CN102391242B - Preparation method of stiripentol - Google Patents
Preparation method of stiripentol Download PDFInfo
- Publication number
- CN102391242B CN102391242B CN 201110417419 CN201110417419A CN102391242B CN 102391242 B CN102391242 B CN 102391242B CN 201110417419 CN201110417419 CN 201110417419 CN 201110417419 A CN201110417419 A CN 201110417419A CN 102391242 B CN102391242 B CN 102391242B
- Authority
- CN
- China
- Prior art keywords
- stiripentol
- phase
- peg
- transfer catalyst
- penten
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 40
- 229960001897 stiripentol Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 41
- 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 19
- 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
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 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
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 claims description 26
- 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 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
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 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
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 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
- 230000035484 reaction time Effects 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 5
- 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
- 239000013078 crystal Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 8
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 238000001035 drying 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
- 238000001514 detection method Methods 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
- 230000015572 biosynthetic process Effects 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
- 238000010189 synthetic method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 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
- 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
- 239000004215 Carbon black (E152) Substances 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
- 125000002947 alkylene group Chemical group 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
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 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
- 229930195733 hydrocarbon Natural products 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
Images
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: Stiripentol.This product is water insoluble, dissolves in ethanol, acetone, is applicable to teenager's lafora's disease.Studies show that, 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 Denmark, Finland, Norway, Sweden on July 31st, 2010 in Germany's listing subsequently simultaneously on January 31st, 2008.The structure of stiripentol is as follows:
In prior art, common stiripentol is by piperonylaldehyde and the reaction of methyl-tert butanone, generates 4,4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-the 1-penten-3-one, then it and reduction reagent react are synthesized stiripentol.
The synthetic method of the stiripentol of US Patent No. 3910959 reports is: the mixture of piperonylaldehyde and methyl-tert butanone is dissolved in the ethanol that has added water and sodium hydroxide, be cooled to room temperature, stirring reaction 15 days, obtain 4,4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-the 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 the ethanol that has added sodium hydroxide, be cooled to room temperature, stir 12h under 0 ℃, add entry, then use chloroform extraction, anhydrous MgSO
4Drying is filtered, and underpressure distillation gets intermediate 4,4-dimethyl-1-[(3,4-methylene-dioxy)-phenyl]-the 1-penten-3-one, then obtain stiripentol through sodium borohydride reduction, total recovery 40%.
Analyze the prior art route as can be known, the first step synthetic intermediate 4,4-dimethyl-1-[(3,4-methylene-dioxy)-phenyl]-the 1-penten-3-one is the key problem in technology of whole synthesis technique.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 4,4-dimethyl-1-[(3 in US Patent No. 3910959, the 4-methylene-dioxy)-phenyl]-process of 1-penten-3-one at room temperature carries out, long reaction time, need to stir 15 days, and react and carry out not exclusively, stopped reaction finds to still have more piperonylaldehyde residue by detecting; J.C. prepare 4 in the article that Madelmont etc. delivers, 4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-characteristics of 1-penten-3-one technological operation are to utilize reflux to accelerate speed of reaction, although this method reaction times is short, can complete in 4 hours, but can produce a large amount of piperonylaldehyde disproportionation products (piperitol a, piperinic acid b) (structure is as follows) in 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 to be solved in the present invention is to provide a kind of preparation method of stiripentol, and the present invention is a kind of simple, efficient, can be under the prerequisite that guarantees product yield obvious Reaction time shorten, the stiripentol synthetic method of improving the quality of products.
The technical solution used in the present invention is: a kind of preparation method of stiripentol comprises the following 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]-the 1-penten-3-one;
(2) step (1) is obtained 4,4-dimethyl-1-[(3,4-methylene-dioxy)-phenyl]-the 1-penten-3-one drops in lower alcohol solvent, adds sodium borohydride or POTASSIUM BOROHYDRIDE, makes stiripentol.
The temperature of reaction of preferred step (1) is 25～50 ℃.
Phase-transfer catalyst is quaternary ammonium salt, and general formula is R
4N
+X
-, R is C
1-C
16One or more in chain alkylene, alicyclic hydrocarbon radical or aryl, 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 benzyl tributyl ammonium chloride.
Phase-transfer catalyst is 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 dibenzo hexaoxacyclooctadecane-6-6.
Preferred lower alcohol is a kind of in methyl alcohol, ethanol or Virahol.
Phase-transfer catalyst is polyethylene glycols, a kind of in PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or 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-phase.After adding piperonylaldehyde, due to the piperonylaldehyde poorly water-soluble, can not be dissolved in fully in reaction system, 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, 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.Add phase-transfer catalyst to increase between reaction raw materials contact area with hydroxide ion, thus fast reaction speed.
In stiripentol important intermediate 4,4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-preparation process of 1-penten-3-one in, take piperonylaldehyde and methyl-tert butanone as starting raw material, take lower alcohol (ethanol, methyl alcohol, Virahol) as solvent, accelerate through Catalyzed By Phase-transfer Catalyst under alkaline condition, the Claisen-Schmidt reaction occurs make 4,4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-the 1-penten-3-one, synthetic route is as follows:
Adopt the beneficial effect that technique scheme produces to be: the present invention is a kind of simple, efficient, can be under the prerequisite that guarantees product yield obvious Reaction time shorten, the stiripentol synthetic method of improving the quality of products.Preparation 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
The present invention is further detailed explanation below in conjunction with the drawings and specific embodiments.
Fig. 1 is the amount effect curve figure of the benzyl tributyl ammonium chloride of the embodiment of the present 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;
Y-axis is the reaction times, and X-axis is phase-transfer catalyst and piperonylaldehyde mol ratio.
Embodiment
Embodiment 1
A kind of preparation method of stiripentol comprises the following steps:
(1) the 120g piperonylaldehyde is dropped in the mixed solvent of 0.2L ethanol and 2.4L distilled 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 dehydrated 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) step (1) is obtained 4, 4-dimethyl-1-[(3, the 4-methylene-dioxy)-phenyl]-the 1-penten-3-one drops in 0.8L ethanol, under 25～40 ℃ of stirrings, add sodium borohydride 14.8g in 10 minutes in batches, add sodium borohydride can avoid the too high reaction that causes of partial concn inhomogeneous in batches, add again 0.08L acetone and 0.12L distilled water, stirred 5 minutes under 50 ℃, Bubble formation is arranged, after bubble collapse, continue to add water, there is solid to separate out, after solid is separated out fully, be cooled to room temperature, decompress filter, filter cake carries out recrystallization with the 0.15L dehydrated alcohol, dry, obtain white crystal stiripentol (91.1g altogether, 93.7%).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 distilled 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 dehydrated 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 target product stiripentol with embodiment 1, obtains white crystal stiripentol (88.2g, 90.7%) altogether.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 distilled 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 dehydrated 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 target product stiripentol with embodiment 1, obtains white crystal stiripentol (89.6g, 92.1%) altogether.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 distilled 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 dehydrated 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 target product stiripentol with embodiment 1, obtains white crystal stiripentol (89.0g, 91.5%) altogether.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 distilled 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 dehydrated 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 target product stiripentol with embodiment 1, obtains white crystal stiripentol (8.9g, 91.5%) altogether.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 steps and each parameter are with embodiment 5, and each data see the following form.
Embodiment 10
(1) the 12g piperonylaldehyde is dropped in the mixed solvent of 20mL methyl alcohol and 240mL distilled 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 dehydrated 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 target product stiripentol with embodiment 1, obtains white crystal stiripentol (8.7g, 90.1%) altogether.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 steps 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 steps and each parameter are with embodiment 1.Each data see the following form.
Claims (3)
1. the preparation method of a stiripentol, is characterized in that, comprises the following 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]-the 1-penten-3-one;
(2) step (1) is obtained 4,4-dimethyl-1-[(3,4-methylene-dioxy)-phenyl]-the 1-penten-3-one drops in lower alcohol solvent, adds sodium borohydride or POTASSIUM BOROHYDRIDE, makes stiripentol;
Described phase-transfer catalyst is quaternary ammonium salt, crown ether-like or polyethylene glycols;
Quaternary ammonium salt-type phase transfer catalyst is a kind of in Tetrabutyl amonium bromide, cetyl trimethylammonium bromide, benzyltriethylammoinium chloride or benzyl tributyl ammonium chloride;
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 dibenzo hexaoxacyclooctadecane-6-6;
The polyethylene glycols phase-transfer catalyst is a kind of in PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or PEG-6000;
Described lower alcohol is a kind of in methyl alcohol, ethanol or Virahol.
2. 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.
3. 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 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110417419 CN102391242B (en) | 2011-12-14 | 2011-12-14 | Preparation method of stiripentol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110417419 CN102391242B (en) | 2011-12-14 | 2011-12-14 | Preparation method of stiripentol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102391242A CN102391242A (en) | 2012-03-28 |
| CN102391242B true CN102391242B (en) | 2013-05-08 |
Family
ID=45858648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110417419 Active CN102391242B (en) | 2011-12-14 | 2011-12-14 | Preparation method of stiripentol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102391242B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690252B (en) * | 2012-06-18 | 2014-04-23 | 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 (2)
| 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》.1992,第31卷(第11期),961-966. |
| MARQUAGE PAR 14C et 3H du 4,4-DIMETHYL-l-(METHYLENDIOXY-3,4 PHENYL)-1-PENTENE-3- OL OU STIRIPENTOL;J.C. MADELMONT et al;《Journal of Labelled Compounds and Radiopharmaceuticals》;19921231;第31卷(第11期);961-966 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102391242A (en) | 2012-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN102079737A (en) | Method for preparing apigenin | |
| CN101302207B (en) | Preparation of 3-o-alkyl-5,6-o-(1-methyl ethylidine)-l-ascorbic acid and preparation of 5,6-o-(1- methyl ethylidine)-l- ascorbic acid | |
| CN102391242B (en) | Preparation method of stiripentol | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| CN111559995B (en) | Preparation process of ascorbic acid ethyl ether | |
| CN105906614A (en) | Preparation method of olmesartan medoxomil | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| CN101735165A (en) | Preparation method of 3-morpholone | |
| KR20170029141A (en) | Method for the preparation of high purity Bazedoxifene Acetate | |
| CN103664985A (en) | Stereoselectivity preparation method of beta-hydroxy sweet wormwood herb alkyl ether | |
| CN111925317B (en) | Ropivacaine hydrochloride impurity and preparation method thereof | |
| CN108017549A (en) | A kind of preparation method of 1- aryl -2- amino -1,3- propanediol hydrochloride derivatives | |
| CN108084145A (en) | Ticagrelor midbody and preparation method thereof | |
| CN114163364A (en) | 2-methoxy allyl sulfonic ester and its synthesis method | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN108727445B (en) | Synthesis method of azithromycin impurity F | |
| CN100368375C (en) | 3- alkoxy -4-carbalkoxyphenylacetate and 3-alkoxy-4-carbalkoxyphenylacetic acid synthesis method | |
| CN103450141B (en) | A kind of Benzofurantone compound, its preparation method and application thereof | |
| CN113801104A (en) | Preparation method of epivimos macrocyclic lactone hydrolysis impurities | |
| CN105732613B (en) | A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins | |
| CN109627228A (en) | A kind of synthetic method of 3- oxetanone | |
| US9040739B2 (en) | Catalyst and method for synthesis of lactic acid and its derivatives | |
| CN111592471B (en) | Method for synthesizing cephalosporin active ester intermediate through bromination reaction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JUNLIN PHARMACEUTICAL CO., LTD., HEBEI Free format text: FORMER OWNER: SHIJIAZHUANG BOCE BIOTECHNOLOGY CO., LTD. Effective date: 20140922 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 050000 SHIJIAZHUANG, HEBEI PROVINCE TO: 054300 XINGTAI, HEBEI PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140922 Address after: The 054300 Xingtai city of Hebei province Lincheng County Road Patentee after: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Address before: 050000 dormitory 4-2-103, Hebei Medical University, 361 East Zhongshan Road, Hebei, Shijiazhuang Patentee before: SHIJIAZHUANG BOCE BIO-TECHNOLOGY Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of stilbene alcohol Effective date of registration: 20201209 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020130000027 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210302 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020130000027 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of stilbestrol Effective date of registration: 20210315 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021130000003 |
|
| CP02 | Change in the address of a patent holder |
Address after: No.47 Zhongxing Street, Lincheng Economic Development Zone, Xingtai City, Hebei Province 054300 Patentee after: HEBEI JUNLIN PHARMACEUTICAL Co.,Ltd. Address before: 054300 Beihuan East Road, Lincheng County, Xingtai City, Hebei Province Patentee before: HEBEI JUNLIN PHARMACEUTICAL Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20211110 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2021130000003 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of stilamyl alcohol Effective date of registration: 20211124 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2021130000036 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230103 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2021130000036 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of stilamyl alcohol Effective date of registration: 20230116 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2023130000015 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20231109 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2023130000015 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of sitapenol Effective date of registration: 20231117 Granted publication date: 20130508 Pledgee: Hebei Lincheng Rural Commercial Bank Co.,Ltd. Pledgor: HEBEI JUNLIN PHARMACEUTICAL CO.,LTD. Registration number: Y2023980066388 |