JP4826133B2 - S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and process for producing the same - Google Patents
S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and process for producing the same Download PDFInfo
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本発明は、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを加水分解して、高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を製造する方法に関する。さらに詳しくは、原料のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを塩基性条件下で加水分解し、得られた反応液から、固液分離性に優れた高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の結晶を安定的に得るための中和処理条件及びその中和処理条件で得られた製造物に関する。光学活性体であるＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸、取り分け、高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸は、ビタミン、又は消炎剤や抗アレルギー剤等の医薬原料として極めて重要である。 The present invention hydrolyzes S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester to produce highly pure S-(−)-6-hydroxy- The present invention relates to a method for producing 2,5,7,8-tetramethylchroman-2-carboxylic acid. More specifically, the raw material S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester is hydrolyzed under basic conditions, and the resulting reaction solution is used. Neutralization conditions for stably obtaining crystals of high purity S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid excellent in solid-liquid separation, and The present invention relates to a product obtained under the neutralization treatment conditions. S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, which is an optically active substance, especially, high-purity S-(-)-6-hydroxy-2,5 , 7,8-tetramethylchroman-2-carboxylic acid is extremely important as a raw material for vitamins or pharmaceuticals such as anti-inflammatory agents and antiallergic agents.
クロマン化合物の製造方法を示した従来例としては、フェノール類、及び不飽和カルボニル化合物を出発原料とする多段階法（例えば、特許文献１参照）、フェノール類、ホルムアルデヒド類、及び不飽和化合物類を無触媒、又は酸若しくはアミンの存在下に反応させる方法（例えば、特許文献２，３，４参照）等がある。 As a conventional example showing a method for producing a chroman compound, a multi-stage method using phenols and unsaturated carbonyl compounds as starting materials (for example, see Patent Document 1), phenols, formaldehydes, and unsaturated compounds There is a method of reacting in the presence of no catalyst or acid or amine (for example, see Patent Documents 2, 3, and 4).
光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸誘導体を得る方法としては、特許文献４の方法に従うことによって得られる６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを、１）光学活性アミンによるジアステレオマー分割法（例えば、特許文献５，６参照）、２）（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマンカルボン酸エステルの酵素触媒による不斉加水分解法（例えば、特許文献７参照）を用い光学的な分割を行うことによって得られる。 As a method for obtaining an optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid derivative, 6-hydroxy-2,5,7, obtained by following the method of Patent Document 4 is used. 8-tetramethylchroman-2-carboxylic acid ester is diastereomer-resolved with optically active amine (see, for example, Patent Documents 5 and 6), 2) (±) -6-hydroxy-2,5,7 , 8-tetramethylchromancarboxylic acid ester is obtained by optical resolution using an enzyme-catalyzed asymmetric hydrolysis method (see, for example, Patent Document 7).
上述の方法に従うことにより、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を製造することは可能であるが、高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を工業的かつ経済的に提供する上では改善工夫すべき点が残されている。既に本発明者等は、６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を簡便かつ収率良く製造する方法について提案している。しかしながら、それらの方法を用いても、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを製造した後、加水分解してＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を製造する場合、加水分解後に行う中和及び温度管理条件が不適切であると反応液がペースト状の分離性の悪いスラリーになる。従って、工業的な実施には、これらの課題を解決して経済的に目的物を取得する手段を確立する必要があった。しかしながら、従来技術及び先行文献には、結晶の固液分離性及び乾燥を容易ならしめるようなＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の晶析分離条件についてはなんら開示されていない。 By following the above-mentioned method, it is possible to produce S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, but high-purity S-(− ) In order to provide 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid industrially and economically, there are points to be improved. The present inventors have already proposed a method for producing 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid simply and with good yield. However, even if these methods are used, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester is produced and then hydrolyzed to produce S-(- ) When producing 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, if the neutralization and temperature control conditions performed after hydrolysis are inadequate, the reaction solution is separated into a paste. It becomes a poor slurry. Therefore, it is necessary for industrial implementation to establish means for solving these problems and obtaining the object economically. However, the prior art and prior art documents describe S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid that facilitates solid-liquid separation and drying of crystals. No crystallization separation conditions are disclosed.
本発明の目的は、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルから、固液分離性に優れた高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を効率的に製造するための、工業的に実施可能な製造方法及びそれによって得られた製品を提供することにある。 The object of the present invention is to obtain high-purity S-(-) excellent in solid-liquid separation from S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester. To provide an industrially feasible production method and a product obtained thereby for efficiently producing -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is there.
本発明者らは、上記課題を解決するべく鋭意検討を重ねた結果、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを加水分解して、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を製造する際、以下の操作条件を採用することで、結晶スラリーの濾過性に優れ、乾燥性が良好でしかも結晶の粉立ちが殆ど無い、取り扱い性に優れた極めて高純度の結晶を収率良く得られることを見出し、本発明を完成させた。 As a result of intensive studies to solve the above problems, the present inventors hydrolyzed S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester. Thus, when producing S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, the following operating conditions are adopted, and the filterability of the crystal slurry is excellent. The inventors have found that extremely high-purity crystals having good drying properties and almost no crystal dusting and excellent handleability can be obtained in good yield, and the present invention has been completed.
すなわち、本発明は、原料のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラクロマン−２−カルボン酸エステルを塩基性条件下に加水分解した後、得られた反応液から固液分離性に優れた高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の結晶を取得するための、以下の（１）〜（６）に示す製造方法及び製造物に関する。
（１）一般式（１）で表されるＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを加水分解してＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を製造する方法に於いて、一般式（１）で表されるＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを塩基性条件下で加水分解した後、該反応液中に含まれる不溶物を除去し、得られた処理液を５０〜８０℃の温度範囲で中和することを特徴とする、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造方法。
That is, the present invention provides a reaction solution obtained by hydrolyzing the raw material S-(-)-6-hydroxy-2,5,7,8-tetrachroman-2-carboxylic acid ester under basic conditions. The following (1) for obtaining crystals of high purity S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid excellent in solid-liquid separation from It relates to the production method and product shown in (6).
(1) S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester represented by the general formula (1) is hydrolyzed to produce S-(-)- In the method for producing 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, S-(−)-6-hydroxy-2,5 represented by the general formula (1) , 7,8-tetramethylchroman-2-carboxylic acid ester is hydrolyzed under basic conditions, then insolubles contained in the reaction solution are removed, and the resulting treatment solution is heated to a temperature of 50 to 80 ° C. A method for producing S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, wherein neutralization is performed in a range.
（但し、一般式（１）におけるＲは、アルキル基又はアリール基を表す。）
（２）塩基性条件下での加水分解反応を５０〜８０℃の温度範囲で行う、（１）に記載のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造方法。
（３）塩基性条件下で加水分解した反応液中に含まれる不溶物の除去を５０〜８０℃の温度範囲で行う、（１）又は（２）に記載のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造方法。
（４）塩基性条件下で加水分解した反応液中に含まれる不溶物の除去を、該反応液のｐＨを５〜７に調整した後に行う、（１）〜（３）の何れかに記載のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造方法。
（５）不溶物を除去することによって得られた処理液を５０〜８０℃の温度範囲で中和する際に、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の結晶を種結晶として添加する、（１）〜（４）の何れかに記載のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造方法。
（６）（１）〜（５）の何れかに記載の製造方法で得られるＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸。
(However, R in the general formula (1) represents an alkyl group or an aryl group.)
(2) S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman according to (1), wherein the hydrolysis reaction under basic conditions is performed in a temperature range of 50 to 80 ° C. A process for producing 2-carboxylic acid.
(3) S-(−)-6 according to (1) or (2), wherein insoluble matters contained in the reaction solution hydrolyzed under basic conditions are removed in a temperature range of 50 to 80 ° C. A method for producing hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.
(4) The method according to any one of (1) to (3), wherein the insoluble matter contained in the reaction solution hydrolyzed under basic conditions is removed after adjusting the pH of the reaction solution to 5 to 7. A process for producing S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.
(5) S-(−)-6-hydroxy-2,5,7,8-tetramethyl when neutralizing the treatment liquid obtained by removing insoluble matter in the temperature range of 50 to 80 ° C. S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman- according to any one of (1) to (4), wherein crystals of chroman-2-carboxylic acid are added as seed crystals. A method for producing 2-carboxylic acid.
(6) S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid obtained by the production method according to any one of (1) to (5).
簡便な方法で固液分離性に優れた結晶を安定的に得ることができる本発明の方法を用いることによって、再結晶等の精製工程を付加することなく、医薬、農薬等の原料として有用なより純度の高い（Ｓ）−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を経済的に製造し提供することが可能となる。 By using the method of the present invention that can stably obtain crystals having excellent solid-liquid separation properties by a simple method, it is useful as a raw material for pharmaceuticals, agricultural chemicals, etc. without adding a purification step such as recrystallization. It becomes possible to economically produce and provide (S)-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid having higher purity.
本発明に用い得る原料は、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルである。このような光学活性なエステルは、ラセミ又は光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の混合物を原料とし、これを立体選択的にエステル化する酵素触媒を用いたりすることによって得ることが出来る。
Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルのアルキル又はアリール基は、炭素数１〜２４迄の、ハロゲン、水酸基等の官能基を置換基として有する事のある脂肪族又は芳香族炭化水素が好ましい。エステルの該炭化水素残基を具体的に挙げれば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチル、ｔ−ブチル、ｎ−アミル、アリル、ｎ−ヘキシル、ｎ−オクチル、２−エチルヘキシル、ラウリル、ステアリル、シクロヘキシル、フェニル、ベンジル基等が好ましい例である、特に好ましいのはメチル基及びエチル基である。
The raw material that can be used in the present invention is S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester. Such an optically active ester is an enzyme that stereoselectively esterifies a racemic or optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid mixture as a raw material. It can be obtained by using a catalyst.
The alkyl or aryl group of S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester is a functional group having 1 to 24 carbon atoms such as halogen and hydroxyl group. Aliphatic or aromatic hydrocarbons that may be present as substituents are preferred. Specific examples of the hydrocarbon residue of the ester include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-amyl, allyl, n-hexyl, n- Octyl, 2-ethylhexyl, lauryl, stearyl, cyclohexyl, phenyl, benzyl group and the like are preferred examples, and particularly preferred are methyl group and ethyl group.
次ぎに、原料として６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルを用いた場合を例にして説明する。原料となる６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルは６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸とメタノールを、酵素触媒（リパーゼ）の存在下、有機溶媒中においてエステル化反応を行うことで得られる。仕込む原料の比率は任意に決める事ができるが、反応効率の点から２４時間程度で目的の収率になるように調節することが好ましい。なお、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルは、既に発明者等によって提案されている方法に基づく実施例１に示した手順に従って製造する事が出来る。 Next, the case where methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate is used as a raw material will be described as an example. 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid methyl as a raw material is 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and methanol. It can be obtained by carrying out an esterification reaction in an organic solvent in the presence of a catalyst (lipase). The ratio of raw materials to be charged can be arbitrarily determined, but it is preferable to adjust the raw material yield to the desired yield in about 24 hours from the viewpoint of reaction efficiency. The methyl S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate is the procedure shown in Example 1 based on the method already proposed by the inventors. Can be manufactured according to
Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルの加水分解反応は、酸性条件下に行う事もできるが、比較的穏和な条件で効率よく加水分解できる点で、水溶媒中、塩基性条件下で行うことが好ましい。加水分解に用いる塩基は、弱塩基性から強塩基性の無機化合物又は有機化合物を用いる事が出来るが、反応性が良好で未反応物が残存し難い点から、強塩基性のアルカリ金属又はアルカリ土類金属の水酸化物が好ましい。特に好ましいのはＫＯＨとＮａＯＨである。加水分解に用いる塩基の量は、基質に対して１〜５倍モルが好ましく、特に１〜２倍モルが好ましい。
加水分解時の反応温度は５０〜８０℃の範囲で行う事が好ましく、反応時間は０．１〜６時間が好ましく、特に１〜３時間で行うのがより好ましい。
Hydrolysis of methyl S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate can be carried out under acidic conditions, but it is efficient under relatively mild conditions. It is preferable to carry out under basic conditions in an aqueous solvent in that it can be hydrolyzed well. As the base used for the hydrolysis, a weakly basic to strongly basic inorganic compound or organic compound can be used. However, since the reactivity is good and unreacted substances hardly remain, a strongly basic alkali metal or alkali is used. Earth metal hydroxides are preferred. Particularly preferred are KOH and NaOH. The amount of the base used for the hydrolysis is preferably 1 to 5 times mol, particularly preferably 1 to 2 times mol for the substrate.
The reaction temperature at the time of hydrolysis is preferably 50 to 80 ° C., and the reaction time is preferably 0.1 to 6 hours, more preferably 1 to 3 hours.
加水分解に用いる溶媒の量は、基質に対して２〜１０倍重量用いることが好ましく、３〜５倍重量用いることがより好ましい。また、水と良く混ざり、基質を溶解し、反応に不活性な有機溶媒を添加する事で、反応をより円滑に進めることが出来る。そのような有機溶媒としては、例えば、アルコール、ニトリル類等が挙げられるが、基質の溶解性やエステル交換反応の恐れが無く、溶媒組成が複雑化しない点でメチルアルコールが特に好ましい。溶媒中に含まれる有機溶媒の水に対する割合は任意でよいが、水に対して０．１〜１倍重量用いる事が好ましい。なお、有機溶媒を更に過剰に用いても大きな支障は無いが反応釜の使用効率、経済的な点から好ましくない。 The amount of the solvent used for the hydrolysis is preferably 2 to 10 times the weight, more preferably 3 to 5 times the weight of the substrate. Further, the reaction can be promoted more smoothly by mixing with water, dissolving the substrate, and adding an organic solvent inert to the reaction. Examples of such an organic solvent include alcohols and nitriles, but methyl alcohol is particularly preferable in that there is no fear of substrate solubility and transesterification reaction, and the solvent composition is not complicated. Although the ratio with respect to the water of the organic solvent contained in a solvent may be arbitrary, it is preferable to use 0.1-1 times weight with respect to water. Further, even if the organic solvent is used in excess, there is no major problem, but it is not preferable from the viewpoint of the use efficiency and economical point of the reaction kettle.
加水分解反応終了後、反応液中に含まれる不溶物を濾過等の分離手段によって除去する。不溶物は、原料中に含まれていた低溶解性の物質、反応中に生成した副生物、又は原料の未転化物等によって構成されており、反応終了後、液中に含まれる不溶物を出来る限り取り除くことが重要である。この不溶物の除去操作は最終的に得られる製品純度に直結する為、必ず実施する必要がある。なお、不溶物の分離手段としては、一般的なデカンテーション、常圧濾過、減圧濾過、加圧濾過、及び遠心分離等の手段を用いることが出来るが、不溶物を分離除去することができれば特にこれらの方法に限定されるものではない。
不溶物を除去する際の液温は、上記加水分解の反応温度と同等の５０〜８０℃の温度範囲で行うことが好ましい。なおその際、冷却し過ぎるとＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸のアルカリ塩が析出する場合があるので、それらが析出する温度よりも高い温度で行う事が好ましい。また、加水分解の反応温度に近い温度で不溶物を除去するのが不溶物の除去効率及び熱効率の面で有利である。
不溶物の除去は、加水分解後の反応液をそのまま処理しても良いが、反応液に酸を加えｐＨ５〜７に調整してから行うとより良い。この操作によって、溶解していた不純物成分が不溶物として析出するため、より高純度のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を取得する事が可能となる。なお、この時、酸を過剰に加えてｐＨを５よりもさらに低下させると、不溶物ばかりかＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の析出も起こり始めるので収率低下に繋がり好ましくない。なお、ｐＨ調整に用いる酸は、次の中和工程と同じものを用いることが作業上好ましい。
After completion of the hydrolysis reaction, insoluble matters contained in the reaction solution are removed by a separation means such as filtration. The insoluble matter is composed of a low-solubility substance contained in the raw material, a by-product generated during the reaction, or an unconverted product of the raw material, and the insoluble matter contained in the liquid after the reaction is completed. It is important to remove as much as possible. Since this insoluble matter removal operation is directly related to the final product purity, it must be carried out. As the insoluble matter separation means, general means such as decantation, atmospheric pressure filtration, reduced pressure filtration, pressure filtration, and centrifugal separation can be used. Especially, insoluble matter can be separated and removed. It is not limited to these methods.
It is preferable to perform the liquid temperature at the time of removing an insoluble matter in the temperature range of 50-80 degreeC equivalent to the reaction temperature of the said hydrolysis. In this case, since the alkali salt of S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid may precipitate if it is cooled too much, the temperature at which they precipitate. It is preferable to carry out at a higher temperature. Moreover, it is advantageous in terms of removal efficiency and thermal efficiency of removing insoluble matters at a temperature close to the reaction temperature of hydrolysis.
The insoluble matter may be removed by treating the reaction solution after hydrolysis as it is, but it is better to adjust the pH to 5 to 7 by adding acid to the reaction solution. As a result of this operation, the dissolved impurity component is precipitated as an insoluble substance, so that higher purity S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is obtained. It becomes possible to do. At this time, if the acid is excessively added to lower the pH further than 5, not only insoluble matter but also S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxyl Acid precipitation also begins to occur, which leads to a decrease in yield. The acid used for pH adjustment is preferably the same as that used in the next neutralization step.
このようにして不溶物を除去した後に反応液の中和を行う。なお、その際、少量のＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の結晶を種結晶を添加した後、中和処理を行うと良い。種結晶を添加しない場合に比較して、より沈降し易く固液分離性に優れたＳ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の結晶を得ることが可能となる。
中和には塩酸、硫酸、硝酸等の強酸性の鉱産、又は硫酸水素ナトリウムや硫酸水素カリウム等の弱酸の何れを用いても良い。硫酸水素ナトリウムや硫酸水素カリウム等の酸を用いる場合、酸に対して１〜１０倍量の水に溶解して用いるのが好ましい。
The reaction solution is neutralized after removing insolubles in this manner. At that time, a small amount of S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid crystal is added to the seed crystal and then neutralized. . Crystals of S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid that are more easily settled and have better solid-liquid separation than when seed crystals are not added. Can be obtained.
For neutralization, any of strong acid minerals such as hydrochloric acid, sulfuric acid and nitric acid, or weak acids such as sodium hydrogen sulfate and potassium hydrogen sulfate may be used. When an acid such as sodium hydrogen sulfate or potassium hydrogen sulfate is used, it is preferably used by dissolving in 1 to 10 times the amount of water with respect to the acid.
中和処理は４０〜８０℃の温度範囲で行う事が好ましく、５０〜７０℃の温度範囲で行う事がより好ましい。４０℃を下回る温度で行った場合、析出する結晶が沈降性の悪い微小結晶になるため液全体がペースト状となる。このペースト状の結晶は濾過性及び乾燥性が極めて悪く、固液分離した際、母液の付着量が非常に多い含液率の高い結晶になる。そのため、母液中に含まれていた無機塩や不純物が残留し易くなり、得られる結晶の純度が低下する。
一方、８０℃を上回る場合には、中和により析出するはずの結晶がオイル状となり２層状態になる。因みに、そのまま中和を継続すると、下層のオイル部分が一度に結晶化し塊状となる場合がある。塊状になると、反応容器からの取り出しが困難になるだけではなく、化学純度も低くなるので好ましくない。
中和時の圧力は、通常、大気圧下で行うが、必要に応じて加圧又は減圧下に実施しても良い。何れの操作に於いても可能であれば不活性ガス雰囲気下に実施する事が好ましい。中和処理後、固液分離した結晶スラリー中に含まれる中和塩を、水で十分に洗浄除去した後、乾燥して最終製品とする事が出来る。
The neutralization treatment is preferably performed in a temperature range of 40 to 80 ° C, more preferably in a temperature range of 50 to 70 ° C. When it is performed at a temperature lower than 40 ° C., the precipitated liquid becomes microcrystals with poor sedimentation, so that the entire liquid becomes a paste. The pasty crystals are extremely poor in filterability and drying properties, and when separated into solid and liquid, they become crystals with a high liquid content with a very large amount of mother liquor. For this reason, inorganic salts and impurities contained in the mother liquor are likely to remain, and the purity of the crystals obtained is lowered.
On the other hand, when it exceeds 80 ° C., the crystals that should be precipitated by neutralization become oily and become a two-layer state. Incidentally, if the neutralization is continued as it is, the lower oil portion may crystallize at once and become a lump. When it is in the form of a lump, it is not preferable because not only it becomes difficult to take out from the reaction vessel, but also the chemical purity becomes low.
The neutralization pressure is usually carried out under atmospheric pressure, but may be carried out under pressure or reduced pressure as necessary. In any operation, it is preferable to carry out in an inert gas atmosphere if possible. After the neutralization treatment, the neutralized salt contained in the solid-liquid separated crystal slurry is sufficiently washed and removed with water, and then dried to obtain a final product.
中和の際の溶液の加え方は、不溶物を除去した処理液に中和用の酸性溶液を加えても、中和用の酸性溶液に処理液を加えても、また、処理液と酸性溶液を、水、又は水に有機溶媒を加えた混合溶液に加える方法の何れをとっても良い。
加え方としては、一度に入れることもできるが、1時間程の時間をかけて除々に滴下するのが好ましい。有機溶媒としては水と良く混ざるアルコール、ニトリル類等が挙げられるが、加水分解反応の時に添加した溶媒と同じ物にすることが好ましい。
The solution for neutralization can be added by adding an acidic solution for neutralization to the treatment solution from which insolubles have been removed, adding a treatment solution to the neutralization acidic solution, Any method of adding the solution to water or a mixed solution obtained by adding an organic solvent to water may be used.
As a method of addition, although it can be added at once, it is preferable to drop gradually over a period of about one hour. Examples of the organic solvent include alcohols and nitriles that are well mixed with water, but it is preferable to use the same solvent as that added during the hydrolysis reaction.
本発明の方法を用いることにより、粒径の大きい固液分離性に優れた結晶を得ることが可能となる。また、結晶濾過性が改善されることにより、塩類等を含む付着母液の洗浄が容易になるとともに濾過時間を大幅に短縮することが出来る。このようにして、従来技術では製造する事が出来なかった粉立ちの少ない、取り扱い性に優れた高純度の（Ｓ）−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を効率的に製造する事が可能となる。 By using the method of the present invention, it is possible to obtain crystals having a large particle size and excellent solid-liquid separation. In addition, by improving the crystal filterability, it is possible to easily wash the adhered mother liquor containing salts and the like, and to significantly reduce the filtration time. In this way, high purity (S)-(−)-6-hydroxy-2,5,7,8-tetramethyl has a low powderiness and is easy to handle, which cannot be produced by the prior art. It becomes possible to produce chroman-2-carboxylic acid efficiently.
以下に本発明を、実施例及び比較例をもってさらに詳細に説明するが、本発明はこれらの例によって限定されるものでは無い。なお、光学純度の分析はＳＵＭＩＣＨＩＲＡＬＯＡ−３２００（住友分析センター、４．６φｍｍ×２５０ｍｍ）を用いたＨＰＬＣで行った。
実施例１
Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples, but the present invention is not limited to these examples. The optical purity was analyzed by HPLC using SUMICHIRALOA-3200 (Sumitomo Analysis Center, 4.6φ mm × 250 mm).
Example 1
１）（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルの製造
１，４−ジヒドロキシ−２，３，５−トリメチルベンゼン１００ｇ（０．６５７ｍｏｌ）、ホルマリン水溶液（ホルムアルデヒド３７ｗｔ％、水５６ｗｔ％、メタノール７ｗｔ％）１１０ｇ、メチルメタクリレート３３０ｇ（３．２９６ｍｏｌ）を１Lのステンレス製オートクレーブに入れ、１８０℃で３時間撹拌しながら反応させた。４０℃まで冷却後、析出した結晶を濾過し、メタノール２００ｇで２回リンスした。回収した結晶を乾燥して目的とする６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチル（以下、ＣＣＭと記す）１３５ｇ（ＣＣＭとして０．４７８ｍｏｌ、収率７２．６％、化学純度９３．５％）を得た。
２）（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造
上記のようにして製造したＣＣＭ１６．７ｇ（ＣＣＭとして５９．１ｍｍｏｌ、化学純度９３．５％）、メタノール１６．７ｇ、ＮaＯＨ３．３ｇ（８２．５ｍｍｏｌ）、水５０ｇを２００ｍｌのガラス容器に仕込み、窒素雰囲気下８０℃で１時間攪拌しながらエステルの加水分解反応を行った。この反応液をそのままの温度で濾過し不溶物を除いた後、３００ｍLのガラス容器に仕込んだ硫酸水素カリウム１１．７ｇ（８５．９ｍｍｏｌ）を５０ｇの水に溶かし８０℃に保った酸性溶液中に１時間かけて滴下した。中和処理終了後、攪拌を止め静置すると、結晶は速やかに沈降した。この結晶を８０℃で濾別し、５０ｍLの水で２回洗浄した後、８０℃で２４時間、真空乾燥し６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸（以下、ＣＣＡと記す）１４．５ｇ（５７．９ｍｍｏｌ）を得た（収率９８．３％、化学純度は９９．７％）。
３）Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチルの製造
上記の操作によって得たＣＣＡ１２００ｇ（４．７９ｍｏｌ）、メタノール７６７ｇ（２３．９３）、イソプロピルエーテル１５０００ｇ、固定化酵素ＣＨＩＲＡＺＹＭＥＬ−２，ｃ−ｆ、Ｃ２（ロッシュ・ダイアグノスティック社製）４００ｇを、２００ｍｌのステンレス製耐圧容器に仕込み、Ａｒで置換した後、８０℃で２４時間反応を行った。２４時間後、濾過によって触媒を取り除き反応液を回収した。この反応液に、炭酸ナトリウム７６０ｇ（７．１７ｍｏｌ）を水６０００ｇに溶解した水溶液を加えて未反応のＣＣＡを水層に除去した。有機層と水層を分離した後に、有機層を濃縮して、析出した結晶を濾過により回収し、Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸メチル（以下、Ｓ−ＣＣＭと記す）５００ｇ（１．８９ｍｏｌ）を得た。（収率３９．５ｍｏｌ％、化学純度９９．０％、光学純度９９％ｅｅ）。
４）Ｓ−（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の製造
上記のようにして製造したＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を６０℃に保って残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３１ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶（図１参照）３６５ｇ（１．４６ｍｏｌ、収率９２．４ｍｏｌ％、化学純度９９．７％、光学純度９９％ｅｅ）を得た。
1) Production of methyl (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate 100 g (0.657 mol) of 1,4-dihydroxy-2,3,5-trimethylbenzene, 110 g of formalin aqueous solution (formaldehyde 37 wt%, water 56 wt%, methanol 7 wt%) and methyl methacrylate 330 g (3.296 mol) were placed in a 1 L stainless steel autoclave and reacted at 180 ° C. with stirring for 3 hours. After cooling to 40 ° C., the precipitated crystals were filtered and rinsed twice with 200 g of methanol. The recovered crystals were dried and 135 g of the desired methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (hereinafter referred to as CCM) (0.478 mol as CCM, yield 72. 6%, chemical purity 93.5%).
2) Production of (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 16.7 g of CCM produced as described above (59.1 mmol as CCM, chemical purity 93.5 %), 16.7 g of methanol, 3.3 g (82.5 mmol) of NaOH, and 50 g of water were charged into a 200 ml glass container, and the ester was subjected to hydrolysis reaction with stirring at 80 ° C. for 1 hour in a nitrogen atmosphere. This reaction solution was filtered at the same temperature to remove insoluble matters, and then 11.7 g (85.9 mmol) of potassium hydrogen sulfate charged in a 300 mL glass container was dissolved in 50 g of water and kept in an acidic solution kept at 80 ° C. The solution was added dropwise over 1 hour. After completion of the neutralization treatment, when the stirring was stopped and the mixture was allowed to stand, the crystals quickly settled. The crystals were filtered off at 80 ° C., washed twice with 50 mL of water, and then vacuum-dried at 80 ° C. for 24 hours to give 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ( Hereinafter, 14.5 g (57.9 mmol) was obtained (referred to as CCA) (yield: 98.3%, chemical purity: 99.7%).
3) Production of methyl S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate 1200 g (4.79 mol) of CCA obtained by the above operation, 767 g (23.93) of methanol. ), 15000 g of isopropyl ether, 400 g of immobilized enzyme CHIRAZYMEL-2, cf, C2 (manufactured by Roche Diagnostics) were charged into a 200 ml stainless steel pressure vessel and replaced with Ar, then at 80 ° C. for 24 hours. Reaction was performed. After 24 hours, the catalyst was removed by filtration, and the reaction solution was recovered. To this reaction solution, an aqueous solution in which 760 g (7.17 mol) of sodium carbonate was dissolved in 6000 g of water was added to remove unreacted CCA in the aqueous layer. After separating the organic layer and the aqueous layer, the organic layer is concentrated, and the precipitated crystals are collected by filtration, and S-(−)-6-hydroxy-2,5,7,8-tetramethylchroman-2- 500 g (1.89 mol) of methyl carboxylate (hereinafter referred to as S-CCM) was obtained. (Yield 39.5 mol%, chemical purity 99.0%, optical purity 99% ee).
4) Production of S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 418 g (1.58 mol) of S-CCM produced as described above, 417.5 g of methanol , 82.0 g (2.05 mol) of NaOH and 1250 g of water were charged into a 3 L glass container, and the reaction was carried out with stirring at 80 ° C. for 1 hour in a nitrogen atmosphere. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 60 ° C. and the remaining acidic solution was added dropwise over 1 hour. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 31 wt%, and both the filterability and the crystal dryness were very good. After drying, 365 g (1.46 mol, yield 92.4 mol%, chemical purity 99.7%, optical purity 99% ee) of S-CCA granular crystals (see FIG. 1) were obtained.
実施例２
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を５０℃に保って残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３０ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶３６８ｇ（１．４７ｍｏｌ、収率９３．０ｍｏｌ％、化学純度９９．５％、光学純度９９％ｅｅ）を得た。
Example 2
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 50 ° C., and the remaining acidic solution was added dropwise over 1 hour. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 30 wt%, and both the filterability and the crystal dryness were very good. After drying, 368 g (1.47 mol, yield 93.0 mol%, chemical purity 99.5%, optical purity 99% ee) of S-CCA granular crystals were obtained.
実施例３
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を７０℃に保って残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は２９ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶３６３ｇ（１．４５ｍｏｌ、収率９１．８ｍｏｌ％、化学純度９９．６％、光学純度９９％ｅｅ）を得た。
Example 3
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 70 ° C., and the remaining acidic solution was added dropwise over 1 hour. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 29 wt%, and both the filterability and the crystal dryness were very good. After drying, 363 g (1.45 mol, yield 91.8 mol%, chemical purity 99.6%, optical purity 99% ee) of S-CCA granular crystals were obtained.
実施例４
実施例1で得られたＳ−ＣＣＭ２０９ｇ（０．７９ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を６０℃に保って残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３０ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶１８６ｇ（０．７４ｍｏｌ、収率９３．６ｍｏｌ％、化学純度９９．８％、光学純度９９％ｅｅ）を得た。
Example 4
209 g (0.79 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 60 ° C. and the remaining acidic solution was added dropwise over 1 hour. When the stirring was stopped after the completion of dropping, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 30 wt%, and both the filterability and the crystal dryness were very good. After drying, 186 g (0.74 mol, yield 93.6 mol%, chemical purity 99.8%, optical purity 99% ee) of S-CCA granular crystals were obtained.
実施例５
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた後、濾過によって不溶物を除いた。濾液に種結晶を1ｇ添加した後に、６０℃に保ちながら残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３１ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶３６８ｇ（１．４７ｍｏｌ、収率９３．０ｍｏｌ％、化学純度９９．７％、光学純度９９％ｅｅ）を得た。
Example 5
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Subsequently, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached, and then insoluble matters were removed by filtration. After adding 1 g of seed crystals to the filtrate, the remaining acidic solution was added dropwise over 1 hour while maintaining the temperature at 60 ° C. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 31 wt%, and both the filterability and the crystal dryness were very good. After drying, 368 g (1.47 mol, yield 93.0 mol%, chemical purity 99.7%, optical purity 99% ee) of S-CCA granular crystals were obtained.
実施例６
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ７になるまで加えた。濾過によって不溶物を除いた後、濾液を６０℃に保って残りの酸性溶液を１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３２ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶（図１参照）３６８ｇ（１．４７ｍｏｌ、収率９３．０ｍｏｌ％、化学純度９９．５％、光学純度９９％ｅｅ）を得た。
Example 6
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 7 was reached. After removing insolubles by filtration, the filtrate was kept at 60 ° C. and the remaining acidic solution was added dropwise over 1 hour. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 32 wt%, and both the filterability and the crystal drying property were very good. After drying, 368 g (1.47 mol, yield 93.0 mol%, chemical purity 99.5%, optical purity 99% ee) of S-CCA granular crystals (see FIG. 1) was obtained.
実施例７
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液を、６０℃に保った反応液に１時間かけて滴下した。滴下終了後、攪拌を停止すると、沈降分離性に優れた結晶が析出した。この結晶を濾過し、１２５０ｍＬの水で２回洗浄した。得られたスラリー状の結晶の含液率は３１ｗｔ％であり、濾過性、結晶の乾燥性共に非常に良好であった。乾燥後にＳ−ＣＣＡの顆粒状結晶（図１参照）３７５ｇ（１．５０ｍｏｌ、収率９４．９ｍｏｌ％、化学純度９９．０％、光学純度９９％ｅｅ）を得た。
Example 7
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution obtained by dissolving 292.5 g (2.15 mol) of potassium hydrogen sulfate in 1250 g of water was added dropwise to the reaction solution kept at 60 ° C. over 1 hour. When the stirring was stopped after the completion of the dropwise addition, crystals having excellent sedimentation properties were precipitated. The crystals were filtered and washed twice with 1250 mL water. The liquid content of the obtained slurry-like crystals was 31 wt%, and both the filterability and the crystal dryness were very good. After drying, 375 g (1.50 mol, yield 94.9 mol%, chemical purity 99.0%, optical purity 99% ee) of S-CCA granular crystals (see FIG. 1) was obtained.
比較例１
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を２５℃に保って残りの酸性溶液を１時間かけて滴下した。中和処理途中から混合液全体がペースト状となり、中和処理終了後、攪拌を止め静置しても、結晶の沈降分離は起こらなかった。濾過は可能であったが、濾過性は非常に悪く６時間を要した。この濾別した結晶を１０００ｇの水で２回洗浄したが洗浄効果に乏しく中和塩の除去は不充分であった（分析の結果２．７ｇの中和塩が残存していた）。スラリー状の結晶を圧搾した後、さらに１０００ｇの水で２回洗浄し水切りした後、８０℃で２４時間、真空乾燥したが乾燥にも長時間を要した。なお、濾別後、真空乾燥に供した結晶スラリーの含液率は７５ｗｔ％で、乾燥し難く、粉立ちも多い取り扱い性の悪い細かい粉末状の結晶（図2参照）となった。最終的に、Ｓ−ＣＣＡの微粉末結晶３６５ｇ（１．４６ｍｏｌ、収率９２．３ｍｏｌ％、化学純度９８．５％、光学純度９９％ｅｅ）を得た。
Comparative Example 1
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 25 ° C., and the remaining acidic solution was added dropwise over 1 hour. From the middle of the neutralization treatment, the whole mixed solution became a paste, and even after the neutralization treatment was finished, even if stirring was stopped and the mixture was allowed to stand, no sedimentation of crystals occurred. Although filtration was possible, the filterability was very poor and took 6 hours. The crystals separated by filtration were washed twice with 1000 g of water, but the washing effect was poor and the removal of neutralized salt was insufficient (analysis of 2.7 g of neutralized salt remained). After the slurry crystals were squeezed and further washed twice with 1000 g of water and drained, they were vacuum-dried at 80 ° C. for 24 hours, but drying took a long time. After filtration, the liquid content of the crystal slurry subjected to vacuum drying was 75 wt%, resulting in fine powder crystals (see FIG. 2) that were difficult to dry and poorly handled with much powdering. Finally, 365 g (1.46 mol, yield 92.3 mol%, chemical purity 98.5%, optical purity 99% ee) of fine powder of S-CCA was obtained.
比較例２
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を３５℃に保って残りの酸性溶液を１時間かけて滴下した。中和処理途中から混合液全体がペースト状となり、中和処理終了後、攪拌を止め静置しても、結晶の沈降分離は起こらなかった。濾過は可能であったが、濾過性は非常に悪く６時間を要した。この濾別した結晶を１０００ｇの水で２回洗浄したが洗浄効果に乏しく中和塩の除去は不充分であった（分析の結果２．６ｇの中和塩が残存していた）。スラリー状の結晶を圧搾した後、さらに１０００ｇの水で２回洗浄し水切りした後、８０℃で２４時間、真空乾燥したが乾燥にも長時間を要した。なお、濾別後、真空乾燥に供した結晶スラリーの含液率は７２ｗｔ％で、乾燥し難く、粉立ちも多い取り扱い性の悪い細かい粉末状の結晶となった。最終的に、Ｓ−ＣＣＡの微粉末結晶３６８ｇ（１．４７ｍｏｌ、収率９３．１ｍｏｌ％、化学純度９８．６％、光学純度９９％ｅｅ）を得た。
Comparative Example 2
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 35 ° C., and the remaining acidic solution was added dropwise over 1 hour. From the middle of the neutralization treatment, the whole mixed solution became a paste, and even after the neutralization treatment was finished, even if stirring was stopped and the mixture was allowed to stand, no sedimentation of crystals occurred. Although filtration was possible, the filterability was very poor and took 6 hours. The crystals separated by filtration were washed twice with 1000 g of water, but the washing effect was poor and the removal of neutralized salt was insufficient (analysis of 2.6 g of neutralized salt remained as a result of analysis). After the slurry crystals were squeezed and further washed twice with 1000 g of water and drained, they were vacuum-dried at 80 ° C. for 24 hours, but drying took a long time. After filtration, the liquid content of the crystal slurry subjected to vacuum drying was 72 wt%, and it became difficult to dry, resulting in fine powdery crystals with poor powder handling properties. Finally, 368 g (1.47 mol, yield 93.1 mol%, chemical purity 98.6%, optical purity 99% ee) of fine powder of S-CCA was obtained.
比較例３
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液をｐＨ５になるまで加えた。濾過によって不溶物を除いた後、濾液を４５℃に保って残りの酸性溶液を１時間かけて滴下した。中和処理途中から混合液全体がペースト状となり、中和処理終了後、攪拌を止め静置しても、結晶の沈降分離は起こらなかった。濾過は可能であったが、濾過性は非常に悪く６時間を要した。この濾別した結晶を１０００ｇの水で２回洗浄したが洗浄効果に乏しく中和塩の除去は不充分であった（分析の結果２．７ｇの中和塩が残存していた）。スラリー状の結晶を圧搾した後、さらに１０００ｇの水で２回洗浄し水切りした後、８０℃で２４時間、真空乾燥したが乾燥にも長時間を要した。なお、濾別後、真空乾燥に供した結晶スラリーの含液率は６０ｗｔ％で、乾燥し難く、粉立ちも多い取り扱い性の悪い細かい粉末状の結晶となった。最終的に、Ｓ−ＣＣＡの微粉末結晶３６２ｇ（１．４５ｍｏｌ、収率９１．５ｍｏｌ％、化学純度９８．７％、光学純度９９％ｅｅ）を得た。
Comparative Example 3
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution in which 292.5 g (2.15 mol) of potassium hydrogen sulfate was dissolved in 1250 g of water was added until pH 5 was reached. After removing insolubles by filtration, the filtrate was kept at 45 ° C., and the remaining acidic solution was added dropwise over 1 hour. From the middle of the neutralization treatment, the whole mixed solution became a paste, and even after the neutralization treatment was finished, even if stirring was stopped and the mixture was allowed to stand, no sedimentation of crystals occurred. Although filtration was possible, the filterability was very poor and took 6 hours. The crystals separated by filtration were washed twice with 1000 g of water, but the washing effect was poor and the removal of neutralized salt was insufficient (analysis of 2.7 g of neutralized salt remained). After the slurry crystals were squeezed and further washed twice with 1000 g of water and drained, they were vacuum-dried at 80 ° C. for 24 hours, but drying took a long time. After filtration, the liquid content of the crystal slurry subjected to vacuum drying was 60 wt%, and it became difficult to dry, resulting in fine powdery crystals with poor powder handling properties. Finally, 362 g (1.45 mol, yield 91.5 mol%, chemical purity 98.7%, optical purity 99% ee) of S-CCA fine powder crystals were obtained.
比較例４
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液を、２５℃に保った反応液に１時間かけて滴下した。中和処理途中から混合液全体がペースト状となり、中和処理終了後、攪拌を止め静置しても、結晶の沈降分離は起こらなかった。濾過は可能であったが、濾過性は非常に悪く６時間を要した。この濾別した結晶を１０００ｇの水で２回洗浄したが洗浄効果に乏しく中和塩の除去は不充分であった（分析の結果２．７ｇの中和塩が残存していた）。スラリー状の結晶を圧搾した後、さらに１０００ｇの水で２回洗浄し水切りした後、８０℃で２４時間、真空乾燥したが乾燥にも長時間を要した。なお、濾別後、真空乾燥に供した結晶スラリーの含液率は７４ｗｔ％で、乾燥し難く、粉立ちも多い取り扱い性の悪い細かい粉末状の結晶となった。最終的に、Ｓ−ＣＣＡの微粉末結晶３６０ｇ（１．４４ｍｏｌ、収率９１．１ｍｏｌ％、化学純度９８．２％、光学純度９９％ｅｅ）を得た。
Comparative Example 4
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution obtained by dissolving 292.5 g (2.15 mol) of potassium hydrogen sulfate in 1250 g of water was added dropwise to the reaction solution maintained at 25 ° C. over 1 hour. From the middle of the neutralization treatment, the whole mixed solution became a paste, and even after the neutralization treatment was finished, even if stirring was stopped and the mixture was allowed to stand, no sedimentation of crystals occurred. Although filtration was possible, the filterability was very poor and took 6 hours. The crystals separated by filtration were washed twice with 1000 g of water, but the washing effect was poor and the removal of neutralized salt was insufficient (analysis of 2.7 g of neutralized salt remained). After the slurry crystals were squeezed and further washed twice with 1000 g of water and drained, they were vacuum-dried at 80 ° C. for 24 hours, but drying took a long time. After filtration, the liquid content of the crystal slurry subjected to vacuum drying was 74 wt%, and it became difficult to dry, resulting in fine powdery crystals with poor powder handling properties. Finally, 360 g (1.44 mol, yield 91.1 mol%, chemical purity 98.2%, optical purity 99% ee) of fine powder of S-CCA was obtained.
比較例５
実施例1で得られたＳ−ＣＣＭ４１８ｇ（１．５８ｍｏｌ）、メタノール４１７．５ｇ、ＮａＯＨ８２．０ｇ（２．０５ｍｏｌ）、水１２５０ｇを３Ｌのガラス容器に仕込み、窒素雰囲気下に８０℃で１時間攪拌しながら反応を行った。次いで、硫酸水素カリウム２９２．５ｇ（２．１５ｍｏｌ）を１２５０ｇの水に溶かした酸性溶液を、１００℃に保った反応液に１時間かけて滴下した。中和処理終了後、攪拌を止め静置すると、オイル層と水層に分離した。これを攪拌しながら室温まで下げると、一度にオイル層の結晶化が起こり塊状の結晶となった。これを取り出し、ろ過を行うと、外観上も不均一な結晶であった。この濾別した結晶を１０００ｇの水で２回洗浄した後、８０℃で２４時間真空乾燥した。なお、濾別後、真空乾燥に供した結晶スラリーの含液率は５０ｗｔ％で、乾燥し難くかった。最終的に、Ｓ−ＣＣＡの結晶３４９ｇ（１．３９ｍｏｌ、収率８８．３ｍｏｌ％、化学純度９８．０％、光学純度９９％ｅｅ）を得た。
Comparative Example 5
418 g (1.58 mol) of S-CCM obtained in Example 1, 417.5 g of methanol, 82.0 g (2.05 mol) of NaOH, and 1250 g of water were charged into a 3 L glass container and stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. The reaction was carried out. Next, an acidic solution obtained by dissolving 292.5 g (2.15 mol) of potassium hydrogen sulfate in 1250 g of water was added dropwise to the reaction solution maintained at 100 ° C. over 1 hour. After completion of the neutralization treatment, stirring was stopped and the mixture was allowed to stand to separate into an oil layer and an aqueous layer. When the temperature was lowered to room temperature while stirring, the oil layer was crystallized at one time and became massive crystals. When this was taken out and filtered, the crystals were non-uniform in appearance. The crystals separated by filtration were washed twice with 1000 g of water and then vacuum-dried at 80 ° C. for 24 hours. In addition, the liquid content of the crystal slurry subjected to vacuum drying after filtration was 50 wt%, and it was difficult to dry. Finally, 349 g of S-CCA crystals (1.39 mol, yield 88.3 mol%, chemical purity 98.0%, optical purity 99% ee) was obtained.
Claims (5)
（１）
（但し、一般式（１）におけるＲは、アルキル基又はアリール基を表す。） S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid ester represented by the general formula (1) is hydrolyzed to produce S-(-)-6-hydroxy. In the process for producing -2,5,7,8-tetramethylchroman-2-carboxylic acid, S-(-)-6-hydroxy-2,5,7, represented by the general formula (1) After 8-tetramethylchroman-2-carboxylic acid ester is hydrolyzed under basic conditions, insolubles contained in the reaction solution are removed, and the resulting treatment solution is heated at a temperature range of 50 to 80 ° C. A method for producing S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, characterized in that
(1)
(However, R in the general formula (1) represents an alkyl group or an aryl group.)
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