JPS6127996A - Method for separating anomer of 1,2,3,4-tetra-o-acetyl-d-glucopyranuronic acid - Google Patents

Abstract

PURPOSE:To obtain the respective anomers in high recovery ratio, by easily separating alpha-anomer of tetra-O-acetyl-D-glucopyranuronic acid and beta-anomer thereof utilizing the solubility difference in ethyl ether. CONSTITUTION:Ethyl ehter is added to a mixture of alpha-anomer of 1,2,3,4-telra- O-acetyl-alpha-D-glucopyranuronic acid, obtained by acetylating D-glucuronic acid, and expressed by formula I with beta-anomer expressed by formula II to separate both utilizing the fact that the compound expressed by formula I is readily soluble in the ethyl ether and the compound expressed by formula II is sparingly soluble in the ethyl ether. The compound expressed by formula II is preferably separated by a method, e.g. filtration, dried and if necessary recrystallized from toluene. The compound expressed by formula I is usually obtained by removing the ethyl ether under reduced pressure.

Description

【発明の詳細な説明】 １．２．３．４−テトラ−Ｏ−アセチル−Ｄ−グルコピ
ラヌロン酸には、その１位のアセトキシ基の、立体配置
の違いによって、（■）式で示されるα−アノマーと５
（■）式で示されるβ−アノマーの、両異性体が存在す
る。糖類は、一般にアノマー間で、反応性の差異の有る
事が知られて居シ、糖誘導体の合成に於いて、生成物が
アノマー混合物となる場合には、そのアノマーの分離が
必要となる。Detailed Description of the Invention 1.2.3.4-Tetra-O-acetyl-D-glucopyranuronic acid has α -Anomer and 5
Both isomers of the β-anomer represented by the formula (■) exist. It is generally known that there are differences in reactivity between anomers of saccharides, and in the synthesis of sugar derivatives, when the product is a mixture of anomers, it is necessary to separate the anomers.

（Ｉ）式の化合物と（ＩＩ）式の化合物の間にも。Also between a compound of formula (I) and a compound of formula (II).

反応性の差が有シ、特に無水酢酸中での、塩基共存下に
於ける分解反応に於いては、（Ｉ）式の化合物に比較し
て（■）式の化合物が、医薬品等の合成中間体として、
広範な利用が期待されるコマン酸に、分解され易い事を
見出し、コマン酸の製造法として既に特許を出願して居
る、 この例からも判かる様に、（Ｉ）式の化合物と（ＩＩ）
式の化合物とは、それぞれ異なる反応性を秘めて居シ、
１．２．３．４−テトラ−Ｏ−アセチルーＤ−グルコピ
ラヌロン酸を、工業的に利用しようとする場合には、む
しろ、（■）式の化合物と（ＩＦ）式の化合物は、別種
の化合物と考える方が、よシ現実的であると言える。し
かしながら、従来知られて居るアセチル化反応では、（
■）式の化合物、又は（Ｉ［）式の化合物のみを、選択
的に合成する事は困難であり、生成物は、両者の混合物
に成らざるを得ないのが現状である。従って、（Ｉ）式
の化合物、又は（■）式の化合物を、工業的に利用しよ
うとする場合、又はそれらの利用法を開発しようとする
場合にも（Ｉ）式の化合物と、ｌ’ＩＩ）式の化合物の
分離は、重要なプロセスとなる。There is a difference in reactivity, especially in the decomposition reaction in acetic anhydride in the presence of a base, the compound of formula (■) is more effective in the synthesis of pharmaceuticals, etc. than the compound of formula (I). As an intermediate,
We discovered that comanic acid, which is expected to be widely used, is easily decomposed, and have already filed a patent application for a method for producing comanic acid.As can be seen from this example, the compound of formula (I) and (II )
The compounds of the formula have different reactivities,
1.2.3. When attempting to industrially utilize 4-tetra-O-acetyl-D-glucopyranuronic acid, the compound of formula (■) and the compound of formula (IF) should rather be treated as different types of compounds. It is more realistic to think that way. However, in the conventionally known acetylation reaction, (
It is difficult to selectively synthesize only the compound of the formula (2) or the compound of the formula (I[), and the current situation is that the product must be a mixture of both. Therefore, when trying to industrially utilize the compound of formula (I) or the compound of formula (■), or when trying to develop a method for using them, the compound of formula (I) and the compound of formula (■), l' II) The separation of compounds of formula becomes an important process.

従来、（Ｉ）式の化合物と（Ｉ［）式の化合物の分離法
に関しては、唯一、Ｅ、Ｍ、Ｆｒ７の報告（Ｊ。Conventionally, regarding the separation method of the compound of formula (I) and the compound of formula (I[), there is only one report by E, M, Fr7 (J.

Ａｍｅｒ、Ｃｈｅｍ、８ｏｃ、　、　１９５５　、７７
　、３９１５　、］が知られて居る。当該文献に記載さ
れて居る処に依ると、（Ｉ）式の化合物と（ＩＩ）式の
化合物の分離は、一旦、得られた両者の混合物を、ピリ
ジン中に溶解させて、ピリジニウム塩とした後。Amer, Chem, 8oc, 1955, 77
, 3915,] are known. According to the document, the compound of formula (I) and the compound of formula (II) are separated by dissolving the resulting mixture in pyridine to form a pyridinium salt. rear.

ＣＩ）式の化合物のピリジニウム塩が、エーテルして、
両者を分離して居る。しかし、こうして得られる、（Ｉ
）式の化合物と（ＩＩ）式の化合物は、ピリジニウム塩
であシ、カルボキシル基遊離の型にする為には、単離さ
れた（Ｉ）式の化合物及び（ＩＩ）式の化合物のピリジ
ニウム塩を、それぞれ水溶液とした後、塩酸で溶液を酸
性とし、それぞれの、結晶を析出させると言うプロセス
を、経なければならなり０更に、こうして得られる結晶
は、（Ｉ）式の化合物の場合は、そのまま、再結晶に依
って精選出来るが、（■）式の化合物の場合、水和物と
して析出する為、更に結晶水を取除く操作を行なった後
に、再結晶に依る精製を１行わなければならない。The pyridinium salt of the compound of formula CI) is an ether,
The two are kept separate. However, thus obtained, (I
) The compound of formula (I) and the compound of formula (II) are pyridinium salts, and in order to make the carboxyl group free form, the isolated pyridinium salt of the compound of formula (I) and the compound of formula (II) is used. After making each into an aqueous solution, the solution must be acidified with hydrochloric acid to precipitate the respective crystals.Furthermore, in the case of the compound of formula (I), the crystals obtained in this way are However, in the case of the compound of formula (■), since it precipitates as a hydrate, it is necessary to perform a further purification by recrystallization after removing the water of crystallization. Must be.

この様に、従来法ではＣＩ）式の化合物と（■）式の化
合物との混合物からそれぞれを単離する為に、煩雑なプ
ロセスを経なければならない事から、（Ｉ）式の化合物
又は（ＩＩ）式の化合物を、工業的に広く利用する為に
は、よシ簡便な分離法の開発が急務であると考え、鋭意
検討した結果１本発明の方法を、見出すに到った。As described above, in the conventional method, in order to isolate each compound from a mixture of the formula CI) and the compound of the formula (■), a complicated process has to be carried out. In order to widely utilize the compound of formula II) industrially, we believe that there is an urgent need to develop a simpler separation method, and as a result of intensive studies, we have discovered the method of the present invention.

本発明の方法は、Ｄ−グルクロン酸及びＤ−グルクロン
酸の塩類を出発物質とする。アセチル化反応に於いて、
用いるアセチル化剤、触媒、及び反応条件に対応して得
られる１種々の比率の。The method of the invention uses D-glucuronic acid and salts of D-glucuronic acid as starting materials. In the acetylation reaction,
Various ratios can be obtained depending on the acetylating agent, catalyst, and reaction conditions used.

（Ｉ）式の化合物と（■）式の化合物との混合物を、前
述の既知の方法の場合の様に、一旦ピリジニウム塩とす
る事無く、エチルエーテルで処理し。A mixture of a compound of formula (I) and a compound of formula (■) is treated with ethyl ether without first converting it into a pyridinium salt, as is the case in the known process described above.

直接それぞれのアノマー忙高い回収率で分離出来る事を
、特徴としである。It is characterized by the ability to directly separate each anomer with a high recovery rate.

分離操作は、アセチル化反応後、用いたアセチル化剤及
び触媒を除去して得られる（Ｉ）式の化合物と、（Ｉｔ
）式の化合物の混合物に、エチルエニーチルには少量ず
つ溶解する事から、この操作に用いるエーテルの量に、
特に制限は無いが、析出した（ＩＩ）式の化合物を、分
取するのに必要最少限の量にする事が望ましい。炉取等
の方法に依って分取された（ＩＩ）式の化合物は、少量
の予じめ冷却して置いたエーテルで洗浄し、乾燥後、必
要に応じて、トルエンから再結晶する。洗液は。In the separation operation, after the acetylation reaction, the compound of formula (I) obtained by removing the acetylating agent and catalyst used, and (It
) Since ethyl enethyl dissolves in small amounts in the mixture of compounds of formula ), the amount of ether used in this operation is
Although there are no particular limitations, it is desirable to reduce the amount of the precipitated compound of formula (II) to the minimum necessary for fractionation. The compound of formula (II) separated by a method such as furnace collection is washed with a small amount of pre-cooled ether, dried, and then recrystallized from toluene if necessary. The washing liquid.

先に得られたろ液と合せて、減圧下にエーテルを除去し
た後、再びエーテルを加え、結晶が析出する様であれば
、更に前述の分離操作を、繰り返す。After combining the filtrate obtained earlier and removing ether under reduced pressure, ether is added again, and if crystals appear to precipitate, the above separation operation is repeated.

この操作をＦ液と洗液を合わせて、減圧下に濃縮　　　
・して得られる残渣に、エーテルを加え、結晶が析出し
なくなる迄、繰）返す。Combine this operation with solution F and washing solution and concentrate under reduced pressure.
・Add ether to the resulting residue and repeat until no crystals precipitate.

こうして得られるエーテル可溶物は、減圧下でエーテル
を除去すると結晶として得られるが、結晶しにくい場合
には、エタノールを、１〜２滴加え、結晶させる。得ら
れたエーテル可溶の、（］）式の化合物の結晶は、必要
に応じて、エタノールから再結晶させ、精製する。The ether-soluble material thus obtained can be obtained as crystals by removing the ether under reduced pressure, but if crystallization is difficult, add 1 to 2 drops of ethanol to crystallize. The obtained ether-soluble crystals of the compound of formula (]) are purified by recrystallization from ethanol, if necessary.

次に実施例を挙げて、本発明の方法を、更に具体的に説
明するが１本発明は、これに依って何等制限されるもの
では無い。Next, the method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto in any way.

実施例１ ０、１　！ｑの、Ｄ−グル（ロン酸を無水酢酸−スルホ
ン酸型イオン交換樹脂（ＤＯＷＥＸ５０ＷＸ２　）の系
で、アセチル化して得られる、（■）式の化合物と（Ｉ
Ｉ）式の化合物　　　　　　　　　の混合物に、１ｍＡ
！のエーテルを加えると、結晶が析出する。Example 1 0, 1! A compound of formula (■) obtained by acetylating D-glu (ronic acid) of q with an acetic anhydride-sulfonic acid type ion exchange resin (DOWEX50WX2) and (I)
I) 1 mA to a mixture of compounds of formula
! When adding ether, crystals precipitate.

結晶を炉取後、予め冷却したエーテル少量で洗浄する。After the crystals are removed from the furnace, they are washed with a small amount of pre-cooled ether.

この段階で得られる（ＩＩ）式の化合物の結晶は０．１
３４１１（７１，７チ）である。先に得られた。Ｆ液と
洗液を合せ、減圧下に濃縮して得られる瓢オイル状の残
渣に％０．５　ｍｌのエーテルを加えると、更に結晶が
析出する。この結晶は、（ｎ）式の化合物の結晶で、０
．００６．９　（３，２チ）であった。The crystals of the compound of formula (II) obtained in this step are 0.1
It is 3411 (71,7chi). Got it first. When 0.5 ml of ether is added to the gourd oil-like residue obtained by combining the F solution and the washing solution and concentrating under reduced pressure, further crystals are precipitated. This crystal is a crystal of a compound of formula (n), and 0
．． It was 006.9 (3.2ch).

２回目の、（ＩＩ）式の化合物の分離操作で生じ７’Ｃ
，Ｆ液と洗液を合せて、減圧下に濃縮して得られるオイ
ル状の残渣に、エタノールを１滴加え。7'C generated in the second separation operation of the compound of formula (II)
, Add one drop of ethanol to the oily residue obtained by combining solution F and washing solution and concentrating under reduced pressure.

振とりすると、結晶が析出しはじめる。更に少量のエタ
ノールを添加した後、３〜４時間フリーザー中で冷却し
て、充分結晶を析出させる。析出した結晶は、Ｆ取後、
予じめ冷却して置いた少量のエタノールで洗浄後、減圧
下に乾燥する。この操作に依り（１）式の結晶０．３２
．９　（１７，１％　）を得た。When shaken, crystals begin to precipitate. After further adding a small amount of ethanol, the mixture is cooled in a freezer for 3 to 4 hours to sufficiently precipitate crystals. After removing the F, the precipitated crystals are
After washing with a small amount of pre-chilled ethanol, it is dried under reduced pressure. By this operation, the crystal of formula (1) is 0.32
．． 9 (17.1%).

実施例２ １０．９の、Ｄ−グルクロン酸を、無水酢酸−トリフル
オロ酢酸系で、アセチル化して得られる。Example 2 D-glucuronic acid of 10.9 is acetylated with an acetic anhydride-trifluoroacetic acid system.

（Ｉ）式の化合物と（ＩＩ）式の化合物との混合物を、
実施例１の場合に準じた操作で処理し、（Ｉ）式の化合
物３．０８．９　（１６，５％）と、（■）式の「ヒ合
物１４．２．９　（７６，０チ）を得た。A mixture of a compound of formula (I) and a compound of formula (II),
The treatment was carried out in the same manner as in Example 1, and the compound of formula (I) 3.08.9 (16.5%) and the compound of formula (■) 14.2.9 (76.0%) were obtained. h) was obtained.

Claims (1)

【特許請求の範囲】 式 ▲数式、化学式、表等があります▼（ I ） で示される、１，２，３，４−テトラ−Ｏ−アセチル−
α−Ｄ−グルコピラヌロン酸と、式 ▲数式、化学式、表等があります▼（II） で示される、１，２，３，４−テトラ−Ｏ−アセチル−
β−Ｄ−グルコピラヌロン酸との、エチルエーテルへの
溶解性の差を利用する事を特徴とする１，２，３，４−
テトラ−Ｏ−アセチル−Ｄ−グルコピラヌロン酸のアノ
マーの分離法。[Claims] 1,2,3,4-tetra-O-acetyl- represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I)
α-D-glucopyranuronic acid and the 1,2,3,4-tetra-O-acetyl-
1,2,3,4- characterized by utilizing the difference in solubility in ethyl ether from β-D-glucopyranuronic acid.
A method for separating the anomer of tetra-O-acetyl-D-glucopyranuronic acid.