JPS62294637A - Purification of crude iburpofen - Google Patents
Purification of crude iburpofenInfo
- Publication number
- JPS62294637A JPS62294637A JP13869786A JP13869786A JPS62294637A JP S62294637 A JPS62294637 A JP S62294637A JP 13869786 A JP13869786 A JP 13869786A JP 13869786 A JP13869786 A JP 13869786A JP S62294637 A JPS62294637 A JP S62294637A
- Authority
- JP
- Japan
- Prior art keywords
- ibuprofen
- inorganic oxide
- crude
- contacting
- crude ibuprofen
- 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.)
- Granted
Links
- 238000000746 purification Methods 0.000 title description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 30
- 229910052809 inorganic oxide Inorganic materials 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 4
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 3
- 239000011973 solid acid Substances 0.000 claims abstract description 3
- 229910052814 silicon oxide Inorganic materials 0.000 claims abstract 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000000377 silicon dioxide Substances 0.000 abstract description 4
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 2
- 239000002221 antipyretic Substances 0.000 abstract description 2
- 238000009835 boiling Methods 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QEGNUYASOUJEHD-UHFFFAOYSA-N 1,1-dimethylcyclohexane Chemical compound CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 description 2
- VTMSSJKVUVVWNJ-UHFFFAOYSA-N 1-ethenyl-4-(2-methylpropyl)benzene Chemical compound CC(C)CC1=CC=C(C=C)C=C1 VTMSSJKVUVVWNJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229910021536 Zeolite Inorganic materials 0.000 description 2
- -1 alicyclic hydrocarbons Chemical class 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 description 1
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 description 1
- CBKUDUSUCXBKIE-UHFFFAOYSA-N 2-[4-(2-methylpropyl)phenyl]ethanol Chemical compound CC(C)CC1=CC=C(CCO)C=C1 CBKUDUSUCXBKIE-UHFFFAOYSA-N 0.000 description 1
- DMZVZANOMJGHKO-UHFFFAOYSA-N 2-[4-(2-methylpropyl)phenyl]propanal Chemical compound CC(C)CC1=CC=C(C(C)C=O)C=C1 DMZVZANOMJGHKO-UHFFFAOYSA-N 0.000 description 1
- WRJZDDJYWWJLIS-UHFFFAOYSA-N 4-methyl-1-phenylpentan-1-one Chemical compound CC(C)CCC(=O)C1=CC=CC=C1 WRJZDDJYWWJLIS-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 239000002734 clay mineral Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940100890 silver compound Drugs 0.000 description 1
- 150000003379 silver compounds Chemical class 0.000 description 1
- IIPUSGONQVNOBE-UHFFFAOYSA-M sodium;3-methyl-3-[4-(2-methylpropyl)phenyl]oxirane-2-carboxylate Chemical compound [Na+].C1=CC(CC(C)C)=CC=C1C1(C)C(C([O-])=O)O1 IIPUSGONQVNOBE-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
３、発明の詳細な説明
［産業上の利用分野］
本発明は、解熱剤や鎮痛剤などの医薬品として使用され
る粗イブプロフェンの精製方法に関するものである。更
に詳しくは、合成過程から得ら九る粗イブプロフェン中
に含まれる不純物を除去し、使用目的に合った純度まで
効率よく精製する方法を提供するものである。Detailed Description of the Invention 3. Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for purifying crude ibuprofen used as a pharmaceutical such as an antipyretic and analgesic. More specifically, it provides a method for removing impurities contained in crude ibuprofen obtained from the synthesis process and efficiently purifying it to a purity suitable for the intended use.
［従来の技術およびその問題点］
従来から、イブプロフェンの合成については、種々の方
法が提案されている。[Prior art and its problems] Conventionally, various methods have been proposed for the synthesis of ibuprofen.
例えば、イソブチルベンゼンを塩化アルミニウム触媒の
存在下で塩化アセチルによってアセチル化したイソブチ
ルアセトフェノンを出発原料とする方法としては、クロ
ロ酢酸と反応させるタルツエン反応を組合わせた特公昭
４７−２４５５０号、特公昭５：ｌ−：１５０６９号お
よびフランス特許第１５４９７５８号公報等に記載され
た方法がある。また、最終製品であるイブプロフェンに
するための酸化方法としては、銀化合物を用いる特開昭
４９−９５９３１１号、特開昭５８−３５１４０号およ
びフランス特許第１５４５２７０号公報、過マンガン酸
塩を用いる特開昭５１−１０００４２号、特開昭５１−
１０１９４９号および特開昭５２−９７９３０号公報、
ならびにクロム酸などの酸化剤を用いる特開昭５１−１
００４２号、特開昭５３−７６４３号および特開昭５４
−３９０４３号公報、およびヒドロキシルアミンを用い
る特開昭５２−１３１５５３号公報等が例として挙げら
れる。For example, a method using isobutylacetophenone, which is obtained by acetylating isobutylbenzene with acetyl chloride in the presence of an aluminum chloride catalyst, as a starting material includes Japanese Patent Publications No. 47-24550 and Japanese Patent Publication No. 5, which combine the tartzene reaction with chloroacetic acid. There are methods described in :l-:15069 and French Patent No. 1549758. In addition, the oxidation method for producing the final product ibuprofen includes Japanese Patent Application Laid-open Nos. 49-959311 and 1982-35140 using silver compounds, French Patent No. 1545270, and oxidation methods using permanganate. 1973-100042, JP-A-51-
No. 101949 and Japanese Patent Application Laid-open No. 52-97930,
and JP-A-51-1 using an oxidizing agent such as chromic acid.
No. 0042, JP-A-53-7643 and JP-A-54
Examples include JP-A-39043 and JP-A-52-131553, which uses hydroxylamine.
医薬品として使用されるイブプロフェンは、高い純度と
高い安全性とが要求されており、このために、日本薬局
方、米国薬局方などには薄層クロマトグラフィによる純
度試験が厳密に規定されている。従って、医薬品として
使用できる品質にするためには、微量不純物の除去が重
要なこととなる。Ibuprofen used as a pharmaceutical is required to have high purity and high safety, and for this reason, the Japanese Pharmacopoeia, the United States Pharmacopoeia, etc. strictly stipulate purity testing by thin layer chromatography. Therefore, in order to obtain a quality that can be used as a pharmaceutical product, it is important to remove trace impurities.
前記のイブプロフェンの合成に関する従来技術は、いず
れも化学的な意味でイブプロフェンを与えるものであり
、医薬品としての精製にまで完成された技術は言えない
。The conventional techniques for synthesizing ibuprofen described above all provide ibuprofen in a chemical sense, and cannot be said to be a technique that has been perfected to purify it as a pharmaceutical product.
通常は、精製操作として再結晶が行なわれているが、し
かし再結晶による精製では、濾別された結晶に不純物の
濃縮された濾液が付着残留することは避けられない。従
って、結晶純度を上げるだに回収率を犠牲にしても、再
結晶操作を繰り返すか、改めて結晶を洗浄するなどの手
段が採用されている。Usually, recrystallization is performed as a purification operation, but in purification by recrystallization, it is inevitable that the filtrate containing concentrated impurities remains attached to the filtered crystals. Therefore, measures such as repeating the recrystallization operation or washing the crystals anew are employed, even if the crystal purity is increased at the expense of the recovery rate.
従って、高純度イブプロフェンを効率よく得るための方
法が望まれている。本発明者らは、合成工程で得られた
粗イブプロフェンの効率的な絹製法について検討した結
果、効率のよい方法を見出し本発明を完成したものであ
る。Therefore, a method for efficiently obtaining high purity ibuprofen is desired. The present inventors investigated an efficient method for producing silk from crude ibuprofen obtained in the synthesis process, and as a result found an efficient method and completed the present invention.
［問題点を解決するための手段］
すなわち、本発明は粗イブプロフェンを、比表面積５０
ｍ’／ｇ以上の５１． ＡｌおよびＭｇの酸化物から
なる群の少なくとも一種の無機酸化物と接触させること
を特徴とする粗イブプロフェンの精製方法を提供するも
のである。[Means for solving the problems] That is, the present invention provides crude ibuprofen with a specific surface area of 50
m'/g or more 51. The present invention provides a method for purifying crude ibuprofen, which comprises contacting the crude ibuprofen with at least one inorganic oxide of the group consisting of oxides of Al and Mg.
本発明で使用する酸化物は、シリカ、アルミナまたはマ
グネシアからなる無機酸化物である。これらの無機酸化
物は合成無機鉱物あるいは天然無機鉱物である。合成無
機鉱物として、例えば、シリカゲル、アルミナ、マグネ
シアおよびシリカアルミナ、シリカマグネシア、合成ゼ
オライト等が挙げられる。また、天然無機鉱物の例とし
ては、活性白土、酸性白土、天然ゼオライトのような粘
土鉱物が挙げられる。これらの無機酸化物の中では酸性
活性のあるいわゆる固体酸か好ましい。The oxide used in the present invention is an inorganic oxide consisting of silica, alumina or magnesia. These inorganic oxides are synthetic inorganic minerals or natural inorganic minerals. Examples of synthetic inorganic minerals include silica gel, alumina, magnesia, silica alumina, silica magnesia, and synthetic zeolite. Further, examples of natural inorganic minerals include clay minerals such as activated clay, acid clay, and natural zeolite. Among these inorganic oxides, so-called solid acids having acidic activity are preferred.
本発明の無機酸化物としては、比表面積が５０ＩＩ＋２
７ｇ以上のものを使用する。比表面積が５０ ｒｎ２／
ｇ未満のものでは、精製の効果が著しく低下するので好
ましくない。The inorganic oxide of the present invention has a specific surface area of 50II+2
Use 7g or more. Specific surface area is 50 rn2/
If it is less than 1 g, the purification effect will be significantly reduced, which is not preferable.
精製のための接触はイブプロフェンを溶媒に溶解した状
態で行う。これらの溶媒としては、イブプロフェンを溶
解するものであれば適宜に選択できるか、脂肪族炭化水
素、脂環族炭化水素、芳香族炭化水素、ハロゲン化炭化
水素などのような非極性溶媒中で接触させるこヒか好ま
しい。このような溶媒としては、例えば、ヘキサン、ヘ
プタン、オクタンなどの脂肪族炭化水素；シクロヘキサ
ン、メチルシクロヘキサン、ジメチルシクロヘキサン、
デカリンなどの脂環族炭化水素；ヘンゼン、トルエン、
キシレンなとの芳香族炭化水素；クロロホルム、四塩化
炭素、ジクロルメタン、トリクレンなとのハロゲン化炭
化水素が例示される。これらの中ても精製物からの分離
の容易さの点から低沸点の溶媒がより好ましい。Contact for purification is performed with ibuprofen dissolved in a solvent. These solvents can be selected as appropriate as long as they dissolve ibuprofen, or they can be contacted with non-polar solvents such as aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, etc. It is preferable to let it go. Such solvents include, for example, aliphatic hydrocarbons such as hexane, heptane, octane; cyclohexane, methylcyclohexane, dimethylcyclohexane,
Alicyclic hydrocarbons such as decalin; Hensen, toluene,
Examples include aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, and trichlene. Among these, low boiling point solvents are more preferred from the viewpoint of ease of separation from purified products.
接触させる時間および無機酸化物の添加量は、反応工程
で得られた粗イブプロフェンに含まれる不純物の量によ
り適宜選択できる。The contact time and the amount of inorganic oxide added can be appropriately selected depending on the amount of impurities contained in the crude ibuprofen obtained in the reaction step.
しかしながら、無機酸化物の添加量は、粗イブプロフェ
ンに対して、通常１〜５０重量％であり接触時間は１０
分以上であればよい。また接触温度は常温から１５０℃
であるか、加熱することか好ましく、溶媒を還流させつ
つ無機酸化物と接触させることが適当である。接触圧力
は、処理温度で液相を保つ圧力であれば十分である。However, the amount of inorganic oxide added is usually 1 to 50% by weight based on crude ibuprofen, and the contact time is 10% by weight.
It is sufficient if it is at least 1 minute. Also, the contact temperature ranges from room temperature to 150℃.
It is preferable to heat the solution or to heat it, and it is appropriate to bring the solvent into contact with the inorganic oxide while refluxing the solvent. The contact pressure is sufficient as long as it maintains the liquid phase at the processing temperature.
無機酸化物と粗イブプロフェンを接触させる方法として
は、バッチ式または固定床流通式のいずれの方法による
こともできる。The method for bringing the inorganic oxide and crude ibuprofen into contact may be either a batch method or a fixed bed flow method.
なお、本発明の方法においては、従来公知の方法による
粗イブプロフェンの再結晶の方法を適宜組合せることも
可能である。In addition, in the method of the present invention, it is also possible to appropriately combine methods for recrystallizing crude ibuprofen using conventionally known methods.
［発明の効果］
本発明の方法によれば、反応工程から得られた徂イブプ
ロフェンから、簡単な操作によって純度の高いイブプロ
フェンを得ることかできる。[Effects of the Invention] According to the method of the present invention, highly pure ibuprofen can be obtained from the ibuprofen obtained from the reaction step by a simple operation.
［実施例］ 以下、実施例によって本発明を説明する。[Example] The present invention will be explained below with reference to Examples.
（１）２− （４−イソブチルフェニル）プロピオンア
ルデヒド（以下ＩＰＮという）の合成＝（ａ）特公昭４
７−２４５５０号公報に記載された方法に準じて行なっ
た。(1) Synthesis of 2-(4-isobutylphenyl)propionaldehyde (hereinafter referred to as IPN) = (a) Japanese Patent Publication No. 4
This was carried out according to the method described in Japanese Patent No. 7-24550.
ナトリウムを乾ｙＡ＝囲気中でイソプロパツールに溶解
し、これを冷却する。その溶液に４−イソブチルアセト
フェノンとクロル酢酸エチルの混合物を滴下する。次に
温度を高め、これを還流する。Sodium is dissolved in isopropanol in a dry atmosphere and it is cooled. A mixture of 4-isobutylacetophenone and ethyl chloroacetate is added dropwise to the solution. The temperature is then increased and the mixture is refluxed.
イソプロパツールの一部を蒸発除去した後、トルエンと
水を加え、攪拌冷却し静置した後トルエン層を分離する
。これを水洗し、トルエンを蒸発分離する。残留物に対
してエタノールおよびＮａＯＨを加え還流する。エタノ
ールの一部を蒸発除去して冷却し、３−（４−イソブチ
ルフェニル）−２，３−エポキシ酪酸ナトリウムの結晶
を得た。After a portion of isopropanol is removed by evaporation, toluene and water are added, stirred, cooled, and left to stand, and the toluene layer is separated. This is washed with water and the toluene is separated by evaporation. Ethanol and NaOH are added to the residue and refluxed. A portion of the ethanol was removed by evaporation and the mixture was cooled to obtain crystals of sodium 3-(4-isobutylphenyl)-2,3-epoxybutyrate.
特開昭５７−３１６３９号公報に記載された方法に準じ
て、前記結晶を希塩酸と共に炭酸ガスの発生が停止する
まで還流させた。冷却後、有機層をジクロロメタンおよ
び水で洗浄し、乾燥後減圧蒸留によってＩＰＮを得た。According to the method described in JP-A-57-31639, the crystals were refluxed with dilute hydrochloric acid until the generation of carbon dioxide gas ceased. After cooling, the organic layer was washed with dichloromethane and water, dried, and then distilled under reduced pressure to obtain IPN.
（ｂ）特開昭５２−５１３３１３号および特開昭５２−
９７９３０号公報に記載された方法に準じて行なった。(b) JP-A-52-513313 and JP-A-52-
This was carried out according to the method described in Japanese Patent No. 97930.
２−（４−イソブチルフェニル）エチルアルコールにジ
メチルスルホキシドと重合禁止剤としてｍ−ジニトロベ
ンゼンを加えて加熱攪拌した。反応液を冷却し、水で希
釈した後ベンゼンで抽出し、減圧で蒸留し、４−イソブ
チルスチレンを得た。Dimethyl sulfoxide and m-dinitrobenzene as a polymerization inhibitor were added to 2-(4-isobutylphenyl)ethyl alcohol, and the mixture was heated and stirred. The reaction solution was cooled, diluted with water, extracted with benzene, and distilled under reduced pressure to obtain 4-isobutylstyrene.
４−イソブチルスチレン、キシレン、ヒドリドカルボニ
ルトリストリフェニルフォスフインロジウムを耐圧容器
に入れ、（：０／Ｈ２（１： １モル比）でカルボニル
化しＩＰＮを得た。4-isobutylstyrene, xylene, and rhodium hydridocarbonyltristriphenylphosphine were placed in a pressure container and carbonylated with (:0/H2 (1:1 molar ratio)) to obtain IPN.
（２）ＪＰＮの酸化
（イ）特開昭５３−１８５：１４号公報に記載さ九た方
法に準じて行なった。(2) Oxidation of JPN (a) This was carried out according to the method described in JP-A-53-185:14.
製造例（１）の（ａ）で得ら九たＩＰＮをアセトンに溶
解し、酢酸を加え、冷却しなからＮａ０（：１の１２％
水溶液を滴下した。反応終了後アセトンを蒸発除去し、
Ｎａ０）１水溶液でｐｌ＝ １０にし、ヘキサンで洗浄
した後、ｐｌ＝３になるように硫酸を加え分離したイブ
プロフェンをヘキサンで抽出し、水洗した。ヘキサンを
蒸発除去して粗イブプロフェンの結晶を得た。The IPN obtained in (a) of Production Example (1) was dissolved in acetone, acetic acid was added, and after cooling, 12% of Na0 (:1) was dissolved.
An aqueous solution was added dropwise. After the reaction is complete, acetone is removed by evaporation,
After adjusting the PL to 10 with a Na0)1 aqueous solution and washing with hexane, sulfuric acid was added so that the PL was 3, and the separated ibuprofen was extracted with hexane and washed with water. Hexane was removed by evaporation to obtain crude ibuprofen crystals.
（ロ）特開昭５２−１：１１５５３号公報に３己載され
た方法に準じて行なった。(b) The method was carried out in accordance with the method described in JP-A-52-1:11553.
製造例（１）の（ｂ）で得られたＪＰＮをエタノールに
溶解し、攪拌しつつＮＨ２ＯＨ−ＨＣｌを常温で添加し
た。添加終了後、Ｎａ叶氷水溶液加えて中和し油層を分
離した。この油層を予め調製したＫＯＨ水溶液に加え、
加熱して分解させた。アンモニアの発生が終った時点で
、水およびトルエンを加え水層を分離した。水層をトル
エンで洗浄し、ｐＨ＝２になるように硫酸を加えて分離
したイブプロフェンをヘキサンで抽出し、水洗後ヘキサ
ンを除去して粗イブプロフェンの結晶を得た。JPN obtained in Production Example (1) (b) was dissolved in ethanol, and NH2OH-HCl was added at room temperature while stirring. After the addition was completed, an aqueous sodium ice solution was added to neutralize the mixture, and the oil layer was separated. Add this oil layer to a previously prepared KOH aqueous solution,
It was heated and decomposed. When the generation of ammonia ended, water and toluene were added and the aqueous layer was separated. The aqueous layer was washed with toluene, sulfuric acid was added to adjust the pH to 2, and the separated ibuprofen was extracted with hexane. After washing with water, the hexane was removed to obtain crystals of crude ibuprofen.
（ハ）特開昭５２−９７９３０号公報に記載された方法
に準じて行なった。(c) It was carried out according to the method described in JP-A-52-97930.
製造例（１）の（ｂ）で得られたＩＰＮを希硫酸に入れ
冷却し、激しく攪拌しなからＫＭｎＯｎ粉末を加えた。The IPN obtained in Production Example (1) (b) was placed in dilute sulfuric acid, cooled, and stirred vigorously before adding KMnOn powder.
反応終了後ベンゼンを加え、油分を水洗した。に２Ｃ０
３水溶液で酸性部を抽出し、酸性にした後、更にベンゼ
ンで抽出した。その後ベンゼンを蒸発除去し粗イブプロ
フェンを得た。After the reaction was completed, benzene was added and the oil was washed with water. 2C0 to
After extracting the acidic part with 3 aqueous solution and making it acidic, it was further extracted with benzene. Thereafter, benzene was removed by evaporation to obtain crude ibuprofen.
（比較例）
ヘキサン５０ｍ１に、製造例（２）の（イ）、（ロ）お
よび（ハ）で得られた粗イブプロフェン５ｇを溶解させ
た後、０℃に放置して結晶を析出させた。結晶を濾別し
減圧で乾燥した。続いてこの操作を繰り返し、精製イブ
プロフェンの結晶について、日本薬局方のイブプロフェ
ンの項に規定されている方法で薄層クロマト試論を行な
った。(Comparative Example) After dissolving 5 g of crude ibuprofen obtained in (a), (b), and (c) of Production Example (2) in 50 ml of hexane, the solution was left at 0° C. to precipitate crystals. The crystals were filtered off and dried under reduced pressure. Subsequently, this operation was repeated, and the purified ibuprofen crystals were subjected to thin layer chromatography using the method specified in the section on ibuprofen in the Japanese Pharmacopoeia.
クロマトの結果を第１表に示す。The chromatographic results are shown in Table 1.
ヘキサン１００ｍ１に、製造例（２）の（イ）、（ロ）
および（ハ）で得られた粗イブプロフェン５ｇと第２表
に示す無機酸化物０．２５ ｇとを加えて３時間還流し
た。冷却後、無Ｒ酸化物を濾別し、ヘキサンを５０〜５
５ｍ１蒸発分離し、残ったヘキサン溶液を０℃に放置し
て結晶を析出させた。Add (a) and (b) of Production Example (2) to 100ml of hexane.
5 g of the crude ibuprofen obtained in (c) and 0.25 g of the inorganic oxide shown in Table 2 were added, and the mixture was refluxed for 3 hours. After cooling, remove R-free oxides by filtration, and remove hexane from 50 to 50%
5ml was evaporated and the remaining hexane solution was left at 0°C to precipitate crystals.
結晶を濾別し、減圧で乾燥した。The crystals were filtered off and dried under reduced pressure.
結晶の収率については、上記各比較例および本実施例に
おいてほぼ同一であった。The yield of crystals was almost the same in each of the above comparative examples and this example.
得られた結晶について同様に日本薬局方に従って薄層ク
ロマト試験を行なった。その結果を第２表に示す。The obtained crystals were similarly subjected to thin layer chromatography tests according to the Japanese Pharmacopoeia. The results are shown in Table 2.
Claims (2)
上のＳｉ、ＡｌおよびＭｇの酸化物からなる群の少なく
とも一種の無機酸化物と接触させることを特徴とする粗
イブプロフェンの精製方法。(1) A method for purifying crude ibuprofen, which comprises contacting crude ibuprofen with at least one inorganic oxide of the group consisting of oxides of Si, Al, and Mg having a specific surface area of 50 m^2/g or more.
である特許請求の範囲第１項記載の粗イブプロフェンの
精製方法。(2) The method for purifying crude ibuprofen according to claim 1, wherein the inorganic oxide is an inorganic oxide having solid acid activity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61138697A JPH0657670B2 (en) | 1986-06-14 | 1986-06-14 | Purification method of crude ibuprofen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61138697A JPH0657670B2 (en) | 1986-06-14 | 1986-06-14 | Purification method of crude ibuprofen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62294637A true JPS62294637A (en) | 1987-12-22 |
| JPH0657670B2 JPH0657670B2 (en) | 1994-08-03 |
Family
ID=15228006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61138697A Expired - Lifetime JPH0657670B2 (en) | 1986-06-14 | 1986-06-14 | Purification method of crude ibuprofen |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0657670B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5151551A (en) * | 1990-09-06 | 1992-09-29 | Hoechst Celanese Corporation | Method for purification of ibuprofen comprising mixtures |
| WO2007042445A1 (en) * | 2005-10-11 | 2007-04-19 | Basf Se | Method for the production of directly compressible ibuprofen formulations |
| CN102701948A (en) * | 2012-06-14 | 2012-10-03 | 山东新华制药股份有限公司 | Refining method for ibuprofen production |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5363343A (en) * | 1976-11-12 | 1978-06-06 | Mitsui Toatsu Chem Inc | Preparation of alpha-phenylpropionic acid derivs. |
-
1986
- 1986-06-14 JP JP61138697A patent/JPH0657670B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5363343A (en) * | 1976-11-12 | 1978-06-06 | Mitsui Toatsu Chem Inc | Preparation of alpha-phenylpropionic acid derivs. |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5151551A (en) * | 1990-09-06 | 1992-09-29 | Hoechst Celanese Corporation | Method for purification of ibuprofen comprising mixtures |
| WO2007042445A1 (en) * | 2005-10-11 | 2007-04-19 | Basf Se | Method for the production of directly compressible ibuprofen formulations |
| US8846085B2 (en) | 2005-10-11 | 2014-09-30 | Basf Se | Method for production of directly compressible ibuprofen formulations |
| CN102701948A (en) * | 2012-06-14 | 2012-10-03 | 山东新华制药股份有限公司 | Refining method for ibuprofen production |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0657670B2 (en) | 1994-08-03 |
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