CN85102263A - Synthetic technique for " new cinnarizine " - Google Patents
Synthetic technique for " new cinnarizine " Download PDFInfo
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- CN85102263A CN85102263A CN 85102263 CN85102263A CN85102263A CN 85102263 A CN85102263 A CN 85102263A CN 85102263 CN85102263 CN 85102263 CN 85102263 A CN85102263 A CN 85102263A CN 85102263 A CN85102263 A CN 85102263A
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- cinnarizine
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Abstract
New cinnarizine is a cerebrovascular new drug, with the cinnarizine ratio, and advantage such as it is higher to have drug effect, and side effect is littler.The present invention is initiation material with DDM, passes through diazotising, adds reactions steps such as thermal decomposition, bromination, condensation, makes and obtains new cinnarizine.
Description
The invention belongs to meticulous organic chemical industry (medicine is synthetic) field.
French Patent (FRP) (Fr.Demande) 2,014,487.
Janssen，Paul A.J.
N-arallyl-N '-aralkyl Piperazines et laurs comPositions Pharmaceutiques.(classification number C 07 d 51/00).
17 aPr.1970;20PP.
The synthetic of the new cinnarizine of cerebrovascular new drug (Flunarizine) disclosed, be make 4,4 '-difluorodiphenyl chloromethanes and cinnamyl
Piperazine is at methyl.Condensation in the isobutyl ketone generates new cinnarizine.As 4,4 of raw material '-the difluorodiphenyl chloromethanes, then be by 4,4 '-difluoro diphenyl methanol and hydrochloric acid effect and obtain.Its reaction equation is:
The shortcoming of this synthesis technique be used initiation material 4,4 '-the difluoro diphenyl methanol market supply has any problem, be with just making than the multistep synthetic reaction.
The present invention be with 4,4 '-MDA (being called for short DDM) be an initiation material, passes through following reactions steps, makes the new cinnarizine of cerebrovascular new drug.New synthesis process be make DDM the cooling under and sodium nitrite and fluoboric acid effect, obtain the diazonium fluoride borate (I) of DDM, (I) adds thermal decomposition, generate 4,4 '-difluoro-diphenylmethane (II), under heating and rayed (II) and bromine effect obtain 4,4 '-difluorodiphenyl Celfume (III), (III) and cinnamyl
Piperazine is condensation in acetone, just generates new cinnarizine.Its reaction equation is:
The new synthesis process of new cinnarizine is compared with original technology, difference has been conversion initiation material.New technology is initiation material with DDM, and it is the intermediate of dye industry, and industrial goods are arranged, and price is cheap, and supply fully.Because the aromatics fluoride generally is to be obtained by the Xi Man reaction,, is adapted at China and uses so new synthesis process reduces by two step synthetic reactions than former technology.To use DDM instead be raw material after fluoridize, bromination just can be used in production with the synthetic method of former technology.Moreover, it is solvent that the condensation reaction of new technology is used acetone instead, than former technology methyl.Isobutyl ketone is a solvent, not only can reduce production costs, and post processing is become different.In a word, the outstanding advantage of the new synthesis process of new cinnarizine has provided the synthetic method of a new cinnarizine that uses in being fit to produce.
Embodiment:
40 gram DDM and 168 milliliter of 40% fluoboric acid and 800 ml waters are added respectively in the reaction bulb, slowly drip 28.8 gram sodium nitrite solutions being no more than under 5 ℃ the temperature.Reaction is finished, and takes out Lu, drying, gets about 72 grams of diazonium fluoride borate (I), productive rate 90%.
(I) and the sodium fluoride that is equivalent to its weight 0.5%～1% are mixed, in flask at the bottom of the garden, add thermal decomposition, must be right through steam distillation, right ' difluoro-diphenylmethane (II) 25 grams, 29～30.5 ℃ of fusing points.
The two-step reaction gross production rate is 60%.
In reaction bulb, add (II) 20.4 grams, use rayed, and be not higher than under 170 ℃ the temperature slowly Dropwise 5 milliliter bromine.154-7 ℃/100mm Hg fraction is collected in reaction Bi Jinhang distilling under reduced pressure.Must be right, right '-difluorodiphenyl Celfume (III) 24 grams, productive rate 85%.
With 21.3 grams (III), 30.3 gram cinnamyls
Piperazine, about 250 milliliters of acetone add respectively in the reaction bulb, widely different stream 4 hours, and reaction is finished, and takes out the Lu.The Lu slag is a cinnamyl
The piperazine hydrobromate can obtain cinnamyl through neutralization
Piperazine.Lu liquid is poured in the conical flask, feeds dry hydrogen chloride, and extremely regeneration only is not precipitated as.Take out Lu, airing, new cinnarizine crude product 32 grams, through ethyl alcohol recrystallization, about 20 grams of new cinnarizine elaboration, yield is about 56%, 201～206 ℃ of fusing points (capillary tube method).The structure that meets new cinnarizine through the NMR spectroscopic assay.
From the mother solution of recrystallization, still can obtain being equivalent to 5% product through concentrating again recrystallization.
The total recovery of four-step reaction is about 28.5～31%.
Claims (5)
1, a kind of employing DDM has been a raw material, through the certain reaction step, makes the new technique for synthesizing that obtains the new cinnarizine of cerebrovascular new drug, it is characterized in that making DDM and sodium nitrite and fluoboric acid effect, obtain the diazonium fluoride borate (I) of DDM, (I) adds thermal decomposition, generates 4,4 '-difluoro-diphenylmethane (II), (II) and bromine effect, obtain 4,4 '-difluorodiphenyl Celfume (III), (III) and cinnamyl piperazine condensation in acetone just generate new cinnarizine.Its reaction equation is:
2, according to the new technique for synthesizing of the said new cinnarizine of claim 1,, during the diazonium fluoride borate (I) of preparation DDM, it is characterized in that reaction remains on-2 ℃～5 ℃ and carries out by DDM and sodium nitrite and fluoboric acid effect.
3, according to the new technique for synthesizing of the said new cinnarizine of claim 1, add thermal decomposition, when synthetic (II), it is characterized in that heating-up temperature remains on 60～180 ℃ by (I).
4, according to the new technique for synthesizing of the said new cinnarizine of claim 1, during by (II) bromination synthetic (III), it is characterized in that reaction temperature is 120～180 ℃, its optimum temperature is 150 ± 4 ℃.
5, according to the new technique for synthesizing of the said new cinnarizine of claim 1, by (III) and cinnamyl
The piperazine condensation when generating new cinnarizine, is characterized in that with acetone be the condensation reaction solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN85102263A CN85102263B (en) | 1985-04-01 | 1985-04-01 | Synthetic technique for "new cinnarizine" |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN85102263A CN85102263B (en) | 1985-04-01 | 1985-04-01 | Synthetic technique for "new cinnarizine" |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85102263A true CN85102263A (en) | 1986-05-10 |
| CN85102263B CN85102263B (en) | 1988-03-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85102263A Expired CN85102263B (en) | 1985-04-01 | 1985-04-01 | Synthetic technique for "new cinnarizine" |
Country Status (1)
| Country | Link |
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| CN (1) | CN85102263B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254152A (en) * | 2013-03-19 | 2013-08-21 | 珠海保税区丽珠合成制药有限公司 | New synthesis method of cinnarizine |
| CN103265820A (en) * | 2013-05-23 | 2013-08-28 | 大连理工大学 | Method for preparing azo dye with alkalescent arylamine serving as diazotization ingredient |
| CN110713470A (en) * | 2019-11-02 | 2020-01-21 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
-
1985
- 1985-04-01 CN CN85102263A patent/CN85102263B/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254152A (en) * | 2013-03-19 | 2013-08-21 | 珠海保税区丽珠合成制药有限公司 | New synthesis method of cinnarizine |
| CN103254152B (en) * | 2013-03-19 | 2016-01-27 | 珠海保税区丽珠合成制药有限公司 | A kind of novel method of synthesizing CN |
| CN103265820A (en) * | 2013-05-23 | 2013-08-28 | 大连理工大学 | Method for preparing azo dye with alkalescent arylamine serving as diazotization ingredient |
| CN103265820B (en) * | 2013-05-23 | 2014-07-30 | 大连理工大学 | Method for preparing azo dye with alkalescent arylamine serving as diazotization ingredient |
| CN110713470A (en) * | 2019-11-02 | 2020-01-21 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
| CN110713470B (en) * | 2019-11-02 | 2022-01-18 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN85102263B (en) | 1988-03-23 |
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