JPS6224431B2 - - Google Patents
Info
- Publication number
- JPS6224431B2 JPS6224431B2 JP52016141A JP1614177A JPS6224431B2 JP S6224431 B2 JPS6224431 B2 JP S6224431B2 JP 52016141 A JP52016141 A JP 52016141A JP 1614177 A JP1614177 A JP 1614177A JP S6224431 B2 JPS6224431 B2 JP S6224431B2
- Authority
- JP
- Japan
- Prior art keywords
- solvent
- water
- reflux
- reaction
- acetate
- 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.)
- Expired
Links
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 12
- KEVYVLWNCKMXJX-ZCNNSNEGSA-N Isophytol Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)C=C KEVYVLWNCKMXJX-ZCNNSNEGSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 229940087168 alpha tocopherol Drugs 0.000 claims description 6
- 239000002808 molecular sieve Substances 0.000 claims description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 6
- 229960000984 tocofersolan Drugs 0.000 claims description 6
- 239000002076 α-tocopherol Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BOTWFXYSPFMFNR-PYDDKJGSSA-N phytol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO BOTWFXYSPFMFNR-PYDDKJGSSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 claims description 3
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 claims description 3
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 claims description 3
- BOTWFXYSPFMFNR-OALUTQOASA-N all-rac-phytol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)=CCO BOTWFXYSPFMFNR-OALUTQOASA-N 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- AUFZRCJENRSRLY-UHFFFAOYSA-N 2,3,5-trimethylhydroquinone Chemical compound CC1=CC(O)=C(C)C(C)=C1O AUFZRCJENRSRLY-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- -1 acetate ester compound Chemical class 0.000 description 8
- 235000005074 zinc chloride Nutrition 0.000 description 7
- 239000011592 zinc chloride Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QHMGJGNTMQDRQA-UHFFFAOYSA-N dotriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC QHMGJGNTMQDRQA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
【発明の詳細な説明】
本発明は、高純度d1―α―トコフエロールの
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing high purity d1-α-tocopherol.
従来d1―α―トコフエロールの製造法として
は、２，３，５―トリメチル―1.4―ハイドロキ
ノン（以下トリメチルハイドロキノンと略称す
る）とフイトール類とを酢酸エチル、酢酸ブチル
等の酢酸エステル化合物、ジオキサン等のエーテ
ル化合物、ベンゼン、トルエン等の芳香族炭化水
素化合物、メチルエチルケトン等のケトン化合物
などの溶媒を使用して、塩化亜鉛、三弗化ほう素
エーテル錯体等のルイス酸またはルイス酸と塩
酸、硫酸等のプロトン酸との複合触媒等の触媒の
存在下で縮合する方法が知られている。これらの
縮合方法によればかなり高い収率でd1―α―ト
コフエロールが得られることも公知である。 Conventionally, d1-α-tocopherol has been produced by mixing 2,3,5-trimethyl-1,4-hydroquinone (hereinafter abbreviated as trimethylhydroquinone) and phytols with an acetate ester compound such as ethyl acetate or butyl acetate, or with an acetate compound such as dioxane. Using solvents such as ether compounds, aromatic hydrocarbon compounds such as benzene and toluene, and ketone compounds such as methyl ethyl ketone, Lewis acids such as zinc chloride and boron trifluoride ether complexes, or Lewis acids and hydrochloric acid, sulfuric acid, etc. A method of condensation in the presence of a catalyst such as a composite catalyst with a protonic acid is known. It is also known that d1-α-tocopherol can be obtained in fairly high yields by these condensation methods.
最近は分析技術の進歩等にともない、より一層
高純度の商品が要求されるようになつている。 Recently, with advances in analytical technology, products with even higher purity are required.
しかしながら従来の方法ではその要求を満すこ
とは極めて困難である。例えばd1―α―トコフ
エリルアセテートに関するアメリカ国民医薬品集
（National Formula 14 edition）の規格によれ
ば、ガスクロマトグラフイーによる純度96％以上
有することが要求されているが、従来の方法によ
る場合は高真空蒸留等の精製技術を駆使しても収
率の低下を来たすのみで、かかる高純度のd1―
α―トコフエリル―アセテートを得ることは極め
て困難である。 However, it is extremely difficult to meet this requirement using conventional methods. For example, according to the American National Formula 14 edition standard for d1-α-tocopheryl acetate, it is required to have a purity of 96% or more by gas chromatography, but when using conventional methods, high vacuum Even if purification techniques such as distillation are used, the yield will only decrease, and such high purity d1-
α-Tocopheryl-acetate is extremely difficult to obtain.
本発明者等はこれら従来の欠点を解決するため
に種々研究を重ねた結果高純度d1―α―トコフ
エロールを得る方法を見出した。 The present inventors have conducted various studies to solve these conventional drawbacks, and as a result, have discovered a method for obtaining highly purified d1-α-tocopherol.
すなわち本発明方法はトリメチルハイドロキノ
ンとフイトールまたはイソフイトールとを水と共
沸する溶媒中で溶媒の存在下に加熱還流せしめ
て、生成する水を反応系外に分離して脱水縮合せ
しめるに当り、共沸還流液を脱水剤と接触させて
水を物理的に吸着させ、分離した溶媒を循環使用
しながら前記脱水縮合反応を行うことまた水と共
沸する溶媒として酢酸エチルまたはメチルエチル
ケトンを使用することを特徴とする高純度d1―
α―トコフエロールの製造法に係るものである。 That is, in the method of the present invention, trimethylhydroquinone and phytol or isophytol are heated to reflux in the presence of a solvent that is azeotropic with water, and the water produced is separated from the reaction system for dehydration condensation. The reflux liquid is brought into contact with a dehydrating agent to physically adsorb water, and the dehydration condensation reaction is carried out while the separated solvent is recycled. Also, ethyl acetate or methyl ethyl ketone is used as a solvent that is azeotropic with water. High purity d1-
This relates to a method for producing α-tocopherol.
次に本発明方法をさらに詳しく説明する。 Next, the method of the present invention will be explained in more detail.
加熱還流用コンデンサーの下に脱水剤を設置
し、還流液と脱水剤とを接触し得るようにした反
応罐に溶媒を入れる。これにトリメチルハイドロ
キノンを加えて撹拌溶解した後触媒を加え、特定
温度に調整し、次いでフイトールまたはイフイソ
トールを除々に添加する方法が一般的であるが、
勿論この方法に限定されるものではない。反応条
件は60〜90℃において１〜５時間程度で充分であ
るが、特にこれらの条件に限定されるものではな
い。反応生成物は例えば反応混合物を水洗、アル
カリ水で洗浄し、溶媒を脱水処理した後必要に応
じてアセチル化した後高真空蒸留によつて精製す
る。 A dehydrating agent is installed below the heating reflux condenser, and the solvent is poured into a reaction vessel that allows the reflux liquid and the dehydrating agent to come into contact with each other. A common method is to add trimethylhydroquinone to this, stir and dissolve, then add a catalyst, adjust the temperature to a specific temperature, and then gradually add phytol or ifisotol.
Of course, the method is not limited to this method. Reaction conditions at 60 to 90°C for about 1 to 5 hours are sufficient, but are not particularly limited to these conditions. The reaction product is purified by, for example, washing the reaction mixture with water or alkaline water, dehydrating the solvent, acetylating if necessary, and then performing high vacuum distillation.
本発明に使用する水と共沸する溶媒としては、
酢酸エチル、酢酸ブチル等の酢酸エステル化合
物、ジオキサン等の共沸性エーテル化合物、メチ
ルエチルケトン等の共沸性ケトン化合物等の溶媒
が挙げられるが、比較的水に対する溶解度の大き
い溶媒が好ましい。なかでも特に酢酸エチルおよ
びメチルエチルケトンが効果的である。本発明方
法において特に水に対する溶解度の大きい溶媒を
使用すると塩化亜鉛等の触媒をよく溶解するので
反応系が均一になり、反応が容易に進行する。 As the solvent azeotropic with water used in the present invention,
Examples include solvents such as acetate ester compounds such as ethyl acetate and butyl acetate, azeotropic ether compounds such as dioxane, and azeotropic ketone compounds such as methyl ethyl ketone, but solvents with relatively high solubility in water are preferred. Among them, ethyl acetate and methyl ethyl ketone are particularly effective. In the method of the present invention, when a solvent having particularly high solubility in water is used, the catalyst such as zinc chloride is well dissolved, so that the reaction system becomes uniform and the reaction proceeds easily.
次に本発明に使用する脱水剤としてはモレキユ
ラーシーブ（ユニオン昭和株式会社製商品名）、
シリカゲル、酸化アルミニウム等が挙げられる
が、吸水力、再使用等の点を考慮すると特にモレ
キユラーシーブが好ましい。なおモレキユラーシ
ーブとしては溶媒および溶質を吸着しないものな
らば支障なく使用できるが、例えば細孔直径３Å
の3A型が通常使用される。 Next, the dehydrating agent used in the present invention is Molecular Sieve (trade name manufactured by Union Showa Co., Ltd.),
Examples include silica gel and aluminum oxide, but molecular sieves are particularly preferred in consideration of water absorption and reuse. Note that molecular sieves that do not adsorb solvents and solutes can be used without any problems, but for example, those with a pore diameter of 3 Å
Type 3A is usually used.
また使用する触媒としては、この種の反応に使
用できるものならばいずれのものでもよく、特に
制限されるものではない。本発明方法を実施する
に当つて、使用する溶媒の量は、原料のトリメチ
ルハイドロキノンを溶解させることができる量で
あればよいが、勿論適宜増量使用することもでき
る。脱水剤の使用量は縮合反応によつて生成する
水を吸収できる量以上であればよい。触媒量は通
常使用する量でよく特に限定されるものではな
い。 Further, the catalyst used may be any catalyst that can be used in this type of reaction, and is not particularly limited. In carrying out the method of the present invention, the amount of solvent to be used may be any amount that can dissolve trimethylhydroquinone as a raw material, but the amount can of course be increased as appropriate. The amount of the dehydrating agent used may be at least an amount that can absorb water generated by the condensation reaction. The amount of catalyst may be a commonly used amount and is not particularly limited.
以上詳説した本発明方法によれば、粗d1―α
―トコフエリルアセテートを１回の真空蒸留操作
を行うだけで高純度のd1―α―トコフエリルア
セテートを得ることができ、商業的に極めて有利
な方法である。 According to the method of the present invention detailed above, the rough d1−α
-High purity d1-α-tocopheryl acetate can be obtained by performing a single vacuum distillation operation on tocopheryl acetate, and this is an extremely commercially advantageous method.
次に本発明を具体的に示すために実施例を挙げ
て説明するが、本発明は以下の実施例に限定され
るものではない。なお以下の実施例および参考例
の純度測定はｎ―ドトリアコンタンを内部標準と
したガスクロマトグラフイーにより行つた。 EXAMPLES Next, the present invention will be described with reference to examples to specifically illustrate the present invention, but the present invention is not limited to the following examples. Note that the purity measurements in the following Examples and Reference Examples were performed by gas chromatography using n-dotriacontane as an internal standard.
実施例 １
トリメチルハイドロキノン50ｇを酢酸エチルエ
ステル250mlに溶解し、窒素気流中で無水塩化亜
鉛22ｇ、亜鉛末0.5ｇ、濃塩酸1.5mlを加えて加熱
還流させる。還流下で、撹拌しながらイソフイト
ール93ｇを約３時間で滴下する。この時生成する
水は共沸混合液としてモレキユラーシーブ（3A
型）70ｇを充填したカラムを通して脱水分離し、
溶媒を連続的に循環使用する。Example 1 50 g of trimethylhydroquinone is dissolved in 250 ml of ethyl acetate, 22 g of anhydrous zinc chloride, 0.5 g of zinc powder, and 1.5 ml of concentrated hydrochloric acid are added in a nitrogen stream, and the mixture is heated to reflux. Under reflux and stirring, 93 g of isophytol is added dropwise over about 3 hours. The water produced at this time is used as an azeotropic mixture using a molecular sieve (3A
Dehydrated and separated through a column packed with 70g of
Continuously cycle the solvent.
滴下終了後２時間加熱還流させる。次に溶媒を
留去し、残渣をヘキサン250mlに溶解し、80％メ
タノール液で水洗した後乾燥する。溶媒を留去し
て得た濃縮液は常法によりアセチル化し、粗d1
―α―トコフエリルアセテートとし沸点200〜210
℃／0.01〜0.03mmHg）で高真空蒸留して精製す
る。収量128.4ｇ（収率86.6％）。 After completion of the dropwise addition, the mixture was heated under reflux for 2 hours. Next, the solvent is distilled off, the residue is dissolved in 250 ml of hexane, washed with 80% methanol solution, and then dried. The concentrated liquid obtained by distilling off the solvent was acetylated by a conventional method to obtain crude d1.
-α-Tocopheryl acetate boiling point 200-210
Purify by high vacuum distillation at ℃/0.01~0.03mmHg). Yield: 128.4g (yield: 86.6%).
純度96.3％。 Purity 96.3%.
実施例 ２
トリメチルハイドロキノン25ｇをメチルエチル
ケトン50mlに溶解し、窒素気流中で塩化亜鉛11
ｇ、亜鉛末0.25ｇおよび硫酸0.1mlを加えて加熱
し還流させる。還流下で撹拌しながらイソフイト
ール46.5ｇを約３時間で滴下する。反応により生
成する水は共沸混合液としてモレキユラシーブ
（3A型）35ｇを充填したカラムを通して脱水分離
し、溶媒は連続的に循環使用する。以下実施例１
と同様にして処理、精製する。収量57.7ｇ（収率
77.8％）。純度96.5％。Example 2 25 g of trimethylhydroquinone was dissolved in 50 ml of methyl ethyl ketone, and 11 g of zinc chloride was dissolved in 50 ml of methyl ethyl ketone.
g, 0.25 g of zinc powder and 0.1 ml of sulfuric acid are added and heated to reflux. While stirring under reflux, 46.5 g of isophytol is added dropwise over about 3 hours. The water produced by the reaction is dehydrated and separated as an azeotropic liquid through a column packed with 35 g of molecular sieves (type 3A), and the solvent is continuously recycled. Example 1 below
Treat and purify in the same manner. Yield 57.7g (yield
77.8%). Purity 96.5%.
実施例 ３
トリメチルハイドロキノン25ｇを酢酸エチル
250mlに溶解し、窒素気流中で無水塩化亜鉛11
ｇ、亜鉛末0.25ｇおよび濃塩酸0.75mlを加えて加
熱還流させる。還流下に撹拌しながらイソフイト
ール46.5ｇを約３時間で滴下する。反応により生
成する水は共沸混合液として酸化アルミニウム70
ｇを充填したカラムを通して脱水し、溶媒は循環
使用する。滴下終了後２時間反応を続けた後実施
例１と同様に処理し精製する。収量61.2ｇ（収率
82.5％）。純度96.3％。Example 3 25g of trimethylhydroquinone was added to ethyl acetate.
Anhydrous zinc chloride 11 in a nitrogen stream dissolved in 250ml
g, 0.25 g of zinc powder and 0.75 ml of concentrated hydrochloric acid were added and heated to reflux. While stirring under reflux, 46.5 g of isophytol is added dropwise over about 3 hours. The water produced by the reaction is an azeotropic mixture of aluminum oxide 70
The solvent is recycled and used. After the completion of the dropwise addition, the reaction was continued for 2 hours, and then treated and purified in the same manner as in Example 1. Yield 61.2g (yield
82.5%). Purity 96.3%.
参考例 １
トリメチルハイドロキノン31ｇ、パラトルエン
スルホン酸３ｇおよびトルエン400mlを混合し、
Ｈ管を使用して加熱しながらイソフイトール59ｇ
を徐々に滴下し、生成する水をＨ管の取出口より
順次除去し、分離した溶媒を循環使用した。反応
は１時間で終了する。冷却後実施例１と同様に後
処理しアセチル化して粗d1―α―トコフエリル
アセテートとし、高真空蒸留して精製する。沸点
200〜210℃／0.01〜0.03mmHg。収量70.1ｇ（収率
74.5％）。純度94.1％。Reference example 1 Mix 31g of trimethylhydroquinone, 3g of para-toluenesulfonic acid and 400ml of toluene,
59g of isophytol while heating using H tube.
was gradually added dropwise, the produced water was sequentially removed from the outlet of the H tube, and the separated solvent was recycled and used. The reaction is completed in 1 hour. After cooling, it is post-treated and acetylated in the same manner as in Example 1 to obtain crude d1-α-tocopheryl acetate, which is purified by high vacuum distillation. boiling point
200~210℃/0.01~0.03mmHg. Yield 70.1g (yield
74.5%). Purity 94.1%.
参考例 ２
トリメチルハイドロキノン50ｇを酢酸エチル
250mlに溶解し、窒素気流中で無水塩化亜鉛22
ｇ、亜鉛末0.5ｇ、濃塩酸1.5mlを加え、加熱還流
させた。還流下、Ｈ管を使用して脱水しつつ、イ
ソフイトール93ｇを３時間で滴下した。滴下終了
後、２時間加熱還流させた。次に溶媒を留去し、
残渣をｎ―ヘキサン250mlに溶解し、80％メタノ
ール液で洗滌した後、乾燥した。溶媒を留去して
得た残渣を常法によりアセチル化し、粗d1―α
―トコフエリルアセテートとし、沸点200〜210
℃／0.01〜0.03mmHgで高真空蒸留して精製した。Reference example 2 50g of trimethylhydroquinone in ethyl acetate
Anhydrous zinc chloride in a nitrogen stream dissolved in 250ml 22
g, 0.5 g of zinc powder, and 1.5 ml of concentrated hydrochloric acid were added, and the mixture was heated to reflux. Under reflux and dehydration using an H tube, 93 g of isophytol was added dropwise over 3 hours. After the dropwise addition was completed, the mixture was heated under reflux for 2 hours. Next, the solvent is distilled off,
The residue was dissolved in 250 ml of n-hexane, washed with 80% methanol solution, and then dried. The residue obtained by distilling off the solvent was acetylated by a conventional method to obtain crude d1-α
-Tocopheryl acetate, boiling point 200-210
It was purified by high vacuum distillation at °C/0.01-0.03 mmHg.
収量 117.2ｇ（収率79.0％）
純度 94.0％（ｎ―ドトリアコンタンを内部標
準とするガスクロマトグラフイーによる定量
値）
参考例 ３
トリメチルハイドロキノン12.17ｇ、無水塩化
亜鉛11.99ｇ、モノクロル酢酸1.13ｇ、微量の重
亜硫酸ソーダ0.1ｇを酢酸イソプロピル100mlに溶
解し、Ｈ管を使用して撹拌還流下にイソフイトー
ル25.01ｇ（純度94.7％）を30分間で滴下した。
滴下後撹拌還流を１時間継続した。 Yield 117.2g (yield 79.0%) Purity 94.0% (determined value by gas chromatography using n-dotriacontane as internal standard) Reference example 3 Trimethylhydroquinone 12.17g, anhydrous zinc chloride 11.99g, monochloroacetic acid 1.13g, trace amount 0.1 g of sodium bisulfite was dissolved in 100 ml of isopropyl acetate, and 25.01 g of isophytol (purity 94.7%) was added dropwise over 30 minutes under stirring and reflux using an H tube.
After the addition, stirring and refluxing was continued for 1 hour.
生成する水はＨ管より留去し、溶媒は循環使用
した。反応後Ｈ管を除き、還流冷却器をつけて無
酢9.78ｇ、酢酸ソーダ3.93ｇを加えて２時間加熱
還流した。放冷して濃縮した。残渣を氷中に投入
してNa2CO3で中和し、ベンゼンで抽出し、
Na2SO4で乾燥した。 The water produced was distilled off from the H tube, and the solvent was recycled. After the reaction, the H tube was removed, a reflux condenser was attached, 9.78 g of non-vinegar and 3.93 g of sodium acetate were added, and the mixture was heated under reflux for 2 hours. It was left to cool and concentrated. The residue was placed in ice, neutralized with Na2CO3 , extracted with benzene,
Dried with Na2SO4 .
次いで減圧濃縮して粗d1―α―トコフエリ
ル・アセテート39.41ｇを得た。この粗d1―α―
トコフエリル・アセテートを高真空蒸留して精製
した。その結果、35.1ｇの精製d1―α―トコフエ
リル・アセテートを得た〔収率87.3％、純度94.0
％（ｎ―ドトリアコンタンを内部標準とするガス
クロマトグラフイーによる定量値）〕。 The mixture was then concentrated under reduced pressure to obtain 39.41 g of crude d1-α-tocopheryl acetate. This coarse d1―α―
Tocopheryl acetate was purified by high vacuum distillation. As a result, 35.1 g of purified d1-α-tocopheryl acetate was obtained [yield 87.3%, purity 94.0
% (quantitative value determined by gas chromatography using n-dotriacontane as an internal standard)].
なお、上記方法で得られた精製d1―α―トコ
フエリル・アセテートについて、アメリカ国民医
薬品集第13版（1970年発行）記載の定量法（塩化
第２鉄と反応させ、520nmの吸光度を測定して行
なう方法）に従つて測定した結果、純度は98.5％
であつた。 The purified d1-α-tocopheryl acetate obtained by the above method was determined using the quantitative method described in the 13th edition of the American National Formulary of Pharmaceutical Sciences (published in 1970) (by reacting with ferric chloride and measuring the absorbance at 520 nm). The purity was 98.5% as measured according to
It was hot.
Claims (1)
キノンとフイトールまたはイソフイトールとを水
と共沸する溶媒中で触媒の存在下に加熱還流せし
めて、生成する水を反応系外に分離して脱水縮合
せしめるに当り、共沸還流液を脱水剤と接触させ
て水を物理的に吸着させ、分離した溶媒を循環使
用しながら前記脱水縮合反応を行うことまた水と
共沸する溶媒として酢酸エチルまたはメチルエチ
ルケトンを用いることを特徴とする高純度d1―
α―トコフエロールの製造法。 ２ 脱水剤がモレキユラーシーブである特許請求
の範囲第１項に記載の製造法。[Claims] 1. 2,3,5-trimethyl-1,4-hydroquinone and phytol or isophytol are heated to reflux in the presence of a catalyst in a solvent that is azeotropic with water, and the resulting water is used as a reaction system. When separating and dehydrating condensation, the azeotropic reflux liquid is brought into contact with a dehydrating agent to physically adsorb water, and the dehydration condensation reaction is carried out while the separated solvent is recycled. High purity d1- characterized by using ethyl acetate or methyl ethyl ketone as a solvent for
Method for producing α-tocopherol. 2. The manufacturing method according to claim 1, wherein the dehydrating agent is a molecular sieve.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1614177A JPS53103475A (en) | 1977-02-18 | 1977-02-18 | Preparation of highly pure d1-alpha-tocopherol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1614177A JPS53103475A (en) | 1977-02-18 | 1977-02-18 | Preparation of highly pure d1-alpha-tocopherol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS53103475A JPS53103475A (en) | 1978-09-08 |
| JPS6224431B2 true JPS6224431B2 (en) | 1987-05-28 |
Family
ID=11908210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1614177A Granted JPS53103475A (en) | 1977-02-18 | 1977-02-18 | Preparation of highly pure d1-alpha-tocopherol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS53103475A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59190987A (en) * | 1983-04-11 | 1984-10-29 | Mitsui Toatsu Chem Inc | Preparation of dl-alpha-tocopherol |
| JP2013063912A (en) * | 2011-08-31 | 2013-04-11 | Eisai R & D Management Co Ltd | PRODUCTION METHOD OF α-TOCOPHEROL AND ACETIC ACID α-TOCOPHEROL |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4872167A (en) * | 1971-12-29 | 1973-09-29 |
-
1977
- 1977-02-18 JP JP1614177A patent/JPS53103475A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4872167A (en) * | 1971-12-29 | 1973-09-29 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS53103475A (en) | 1978-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rolston et al. | Polar additions to the styrene and 2-butene systems. I. Distribution stereochemistry of bromination products in acetic acid | |
| JPS6019309B2 (en) | Production method of high purity dl-α-tocopherol | |
| US4217285A (en) | Process for the preparation of Dl-α-tocopherol of high purity | |
| CN113372187A (en) | Industrial synthesis method of BVPE | |
| Adams et al. | CYCLIC ETHERS FROM o-ALLYL PHENOLS; METHYLENE COUMARANES. | |
| Eisenbraun et al. | Synthesis of polyalkyl-1-tetralones and the corresponding naphthalenes | |
| JPS6224431B2 (en) | ||
| Breslow et al. | Approaches to “push-pull” stabilized cyclobutadienes1 | |
| US3444213A (en) | Continuous process for producing dl alpha tocopherol | |
| Tinsley | Reaction of o-alkenylphenols with peracetic acid | |
| JPS601292B2 (en) | Synthesis method of dihydrocoenzyme Q compounds | |
| US3968163A (en) | Preparation of 4 and 5-methylindanes | |
| Bardshiri et al. | Studies on a synthesis of (RS)-mevalonic acid lactone | |
| JPS62164647A (en) | Synthesis of ester | |
| US4665244A (en) | Chlorinated derivatives of hexadecene, their preparation and their use in the synthesis of vitamin E | |
| Mulvaney et al. | Organolithium compounds and acetylenes. V. Electron transfer plus addition-metalation in the case of a tertiary organolithium compound | |
| JP2001328967A (en) | Method for producing highly pure alkyladamantyl ester | |
| US2345605A (en) | Chromanes and process for their production | |
| Kula | A Preparative Method for Blocking of Ketone Group in 2, 2-Dimethyl-3-(2-Oxopropyl)-Cis-Cyclopropaneacetaldehyde | |
| JP2002255955A (en) | Method for producing alicyclic tetracarboxylic dianhydride | |
| Roberts | Cyclopropylcarbinyl p-toluenesulfonate solvolysis. III. 1-p-Anisyl substituent effect | |
| JPS6054380A (en) | Production of alpha-tocopherol | |
| Jain et al. | Synthesis of isopentenylated chrystins | |
| CN111662260B (en) | Synthetic method of natural product saffloneoside | |
| RU2098416C1 (en) | Method of synthesis of dl-alpha-tocopherol or its acetate |