown in I, to carry out production quality control.
In one embodiment of the invention, provide a kind of pharmaceutical composition, it comprises structure such as formula the compound shown in II and structure such as formula the compound shown in I.In a preference of the present invention, with the total weight of described pharmaceutical composition, wherein structure is less than or equal to 1% such as formula the content of the compound shown in I; Be more preferably less than or equal to 0.1%.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can provide identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Major advantage of the present invention is:
Synthesis quetiapine fumarate related substance 2-[2-[4-(dibenzo [b provided by the invention, f] [1,4] sulphur azatropylidene-11-base) piperazine-1-base] oxyethyl group] ethyl [4-(dibenzo [b, f] [1,4] sulphur azatropylidene-11-base) piperazine-1-base] method of acetic ester, there is the advantages such as with low cost, simple to operate, environmental pollution is little.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or number by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Embodiment 1
The synthesis of 2-[2-[4-(dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene-11-base) piperazine-1-base] oxyethyl group] ethyl 2-chloroethene ester (III)
Quetiapine fumarate (2.0g, 4.5mmol), saturated sodium carbonate solution dissociates, methylbenzene extraction.Separating oil water layer, toluene layer directly throws reaction flask, adds triethylamine (0.55g, 0.54mmol) under stirring, drips chloroacetyl chloride (0.61g, 5.4mmol).Dropping temperature is 0 ~ 10 DEG C.Stir 3h.Reaction solution evaporate to dryness, then adds toluene 30ml and dissolves.Add saturated sodium bicarbonate adjust pH to 7.Separating oil water layer, toluene layer, concentrated evaporate to dryness, obtains brown oil (III) 1.67g(3.63mmol), yield 80.7%.[M+H]
+=460.15。
Embodiment 2
2-[2-[4-(dibenzo [b, f] [1,4] sulphur azatropylidene-11-base) piperazine-1-base] oxyethyl group] synthesis of ethyl [4-(dibenzo [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene-11-base) piperazine-1-base] acetic ester (I)
(III) 1.67g(3.63mmol is added in reaction flask) and toluene 50ml, triethylamine (0.36g, 3.6mmol), IV (1.4g, 3.8mmol).Reflux, stopped reaction after reaction 24h.Washing is added, separating oil water layer in reaction solution.Oil reservoir is dry, concentrated evaporate to dryness; Post is separated, and obtains solid 1.25g(1.74mmol), yield 48%.HPLC purity 99.4%.Fusing point 83 ~ 84 DEG C.[M+H]
+=444.5。
1HNMR(400MHz,CDCl
3)δ:2.37(t,4H),2.65(t,10H),3.31(s,2H),3.63(t,12H),4.28(t,2H),6.87(t,2H),7.07(d,2H),7.15(t,2H),7.82(m,6H),7.39(d,2H),7.51(d,2H)。
Embodiment 3
The synthesis of III
Quetiapine fumarate (1.0g, 2.3mmol), saturated sodium carbonate solution dissociates, methylbenzene extraction.Separating oil water layer, toluene layer directly throws reaction flask; Add N while stirring, N-xylidene(s) (0.65g, 0.54mmol), chloroacetyl chloride (0.3g, 2.8mmol).Drip process control reacting liquid temperature 0 ~ 10 DEG C.Stir 3h, react complete.Reaction solution evaporate to dryness, then adds toluene and dissolves.Add saturated sodium bicarbonate adjust pH to 7.Separating oil water layer, toluene layer concentrates evaporate to dryness, obtains III 0.69g(1.5mmol), yield 65%.[M+H]
+=460.15。
Embodiment 4
The synthesis of I
III 0.69g(1.5mmol is added in reaction flask) and toluene 150ml, IV (0.59g, 1.6mmol).Be heated to 90 DEG C, after reaction terminates, cooling reaction solution, to normal temperature, is washed, separating oil water layer.Oil reservoir concentrates evaporate to dryness; Post is separated, and obtains yellow powdery solid 0.4g(0.56mmol), yield 37.3%.HPLC purity 99.1%.Fusing point 81 ~ 83 DEG C.
Embodiment 5
The synthesis of III
Quetiapine fumarate (1.0g, 2.3mmol), saturated sodium carbonate solution dissociates, methylbenzene extraction.Separating oil water layer, toluene layer evaporate to dryness.Gained Quetiapine oily matter is dissolved in dimethylbenzene 20ml and throws reaction flask, stirs and adds triethylamine (0.55g, 0.54mmol), drips chloroacetyl chloride (0.3g, 2.8mmol).Drip process control reacting liquid temperature 0 ~ 10 DEG C.Stir 3h, react complete.Reaction solution evaporate to dryness, then adds toluene and dissolves.Add saturated sodium bicarbonate adjust pH to 7.Separating oil water layer, toluene layer concentrates evaporate to dryness, obtains brown oil 0.72g(1.56mmol), yield 67.8%.[M+H]
+=460.15。
Embodiment 6
The synthesis of I
(III) 0.72g(1.56mmol is added in reaction flask) and N, N-diformamide 50ml, IV (0.59g, 1.6mmol), triethylamine (0.36g, 3.6mmol).Be heated to 150 DEG C, reaction terminates rear cooling reaction solution to normal temperature, concentrated evaporate to dryness.Add water-toluene to dissolve, washing, separating oil water layer.Oil reservoir is dry, concentrated evaporate to dryness; Post is separated, and obtains yellow powdery solid 0.46g(0.64mmol), yield 41%.HPLC purity 99.3%.Fusing point 83 ~ 84 DEG C.
Embodiment 7
The synthesis of I
(III) 0.72g(1.56mmol is added in reaction flask) and toluene 50ml, IV (0.59g, 1.6mmol), N, N-xylidene(s) (0.65g, 0.54mmol).Reflux, after reaction terminates, reaction solution concentrates evaporate to dryness.Add toluene to dissolve, washing, separating oil water layer.Oil reservoir is dry, concentrated evaporate to dryness; Post is separated, and obtains yellow powdery solid 0.46g(0.64mmol), yield 41%.HPLC purity 99.3%.Fusing point 83 ~ 84 DEG C.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (23)
1. structure is such as formula the compound shown in I,
2. structure is such as formula the compound shown in III,
3. the preparation method of a compound as claimed in claim 1, it is characterized in that, described method comprises step: structure reacted in a solvent such as formula the compound shown in IV such as formula the compound shown in III and structure, obtain compound as claimed in claim 1; Described reaction is carried out at alkaline condition with under 50 DEG C to the condition of solvent reflux temperature;
4. preparation method as claimed in claim 3, it is characterized in that, described alkaline condition has selected N, N-xylidene(s) or triethylamine.
5. preparation method as claimed in claim 4, is characterized in that, select triethylamine.
6. preparation method as claimed in claim 3, is characterized in that, described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide.
7. preparation method as claimed in claim 6, it is characterized in that, described solvent is toluene.
8. preparation method as claimed in claim 3, it is characterized in that, described reaction is carried out at 90-120 DEG C.
9. preparation method as claimed in claim 8, it is characterized in that, described reaction is carried out at 110-115 DEG C.
10. the preparation method as described in any one of claim 3-9, is characterized in that, described formula III compound is that structure is obtained such as formula the compound shown in II and the reaction of 2-chloroacetyl chloride;
11. preparation methods as claimed in claim 10, is characterized in that, described reaction is carried out at alkaline condition with under the condition of subzero 5-20 DEG C.
12. preparation methods as claimed in claim 11, it is characterized in that, described alkaline condition has selected N, N-xylidene(s) or triethylamine; Preferred triethylamine.
13. preparation methods as claimed in claim 11, is characterized in that, described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; Preferred toluene.
14. preparation methods as claimed in claim 11, it is characterized in that, described reaction is carried out at subzero 5-20 DEG C; Preferably carry out at 0-10 DEG C.
The preparation method of 15. 1 kinds of compounds as claimed in claim 1, is characterized in that, described method comprises step:
(1) structure is reacted such as formula the compound shown in II and 2-chloroacetyl chloride, obtain structure such as formula the compound shown in III;
(2) structure is reacted such as formula the compound shown in IV such as formula the compound shown in III and structure, obtain compound as claimed in claim 1.
16. preparation methods as claimed in claim 15, is characterized in that, step (1) is carried out under the condition of subzero 5-20 DEG C; Reaction in step (2) is carried out under the condition of 90-120 DEG C.
17. preparation methods as claimed in claim 16, it is characterized in that, described alkaline condition has selected N, N-xylidene(s) or triethylamine; Preferred triethylamine.
18. preparation methods as claimed in claim 16, is characterized in that, described solvent is selected from following one or more: benzene,toluene,xylene, methyl-sulphoxide, N, N-diformamide; Preferred toluene.
19. preparation methods as claimed in claim 16, it is characterized in that, step (1) is carried out under the condition of 0-10 DEG C; Reaction in step (2) is carried out at 110-115 DEG C.
The purposes of 20. 1 kinds of compounds as shown in claim 1, for the quality control of structure such as formula compound shown in II; And/or structure such as formula when raw materials of compound shown in II and/or preparation Related substances separation as impurity reference substance.
21. 1 kinds of pharmaceutical compositions, wherein containing structure such as formula the compound shown in II and structure such as formula the compound shown in I.
22. pharmaceutical compositions as claimed in claim 21, it is characterized in that, with the total weight of described pharmaceutical composition, wherein structure is less than or equal to 1% such as formula the content of the compound shown in I.
23. pharmaceutical compositions as claimed in claim 22, it is characterized in that, with the total weight of described pharmaceutical composition, wherein structure is less than or equal to 0.1% such as formula the content of the compound shown in I.
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