CN102391242A - Preparation method of stiripentol - Google Patents
Preparation method of stiripentol Download PDFInfo
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- CN102391242A CN102391242A CN2011104174193A CN201110417419A CN102391242A CN 102391242 A CN102391242 A CN 102391242A CN 2011104174193 A CN2011104174193 A CN 2011104174193A CN 201110417419 A CN201110417419 A CN 201110417419A CN 102391242 A CN102391242 A CN 102391242A
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- transfer catalyst
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- 229960001897 stiripentol Drugs 0.000 title claims abstract description 45
- IBLNKMRFIPWSOY-FNORWQNLSA-N stiripentol Chemical compound CC(C)(C)C(O)\C=C\C1=CC=C2OCOC2=C1 IBLNKMRFIPWSOY-FNORWQNLSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 51
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012046 mixed solvent Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 3
- 239000011591 potassium Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VJGNLOIQCWLBJR-UHFFFAOYSA-M benzyl(tributyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 VJGNLOIQCWLBJR-UHFFFAOYSA-M 0.000 claims description 5
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000008118 PEG 6000 Substances 0.000 claims description 3
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 claims description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical class 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 2
- VUYXVWGKCKTUMF-UHFFFAOYSA-N tetratriacontaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO VUYXVWGKCKTUMF-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 9
- 230000035484 reaction time Effects 0.000 abstract description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 3
- 239000012279 sodium borohydride Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- LXFNQCGNCFRKRR-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one Chemical compound CC(C)(C)C(=O)C=CC1=CC=C2OCOC2=C1 LXFNQCGNCFRKRR-UHFFFAOYSA-N 0.000 abstract 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 235000019441 ethanol Nutrition 0.000 description 17
- 239000013078 crystal Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010606 normalization Methods 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007323 disproportionation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- -1 stiripentol compound Chemical class 0.000 description 2
- RHBGITBPARBDPH-ZPUQHVIOSA-N (E,E)-piperic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=C2OCOC2=C1 RHBGITBPARBDPH-ZPUQHVIOSA-N 0.000 description 1
- VBIRCRCPHNUJAS-AFHBHXEDSA-N 4-[(1S,3aR,4S,6aR)-4-(1,3-benzodioxol-5-yl)tetrahydrofuro[3,4-c]furan-1-yl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@@H]3[C@@H]([C@H](OC3)C=3C=C4OCOC4=CC=3)CO2)=C1 VBIRCRCPHNUJAS-AFHBHXEDSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 208000005870 Lafora disease Diseases 0.000 description 1
- 208000014161 Lafora myoclonic epilepsy Diseases 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- VPSRGTGHZKLTBU-UHFFFAOYSA-N piperitol Natural products COc1ccc(cc1OCC=C(C)C)C2OCC3C2COC3c4ccc5OCOc5c4 VPSRGTGHZKLTBU-UHFFFAOYSA-N 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HPOHAUWWDDPHRS-UHFFFAOYSA-N trans-piperitol Natural products CC(C)C1CCC(C)=CC1O HPOHAUWWDDPHRS-UHFFFAOYSA-N 0.000 description 1
- BURBOJZOZGMMQF-UHFFFAOYSA-N xanthoxylol Natural products C1=C(O)C(OC)=CC=C1C1C(COC2C=3C=C4OCOC4=CC=3)C2CO1 BURBOJZOZGMMQF-UHFFFAOYSA-N 0.000 description 1
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Abstract
Belonging to the field of organic synthesis, the invention discloses a preparation method of stiripentol. The method comprises the steps of: (1) putting heliotropin and methyl tert-butanone into a mixed solvent of lower alcohol and water, adding a phase-transfer catalyst and alkali, thus obtaining 4, 4-dimethyl-1-[(3, 4-methylenedioxy)-phenyl]-1-penten-3-one; (2) placing the 4, 4-dimethyl-1-[(3, 4-methylenedioxy)-phenyl]-1-penten-3-one obtained in step (1) into a lower alcohol solvent, and adding sodium borohydride or potassium borohydride, thus obtaining stiripentol. Characterized by simplicity and high efficiency, the synthesis method of stiripentol in the invention can obviously shorten the reaction time under the premise of an ensured product yield, and can improve product quality.
Description
Technical field
The present invention relates to a kind of preparation method of stiripentol, belong to the organic synthesis field.
Background technology
Stiripentol, English name: Stiripentol, chemical name: 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-amylene-3-alcohol.These article are water insoluble, dissolve in ethanol, acetone, are applicable to teenager's lafora's disease.Research shows, the antiepileptic action of stiripentol a little less than, but when itself and other antiepileptic drug share, can play synergy, and reduce these Side effects of pharmaceutical drugs.This medicine went on the market in Germany on January 31st, 2008, went on the market simultaneously in Denmark, Finland, Norway, Sweden on July 31st, 2010 subsequently.The structure of stiripentol is following:
Common stiripentol is by piperonylaldehyde and the reaction of methyl-tert butanone in the prior art, generates 4, and 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one synthesizes stiripentol with it and reduction reagent react again.
The compound method of the stiripentol of U.S. Pat 3910959 reports is: the mixture of piperonylaldehyde and methyl-tert butanone is dissolved in the ethanol liquid that has added water and sodium hydroxide, is cooled to room temperature, stirring reaction 15 days; Obtain 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one; Then in methanol solution; Obtain stiripentol through sodium borohydride reduction, 93 ℃ of fusing points, total recovery 63%.
J.C.Madelmont once published an article on Journal of Lab-elled Compounds and Radiopharmaceuticals; Introduce piperonylaldehyde and methyl-tert butanone reflux 4h in having added the ethanol liquid of sodium hydroxide; Be cooled to room temperature, stir 12h down, add entry at 0 ℃; Use chloroform extraction then, anhydrous MgSO
4Drying is filtered, and underpressure distillation gets midbody 4, and 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one obtains stiripentol through sodium borohydride reduction, total recovery 40% again.
Analyzing the prior art route can know, the first step synthetic intermediate 4, and [(3, the 4-methylene-dioxy)-phenyl]-the 1-penten-3-one is the key problem in technology of whole synthesis technique to 4-dimethyl--1-.This step reaction type belongs to the Claisen-Schmidt reaction, and speed of response is slow, follows the rising of temperature of reaction and the prolongation in reaction times, and piperonylaldehyde disproportionation reaction by product can obviously increase, and the yield of finished product and purity all are affected.Prepare 4 in the U.S. Pat 3910959, the process of 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one is at room temperature carried out; Long reaction time; Need to stir 15 days, and react and carry out not exclusively, stopped reaction is after detection finds to still have more piperonylaldehyde residue; J.C. prepare 4 in the article that Madelmont etc. delivers; The characteristics of 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one technological operation are to utilize reflux to accelerate speed of reaction, though this method reaction times is short; Can accomplish in 4 hours; But it is can produce a large amount of piperonylaldehyde disproportionation products (piperitol a, piperinic acid b) (structure is following) in the reflux course, and necessary after the reaction end
Through column chromatographic isolation and purification, just can obtain target compound, yield is low, and therefore complex operation is not suitable for suitability for industrialized production.
Summary of the invention
The technical problem that the present invention will solve provides a kind of preparation method of stiripentol, and the present invention is a kind of simple, efficient, can under the prerequisite that guarantees product yield, obviously shorten the reaction times, the stiripentol compound method of improving the quality of products.
The technical scheme that the present invention taked is: a kind of preparation method of stiripentol may further comprise the steps:
(1) piperonylaldehyde and methyl-tert butanone are dropped in the mixed solvent of lower alcohol and water, add phase-transfer catalyst and alkali, make 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one;
(2) with step (1) obtain 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one drops in the lower alcohol solvent, adds Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, makes stiripentol.
The temperature of reaction of preferred step (1) is 25～50 ℃.
Phase-transfer catalyst is a quaternary ammonium salt, and general formula is R
4N
+X
-, R is C
1-C
16In chain alkylene, alicyclic hydrocarbon radical or the aryl one or more, X are Cl, Br, I or HSO
4In a kind of.
Quaternary ammonium salt-type phase transfer catalyst is a kind of in Tetrabutyl amonium bromide, cetyl trimethylammonium bromide, benzyltriethylammoinium chloride or the benzyl tributyl ammonium chloride.
Phase-transfer catalyst is a crown ether-like, and general formula is (C
2H
4O-)
n, n is 1,2,3,4,5 or 6.
Crown ether-like phase transfer catalysts is a kind of in 15-crown ether-5, hexaoxacyclooctadecane-6-6,12-crown ether-4, dicyclohexyl hexaoxacyclooctadecane-6-6 or the dibenzo hexaoxacyclooctadecane-6-6.
Preferred lower alcohol is a kind of in methyl alcohol, ethanol or the Virahol.
Phase-transfer catalyst is a polyethylene glycols, a kind of among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or the PEG-6000.
The mol ratio of preferred phase-transfer catalyst and piperonylaldehyde is 0.005～0.014:1.
Lower alcohol and water are miscible in theory, and piperonylaldehyde dissolves in lower alcohol, so reaction solution should become homogeneous phase.But, the formation sodium hydroxide solution that can be dissolved in the water after sodium hydroxide adds, sodium hydroxide solution and lower alcohol do not dissolve each other under finite concentration, so that the reaction solution layering, are two phases.After adding piperonylaldehyde, because the piperonylaldehyde poorly water-soluble can not be dissolved in the reaction system fully, therefore, reaction system is three-phase (solid phase, organic phase, water).The Claisen-Schmidt speed of response is slower; And require to carry out at certain alkaline environment; If piperonylaldehyde can not dissolve fully, then more be unfavorable for contacting with hydroxide ion between reaction raw materials, cause speed of reaction further to descend; Therefore, cause long-time reaction can not reach the reaction end result.Adding phase-transfer catalyst increases between reaction raw materials the contact area with hydroxide ion, thus fast reaction speed.
In stiripentol important intermediate 4, in the preparation process of 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one; With piperonylaldehyde and methyl-tert butanone is starting raw material, is solvent with lower alcohol (ethanol, methyl alcohol, Virahol), quickens through phase-transfer catalyst catalysis under the alkaline condition; The Claisen-Schmidt reaction takes place make 4; 4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one, synthetic route is following:
Adopt the beneficial effect that technique scheme produced to be: the present invention is a kind of simple, efficient, can under the prerequisite that guarantees product yield, obviously shorten the reaction times, the stiripentol compound method of improving the quality of products.Preparing method's total recovery of stiripentol disclosed by the invention can reach more than 75%, and the stiripentol purity of preparation can reach more than 99.0% after using the organic solvent primary crystallization.
Description of drawings
Below in conjunction with accompanying drawing and embodiment the present invention is done further detailed explanation.
Fig. 1 is the amount effect curve figure of the benzyl tributyl ammonium chloride of the embodiment of the invention 15～18;
Fig. 2 is the amount effect curve figure of hexaoxacyclooctadecane-6 of the present invention-6;
Fig. 3 is PEG-6000 amount effect curve figure of the present invention;
The Y axle is the reaction times, and the X axle is phase-transfer catalyst and piperonylaldehyde mol ratio.
Embodiment
Embodiment 1
A kind of preparation method of stiripentol may further comprise the steps:
(1) the 120g piperonylaldehyde is dropped in the mixed solvent of 0.2L ethanol and 2.4L zero(ppm) water, add 160g solid NaOH, 2.6g benzyl tributyl ammonium chloride and 120g methyl-tert butanone, in 40 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 16h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (172.5g, 93.2%), 93.7～95.1 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) with step (1) obtain 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one drops in the 0.8L ethanol, under 25～40 ℃ of stirrings; Add Peng Qinghuana 14.8g in 10 minutes in batches, add Peng Qinghuana in batches and can avoid the too high reaction that causes of partial concn inhomogeneous, add 0.08L acetone and 0.12L zero(ppm) water again, 50 ℃ were stirred 5 minutes down; Have bubble to produce, treat bubble collapse after, continue to add water, have solid to separate out; After treating that solid is separated out fully, be cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.15L absolute ethyl alcohol; Drying obtains white crystal stiripentol (91.1g, 93.7%) altogether.M.p. 74.7～75.5 ℃ of IR:KBr ν (cm-1): 3520 (OH), 3005～3060 (CH ar), 2800～2960 (CH), 1595 (C=C), purity 99.6% (HPLC area normalization method).
Embodiment 2
(1) the 120g piperonylaldehyde is dropped in the mixed solvent of 0.2L ethanol and 2.4L zero(ppm) water, add 160g solid NaOH, 2.84g cetyl trimethylammonium bromide and 120g methyl-tert butanone, in 40 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 32h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (167.6g, 90.1%), 93.5～95.3 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) step of synthetic title product stiripentol obtains white crystal stiripentol (88.2g, 90.7%) altogether with embodiment 1.M.p. 74.5～75.6 ℃, purity 99.7% (HPLC area normalization method).
Embodiment 3
(1) the 120g piperonylaldehyde is dropped in the mixed solvent of 0.2L ethanol and 2.4L zero(ppm) water, add 160g solid NaOH, 2.82g Tetrabutyl amonium bromide and 120g methyl-tert butanone, in 40 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 108h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (166.6g, 89.7%), 93.5～95.3 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) step of synthetic title product stiripentol obtains white crystal stiripentol (89.6g, 92.1%) altogether with embodiment 1.M.p. 74.5～75.7 ℃, purity 99.5% (HPLC area normalization method).
Embodiment 4
(1) the 120g piperonylaldehyde is dropped in the mixed solvent of 0.2L ethanol and 2.4L zero(ppm) water, add 160g solid NaOH, 2.56g benzyltriethylammoinium chloride and 120g methyl-tert butanone, in 40 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 21h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (168.5g, 91.1%), 93.5～95.2 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) step of synthetic title product stiripentol obtains white crystal stiripentol (89.0g, 91.5%) altogether with embodiment 1.M.p. 75.5～76.7 ℃, purity 99.6% (HPLC area normalization method).
Embodiment 5
(1) the 12g piperonylaldehyde is dropped in the mixed solvent of 20mL methyl alcohol and 240mL zero(ppm) water, add 16g solid NaOH, 0.11g18-crown ether-6 and 12g methyl-tert butanone, in 35 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 46h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (16.6g, 90.9%), 94.5～95.4 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) step of synthetic title product stiripentol obtains white crystal stiripentol (8.9g, 91.5%) altogether with embodiment 1.M.p. 75.5～76.7 ℃, purity 99.6% (HPLC area normalization method).
Embodiment 6～9
Add different crown ether-like phase transfer catalysts, other reactions step and each parameter are with embodiment 5, and each data see the following form.
(1) the 12g piperonylaldehyde is dropped in the mixed solvent of 20mL methyl alcohol and 240mL zero(ppm) water, add 16g solid NaOH, 0.24gPEG-6000 and 12g methyl-tert butanone, in 35 ℃ of stirring reactions.(developping agent: petroleum ether-ethyl acetate (6:1)), the 72h afterreaction is complete for the TLC detection reaction.Reaction solution is cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.12L absolute ethyl alcohol; Drying obtains yellow needle crystal 4,4-dimethyl--1-[(3; The 4-methylene-dioxy)-phenyl]-1-penten-3-one (15.9g, 85%), 93.7～95.4 ℃ of m.p..ESI-MS(m/z):?233.1[M+H]+,?255.1[M+Na]+。
(2) step of synthetic title product stiripentol obtains white crystal stiripentol (8.7g, 90.1%) altogether with embodiment 1.M.p. 75.5～76.7 ℃, purity 99.6% (HPLC area normalization method).
Embodiment 11～14
Add different polyethylene glycols phase-transfer catalysts, other reactions step and each parameter are with embodiment 10.Each data see the following form.
Embodiment 15～18
Add the benzyl tributyl ammonium chloride of various dose, other reactions step and each parameter are with embodiment 1.Each data see the following form.
Claims (9)
1. the preparation method of a stiripentol is characterized in that, may further comprise the steps:
(1) piperonylaldehyde and methyl-tert butanone are dropped in the mixed solvent of lower alcohol and water, add phase-transfer catalyst and alkali, make 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one;
(2) with step (1) obtain 4,4-dimethyl--1-[(3, the 4-methylene-dioxy)-phenyl]-1-penten-3-one drops in the lower alcohol solvent, adds Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN, makes stiripentol.
2. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, described phase-transfer catalyst is a quaternary ammonium salt, and general formula is R
4N
+X
-, R is C
1-C
16In chain alkylene, alicyclic hydrocarbon radical or the aryl one or more, X are Cl, Br, I or HSO
4In a kind of.
3. the preparation method of a kind of stiripentol according to claim 2; It is characterized in that said quaternary ammonium salt-type phase transfer catalyst is a kind of in Tetrabutyl amonium bromide, cetyl trimethylammonium bromide, benzyltriethylammoinium chloride or the benzyl tributyl ammonium chloride.
4. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, described phase-transfer catalyst is a crown ether-like, and general formula is (C
2H
4O-)
n, n is 1,2,3,4,5 or 6.
5. the preparation method of a kind of stiripentol according to claim 4 is characterized in that, described crown ether-like phase transfer catalysts is a kind of in 15-crown ether-5, hexaoxacyclooctadecane-6-6,12-crown ether-4, dicyclohexyl hexaoxacyclooctadecane-6-6 or the dibenzo hexaoxacyclooctadecane-6-6.
6. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, said lower alcohol is a kind of in methyl alcohol, ethanol or the Virahol.
7. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, described phase-transfer catalyst is a polyethylene glycols, a kind of among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or the PEG-6000.
8. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, the mol ratio of phase-transfer catalyst and piperonylaldehyde is 0.005～0.014:1.
9. the preparation method of a kind of stiripentol according to claim 1 is characterized in that, the temperature of reaction of step (1) is 25～50 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690252A (en) * | 2012-06-18 | 2012-09-26 | 湖南大学 | Preparation method of stiripentol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910959A (en) * | 1972-02-28 | 1975-10-07 | Unicler | 1-(3,4-Methylenedioxy-phenyl)-4,4-dimethyl-pent-1-en-3-ol |
-
2011
- 2011-12-14 CN CN 201110417419 patent/CN102391242B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910959A (en) * | 1972-02-28 | 1975-10-07 | Unicler | 1-(3,4-Methylenedioxy-phenyl)-4,4-dimethyl-pent-1-en-3-ol |
Non-Patent Citations (1)
| Title |
|---|
| J.C. MADELMONT ET AL: "MARQUAGE PAR 14C et 3H du 4,4-DIMETHYL-l-(METHYLENDIOXY-3,4 PHENYL)-1-PENTENE-3- OL OU STIRIPENTOL", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, vol. 31, no. 11, 31 December 1992 (1992-12-31), pages 961 - 966 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690252A (en) * | 2012-06-18 | 2012-09-26 | 湖南大学 | Preparation method of stiripentol |
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