CN102443000B - Preparation method of iloperidone - Google Patents
Preparation method of iloperidone Download PDFInfo
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- CN102443000B CN102443000B CN201010297208.6A CN201010297208A CN102443000B CN 102443000 B CN102443000 B CN 102443000B CN 201010297208 A CN201010297208 A CN 201010297208A CN 102443000 B CN102443000 B CN 102443000B
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- XMXHEBAFVSFQEX-UHFFFAOYSA-N CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2cc(F)ccc12)=O Chemical compound CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2cc(F)ccc12)=O XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 1
- 0 CC(c(cc1OC)ccc1OCCC*)=O Chemical compound CC(c(cc1OC)ccc1OCCC*)=O 0.000 description 1
- MRMGJMGHPJZSAE-UHFFFAOYSA-N Fc(cc1)cc2c1c(C1CCNCC1)n[o]2 Chemical compound Fc(cc1)cc2c1c(C1CCNCC1)n[o]2 MRMGJMGHPJZSAE-UHFFFAOYSA-N 0.000 description 1
- DAQWROFRHWHKFE-VBKFSLOCSA-N O/N=C(/C1CCNCC1)\c(ccc(F)c1)c1F Chemical compound O/N=C(/C1CCNCC1)\c(ccc(F)c1)c1F DAQWROFRHWHKFE-VBKFSLOCSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of iloperidone. The method of the invention comprises reacting 2, 4-difluorophenyl(4-piperidyl) ketoxime and 4-chloropropoxy-3-methoxyacetophenone in an aqueous solution of an alkali metal hydroxide, with the concentration of the alkali metal hydroxide maintained at 20-40%. The method provided in the invention has the advantages of simple process, easy operation, high overall yield, and no generation of compound hard to separate during preparation, and can obtain a qualified finished product through simple recrystallization as well as has no need for purification by column chromatography, thus being suitable for industrial production.
Description
Technical field
The invention belongs to field of medicaments.Particularly, the present invention relates to a kind of new method of preparing Zomaril.
Background technology
The chemical name of Zomaril (iloperidone) is 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] propoxy-]-3-p-methoxy-phenyl] ethyl ketone, its chemical structural formula is as follows:
Zomaril has antipsychotic activity, and the clinical III phase demonstrates the tolerance and the security that are better than existing antipsychotics, is expected to become a good antischizophrinic thing.
In U.S. Pat 5776963 and patent families EP402644 thereof, the preparation method of Zomaril is disclosed, its synthetic route is as follows:
The method is with 2,4-difluorobenzene-(4-piperidyl) ketoxime (formula 2 compounds) is raw material, in strong alkali aqueous solution, cyclization obtains the fluoro-3-of 6-(4-piperidyl)-1,2-benzoisoxazole (formula 4 compounds), and then with 4-chlorine propoxy--3-methoxyacetophenone (formula 3 compounds) at N, in dinethylformamide, carry out linked reaction and obtain 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] propoxy-]-3-p-methoxy-phenyl] ethyl ketone (formula 1 compound, i.e. Zomaril).But, the productive rate of the method final step linked reaction is lower, be about for 58% (overall yield is about 46%), this is due to side reaction having occurred, as the auto-polymerization reaction of benzisoxazole derivatives (formula 5 compounds), make aftertreatment difficulty, need to purify through column chromatography, be not suitable for scale operation.
Therefore,, in view of the good prospect in medicine of Zomaril, need to develop a kind of novel method of preparing Zomaril.
Summary of the invention
Therefore, the object of the invention is, a kind of method of preparing Zomaril is provided.
The object of the invention is to realize by the following technical solutions.The invention provides a kind of method of preparing Zomaril, wherein said method comprises the following steps: formula (2) compound or its salt and formula (3) compound are reacted in alkali metal hydroxide aqueous solution, and the concentration of wherein said alkali metal hydroxide is 20-40%:
In its Chinese style (3), X is halogen.
Preferably, the salt of wherein said formula (2) compound is selected from hydrochloride, vitriol, acetate, formate and composition thereof, is preferably selected from hydrochloride and acetate.
Preferably, wherein said alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and their mixture.
Preferably, wherein, with respect to 1g formula (2) compound or its salt, the usage quantity of described alkali metal hydroxide aqueous solution is 5-15g.
Preferably, wherein said formula (2) compound or its salt and formula (3) compound mole proportioning are 1: (1～4).
Preferably, wherein said temperature of reaction is reflux temperature, is generally 110～130 ℃; Reaction times, with the control of TLC point plate, is generally 0.5～3 hour.
Preferably, wherein said method also comprises the step of purifying gained reaction product.
Preferably, wherein said purification step is recrystallization in DMF; Preferably, described recrystallization operation is as follows: reaction product is heated to 80 ℃, stirs 5～15 minutes, filter, refrigerate 10～24 hours, filter, and washing, dry.
In addition, the Zomaril that the present invention also provides aforesaid method to prepare, and a kind of pharmaceutical composition, wherein comprise the Zomaril for the treatment of significant quantity.
In sum, the method for preparing Zomaril provided by the invention, its synthetic line is as follows:
That is to say, method provided by the invention is take formula (2) compound or its salt and formula (3) compound as starting raw material, in certain density alkali metal hydroxide aqueous solution, only need single step reaction, can obtain Zomaril finished product, step is simple to operation, and total recovery is higher, in preparation process, be not difficult to the compound separating, just can obtain the Zomaril finished product of content >=99% (HPLC) by simple recrystallization, without column chromatography purification, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the nuclear magnetic spectrum of the prepared Zomaril of the present invention.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
The method of preparing Zomaril provided by the invention, the raw material [2 using, 4-difluorophenyl (4-piperidyl) ketoxime (formula 2 compounds)] and [4-chlorine propoxy--3-methoxyacetophenone (formula 3 compounds)] can be for any obtainable product of approach that is purchased, or preparation by the following method:
A) preparation of 2,4 difluorobenzene base (4-piperidyl) ketoxime (formula 2 compounds):
30g 2,4 difluorobenzene-(4-piperidyl) ketone hydrochloride, 30g oxammonium hydrochloride and 300ml dehydrated alcohol are mixed, be heated to 80 ℃ of backflows, stir, react 5 hours.Be cooled to room temperature, filter, dry by 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride (formula 2 compound hydrochlorides).The 2,4 difluorobenzene base obtaining (4-piperidyl) ketoxime hydrochloride is mixed with 90ml water, with 30% potassium hydroxide aqueous solution its pH value is adjusted to >=11, filter, 60 ℃ of following vacuum-dryings, obtain white solid 25g.Fusing point is 214～218 ℃ (YRT-3 melting point apparatus), and yield is 91%.
B) preparation of 4-chlorine propoxy--3-methoxyacetophenone (formula 3 compounds):
By 50g 3-methoxyl group-4-hydroxyacetophenone, 40g salt of wormwood, 42ml 1,3-bromo-chloropropane and 250ml acetone mix, and are heated to 56 ℃ of backflows, stir, and react 4 hours.Be cooled to room temperature, filter, concentrate filtrate to dryly, and by resistates molecular distillation, collecting boiling range is 187～190 ℃/1～2mmHg cut, obtains colourless liquid 62.5g, and yield is 86%.
embodiment 1the invention provides the optimization of method
The present embodiment, take potassium hydroxide as example, is investigated the Zomaril yield of preparing under Different Alkali metal hydroxides concentration of aqueous solution.
The potassium hydroxide aqueous solution of different concns (10%, 15%, 20%, 30%, 40%, 50% and 60%) 192g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 25g, stirring heating, be warming up to backflow (approximately 115～120 ℃), react 1.5 hours, (developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially.Stop heating, be cooled to room temperature, filter, be dried to obtain crude product.
Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, and washing is dried to obtain white solid, weighs, and result is as shown in table 1.
The product yield of preparing under the different concentration of potassium hydroxide of table 1
| Concentration of potassium hydroxide (%) | 10 | 15 | 20 | 30 | 40 | 50 | 60 |
| The yield (%) of Zomaril | 34 | 47 | 72 | 76 | 71 | 54 | 46 |
As shown in Table 1, the yield of Zomaril changes along with the potassium hydroxide aqueous solution concentration in when preparation.Working concentration scope, at 20～40% potassium hydroxide aqueous solution, can obtain the Zomaril yield higher than 70%.
Below the invention provides for adopting the specific embodiment that method is prepared Zomaril.
embodiment 2
20% potassium hydroxide aqueous solution 96g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 19.4g, stirring heating, be warming up to backflow (approximately 100～105 ℃), react 3 hours, (developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially.Stop heating, be cooled to room temperature, filter, be dried to obtain crude product 34g.Crude product is added in DMF 120ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 24.2g, yield 71%, content 99.5% (HPLC), fusing point is 118～120 ℃ (YRT-3 melting point apparatus).
Adopt Switzerland Bruker AV400 nuclear magnetic resonance spectrometer to measure product, as shown in Figure 1, concrete data are as follows for its nuclear magnetic spectrum:
1H-NMR(CDCl
3)δ2.018-2.190(m，8H)，2.540-2.587(m，5H)，3.011-3.088(m，3H)，3.896(s，3H)，4.148-4.181(t，2H)，6.897-6.918(d，1H)，7.001-7.240(m，2H)，7.504-7.677(m，3H)。
embodiment 3
40% potassium hydroxide aqueous solution 288g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 38.8g, stirring heating, be warming up to backflow (approximately 110～115 ℃), react 1 hour, (developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially.Stop heating, be cooled to room temperature, filter, be dried to obtain crude product 32g.Crude product is added in DMF 113ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 24.5g, yield 72%, content 99.4% (HPLC) fusing point is 118～120 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
embodiment 4
30% lithium hydroxide aqueous solution 96g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 25.2g, stirring heating, is warming up to backflow (approximately 115～120 ℃), reacts 1.5 hours.(developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially.Stop heating, be cooled to room temperature, filter, be dried to obtain crude product 33g.Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 24.8g, yield 73%, content 99.6% (HPLC) fusing point is 120～121 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
embodiment 5
30% aqueous sodium hydroxide solution 192g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 25g, stirring heating, is warming up to backflow (approximately 115～120 ℃), reacts 1.5 hours.(developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially, stops heating, is cooled to room temperature, filters, and is dried to obtain crude product 33g.Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 25.5g, yield 75%, content 99.5% (HPLC), fusing point is 120～122 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
embodiment 6
30% potassium hydroxide aqueous solution 220g is added in reaction flask, add successively formula (2) compound hydrochloride 22g, formula (3) compound 25g, stirring heating, is warming up to backflow (approximately 115～120 ℃), reacts 1.5 hours.(developping agent: ethyl acetate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially, stops heating to TLC point plate, is cooled to room temperature, filters, and is dried to obtain crude product 32.5g.Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 25g, yield 74%, content 99.5% (HPLC), fusing point is 120～122 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
embodiment 7
30% potassium hydroxide aqueous solution 240g is added in reaction flask, add successively formula (2) compound acetate 24g, formula (3) compound 25g, stirring heating, is warming up to backflow (approximately 115～120 ℃), reacts 1.5 hours.(developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially, stops heating, is cooled to room temperature, filters, and is dried to obtain crude product 33g.Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 25.8g, yield 76%, content 99.5% (HPLC), fusing point is 120～122 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
embodiment 8
30% potassium hydroxide aqueous solution 288g is added in reaction flask, add successively formula (2) compound 19.2g, formula (3) compound 77.6g, stirring heating, is warming up to backflow (approximately 115～120 ℃), reacts 1.5 hours.(developping agent is ethyl acetate to TLC point plate: normal hexane=4: 1) display type (2) chemical combination object point disappears substantially, stops heating, is cooled to room temperature, filters, and is dried to obtain crude product 33g.Crude product is added in DMF 116ml, be heated to 80 ℃, stir 5 minutes, filter, refrigeration is spent the night, and filter next day, washing, be dried to obtain white solid 25.2g, yield 74%, content 99.5% (HPLC), fusing point is 120～122 ℃ (YRT-3 melting point apparatus).Nuclear magnetic spectrum is referring to Fig. 1.
Claims (17)
1. prepare a method for Zomaril, wherein said method comprises the following steps:
Formula (2) compound or its salt and formula (3) compound are reacted in alkali metal hydroxide aqueous solution, and the concentration of wherein said alkali metal hydroxide is 20-40%:
In its Chinese style (3), X is halogen.
2. method according to claim 1, the salt of wherein said formula (2) compound is selected from hydrochloride, vitriol, acetate, formate and composition thereof.
3. method according to claim 1, wherein said alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and their mixture.
4. method according to claim 2, wherein said alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and their mixture.
5. according to the method described in any one in claim 1 to 4, wherein, with respect to 1g formula (2) compound or its salt, the usage quantity of described alkali metal hydroxide aqueous solution is 5-15g.
6. according to the method described in any one in claim 1 to 4, wherein said formula (2) compound or its salt and formula (3) compound mole proportioning are 1:(1～4).
7. method according to claim 5, wherein said formula (2) compound or its salt and formula (3) compound mole proportioning are 1:(1～4).
8. according to the method described in any one in claim 1 to 4, wherein said temperature of reaction is 110～130 ℃.
9. method according to claim 5, wherein said temperature of reaction is 110～130 ℃.
10. method according to claim 6, wherein said temperature of reaction is 110～130 ℃.
11. methods according to claim 7, wherein said temperature of reaction is 110～130 ℃.
12. according to the method described in any one in claim 1 to 4, and the wherein said reaction times is 0.5～3 hour.
13. methods according to claim 5, the wherein said reaction times is 0.5～3 hour.
14. methods according to claim 6, the wherein said reaction times is 0.5～3 hour.
15. methods according to claim 7, the wherein said reaction times is 0.5～3 hour.
16. according to the method described in any one in claim 1 to 4, and wherein said method also comprises the step of purifying gained reaction product.
17. methods according to claim 16, wherein said purification step is recrystallization in DMF.
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| CN201010297208.6A CN102443000B (en) | 2010-09-30 | 2010-09-30 | Preparation method of iloperidone |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735208A (en) * | 2009-12-08 | 2010-06-16 | 华东师范大学 | Method for synthesizing Iloperidone |
| CN101781243A (en) * | 2009-01-20 | 2010-07-21 | 天津药物研究院 | Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate |
| CN101822673A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Iloperidone-containing solid medicinal composition |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781243A (en) * | 2009-01-20 | 2010-07-21 | 天津药物研究院 | Pharmaceutical intermediate, preparation method thereof and method for preparing iloperidone by pharmaceutical intermediate |
| CN101822673A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Iloperidone-containing solid medicinal composition |
| CN101735208A (en) * | 2009-12-08 | 2010-06-16 | 华东师范大学 | Method for synthesizing Iloperidone |
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