JPH01315401A - Purification of beta-cyclodextrin sulfuric ester salt - Google Patents
Purification of beta-cyclodextrin sulfuric ester saltInfo
- Publication number
- JPH01315401A JPH01315401A JP6125489A JP6125489A JPH01315401A JP H01315401 A JPH01315401 A JP H01315401A JP 6125489 A JP6125489 A JP 6125489A JP 6125489 A JP6125489 A JP 6125489A JP H01315401 A JPH01315401 A JP H01315401A
- Authority
- JP
- Japan
- Prior art keywords
- cyclodextrin
- salt
- alkali metal
- beta
- metal salt
- 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
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 38
- -1 ester salt Chemical class 0.000 title claims abstract description 36
- 239000001116 FEMA 4028 Substances 0.000 title claims abstract description 35
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 title claims abstract description 35
- 235000011175 beta-cyclodextrine Nutrition 0.000 title claims abstract description 35
- 229960004853 betadex Drugs 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000012141 concentrate Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 229920001353 Dextrin Polymers 0.000 claims 1
- 239000004375 Dextrin Substances 0.000 claims 1
- 235000019425 dextrin Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 22
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000012530 fluid Substances 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 235000019441 ethanol Nutrition 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- AMHIJMKZPBMCKI-PKLGAXGESA-N ctds Chemical compound O[C@@H]1[C@@H](OS(O)(=O)=O)[C@@H]2O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@H](CO)[C@H]1O[C@@H](O[C@@H]1CO)[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H]1O[C@@H](O[C@@H]1CO)[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H]1O[C@@H](O[C@@H]1CO)[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H]1O[C@@H](O[C@@H]1CO)[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H]1O[C@@H](O[C@@H]1CO)[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H]1O2 AMHIJMKZPBMCKI-PKLGAXGESA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- NTSKOZMSQFZPKG-ZENAZSQFSA-N (3s)-3-amino-4-(2-diphenoxyphosphorylpyrrolidin-1-yl)-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](N)C(=O)N1CCCC1P(=O)(OC=1C=CC=CC=1)OC1=CC=CC=C1 NTSKOZMSQFZPKG-ZENAZSQFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000002391 anti-complement effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 108010008730 anticomplement Proteins 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- YYHPEVZFVMVUNJ-UHFFFAOYSA-N n,n-diethylethanamine;sulfur trioxide Chemical compound O=S(=O)=O.CCN(CC)CC YYHPEVZFVMVUNJ-UHFFFAOYSA-N 0.000 description 1
- AFDQGRURHDVABZ-UHFFFAOYSA-N n,n-dimethylformamide;sulfur trioxide Chemical compound O=S(=O)=O.CN(C)C=O AFDQGRURHDVABZ-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は抗炎症作用、免疫賦活作用、抗補体活性。[Detailed description of the invention] [Industrial application field] The present invention has anti-inflammatory effect, immunostimulatory effect, and anti-complement activity.
抗腫瘍作用等の生理活性を示すβ−シクロデキストリン
硫酸エステルアルカリ金属塩の精製方法に関する。The present invention relates to a method for purifying an alkali metal salt of β-cyclodextrin sulfate that exhibits physiological activities such as antitumor activity.
〔従来技術及び発明が解決しようとする課題〕β−シク
ロデキストリン硫酸エステルアルカリ金属塩の精製方法
としては、例えば、ＵＳＰ ２．９２３．７０４にβ−
シクロデキストリンヘニコサ硫酸エステルピリジニウム
塩を含有する反応溶液にメチルアルコールを加えてその
塩を析出させ、これを水に溶解し、ついで酢酸ナトリウ
ム水を加えて塩交換し、これにエチルアルコールを加え
て目的のβ−シクロデキストリンヘニフサ硫酸エステル
ナトリウム塩を析出させ、精製する方法が記載されてい
る。またＵＳＰ ４．０２０．１６０にはβ−シクロデ
キストリンポリ硫酸エステル塩（トリエチルアンモニウ
ム塩等）の反応溶液にア七トン、又はメタノール等を加
えてその塩を析出させ、これを水、酢酸ナトリウム水と
エチルアルコールとの混合溶媒から精製する方法が記載
されている。[Prior Art and Problems to be Solved by the Invention] As a method for purifying β-cyclodextrin sulfate alkali metal salt, for example, β-
Methyl alcohol is added to a reaction solution containing cyclodextrin henicosa sulfate pyridinium salt to precipitate the salt, which is dissolved in water, then sodium acetate water is added for salt exchange, and ethyl alcohol is added to this. A method for precipitating and purifying the desired β-cyclodextrin heniftha sulfate sodium salt is described. In addition, USP 4.020.160 states that a7ton, methanol, etc. are added to a reaction solution of β-cyclodextrin polysulfate salt (triethylammonium salt, etc.) to precipitate the salt, and this is mixed with water, sodium acetate solution, etc. A method of purification from a mixed solvent of and ethyl alcohol is described.
しかしこれらの方法はいずれも大量の溶媒が必要であり
、析出物の粒度が細かくる取が困難であるなど単離が容
易でなく、また取り扱いやすく純度のよい目的物を得る
ためには極めて複雑な処理を必要とするなどの欠点を有
している。However, all of these methods require a large amount of solvent, are difficult to isolate because the particle size of the precipitate is fine and difficult to remove, and are extremely complicated to obtain a target product that is easy to handle and has good purity. It has disadvantages such as requiring extensive processing.
本発明はβ−シクロデキストリン硫酸エステルアルカリ
金属塩を含有する反応液を濃縮乾固し、濃縮物を水に溶
解しこの水溶液を親水性溶媒と混合して目的物を析出さ
せることを特徴をするβ−シクロデキストリン硫酸エス
テルアルカリ金属塩の精製方法に関する。The present invention is characterized in that a reaction solution containing a β-cyclodextrin sulfate alkali metal salt is concentrated to dryness, the concentrate is dissolved in water, and this aqueous solution is mixed with a hydrophilic solvent to precipitate the target product. The present invention relates to a method for purifying β-cyclodextrin sulfate alkali metal salt.
本発明の精製方法で用いられるβ−シクロデキストリン
硫酸エステルアルカリ金属塩は、β−シクロデキストリ
ンの水酸基の少なくとも１個が硫酸エステルアルカリ金
属塩となっていればよい。The β-cyclodextrin sulfate alkali metal salt used in the purification method of the present invention may be such that at least one of the hydroxyl groups of β-cyclodextrin is the sulfate alkali metal salt.
好ましい具体例を挙げれば、例えばβ−シクロデキスト
リンモノ硫酸エステルアルカリ金属塩、ヘプタ硫酸エス
テルアルカリ金属塩、テトラデカ硫酸エステルアルカリ
金属塩またはヘプタ硫酸エステルアルカリ金属塩などで
ある。このうち好ましくは、β−ンクロデキストリンテ
トラデ力硫酸エステルアルカリ金属塩である。Preferred specific examples include alkali metal salts of β-cyclodextrin monosulfate, alkali metal salts of heptasulfate, alkali metal salts of tetradeca sulfate, and alkali metal salts of heptasulfate. Among these, β-cyclodextrin tetradeoxysulfate alkali metal salts are preferred.
β−７クロデキストリン硫酸エステルアルカリ金属塩の
アルカリ金属としては、好ましくはナトリウム、カリウ
ムが用いられる。As the alkali metal of the β-7 clodextrin sulfate alkali metal salt, sodium and potassium are preferably used.
本発明方法に供されるβ−シクロデキストリン硫酸エス
テルアルカリ金属塩の反応液は公知方法もしくはこれに
類似する方法、または下記に詳細に記載する方法により
製造することができる。The reaction solution of β-cyclodextrin sulfate alkali metal salt used in the method of the present invention can be produced by a known method or a method similar thereto, or a method described in detail below.
以下本発明精製方法を各工程ごとに説明する。Each step of the purification method of the present invention will be explained below.
直貧乾恩工韮
本工程はβ−シクロデキストリン硫酸エステルアルカリ
金属塩を含有する反応液を減圧下または常圧下に濃縮す
ることにより行われる。減圧度は好ましくは約０．Ｏｌ
から５００ｍｓＨｇ、さらに好ましくは約０，１から１
００ｍｍ１１ｇである。温度は約０から１００°Ｃ１好
ましくは約１０から５０℃である。The process is carried out by concentrating the reaction solution containing the β-cyclodextrin sulfate alkali metal salt under reduced pressure or normal pressure. The degree of reduced pressure is preferably about 0. Ol
to 500msHg, more preferably about 0.1 to 1
00mm 11g. The temperature is about 0 to 100°C, preferably about 10 to 50°C.
濃縮乾固に要する時間は溶媒量、温度等によっても異な
るが、一般に約ｌから２４時間程度である。The time required for concentration to dryness varies depending on the amount of solvent, temperature, etc., but is generally about 1 to 24 hours.
本工程では反応溶媒や液体状の反応試薬、または反応に
より生じる液体状の副生成物をできるだけ除去し、乾固
状態にすることが重要である。In this step, it is important to remove as much as possible the reaction solvent, liquid reaction reagent, or liquid by-products produced by the reaction, and to dry it.
目的物の析出工程
ｌ農縮物は溶媒などの液体をできるだけ除去した固体状
のものが用いられる。この濃縮物は水に溶解した後、こ
の濃縮物の水溶液を親水性溶媒に加えるか、または濃縮
物の水溶液に親水性溶媒を加えることにより行われる。Step of Precipitating the Target Product 1 The agricultural product used is a solid product from which liquids such as solvents have been removed as much as possible. The concentrate is prepared by dissolving it in water and then adding an aqueous solution of the concentrate to a hydrophilic solvent, or by adding a hydrophilic solvent to an aqueous solution of the concentrate.
親水性溶媒としては、例えばメチルアルコール。Examples of hydrophilic solvents include methyl alcohol.
エチルアルコール、プロピルアルコールなどのアルコー
ル類、アセトン、メチルエチルケトンなどのケトン類、
アセトニトリルなどのニトリル類、ジオキサン、テトラ
ヒドロフランなどのエーテル類が用いられる。好ましく
は、アルコール類である。特に好ましくはエチルアルコ
ールである。Alcohols such as ethyl alcohol and propyl alcohol, ketones such as acetone and methyl ethyl ketone,
Nitriles such as acetonitrile, and ethers such as dioxane and tetrahydrofuran are used. Alcohols are preferred. Particularly preferred is ethyl alcohol.
本工程は十分にかきまぜながら行うのが好ましい。This step is preferably carried out with sufficient stirring.
濃縮物を溶解するために用いられる水の量は、濃縮物に
対して約２から１００重世倍、好ましくは約５から２０
重量倍である。The amount of water used to dissolve the concentrate is about 2 to 100 times the concentrate, preferably about 5 to 20 times the concentrate.
It is twice the weight.
親水性溶媒は濃縮物を溶解するために用いられる水の量
に対して、約１から１０容量倍、好ましくは約１． ５
から５容量倍用いる。The hydrophilic solvent is about 1 to 10 times the volume of water used to dissolve the concentrate, preferably about 1. 5
Use 5 times the capacity.
温度は約０から５０°Ｃ１好ましくは約ｌＯから３０℃
である。The temperature is about 0 to 50°C, preferably about 1O to 30°C.
It is.
濃縮物の水溶液と親水性溶媒とをかきまぜながら混合す
ると直ちに取り扱いやすいガム状もしくは粉末状の析出
物が生じる。この析出物を傾斜法。Mixing the aqueous concentrate and the hydrophilic solvent with stirring immediately results in a gummy or powdery precipitate that is easy to handle. This precipitate is decanted.
濾過などの通常の分離方法により分離、採取する。Separate and collect using standard separation methods such as filtration.
しかしながら析出物としてガム状物質が得られるときは
上記した親水性溶媒中で細粉化（トリチュレイト）する
ことにより精製してもよく、さらに上記と同様にして水
に溶解し、この水溶液を上記した親水性溶媒と混合し、
粉末状の目的物を析出させることにより精製してもよい
。However, when a gummy substance is obtained as a precipitate, it may be purified by trituration in the above-mentioned hydrophilic solvent, and further dissolved in water in the same manner as above, and this aqueous solution mixed with a hydrophilic solvent;
Purification may be performed by precipitating a powdered target product.
β−シクロデキストリン硫酸エステルアルカリ金属塩を
含有する反応液は、公知方法（例、ＵＳＰ２、９２３．
７０４またはＵＳＰ ４．０２０．１６０に記載の方法
）または自体公知の方法により製造される。The reaction solution containing the β-cyclodextrin sulfate alkali metal salt was prepared by a known method (eg, USP 2, 923.
704 or USP 4.020.160) or methods known per se.
例えば、β−シクロデキストリンをスルホン化剤でスル
ホン化し、必要により塩交換反応に付すことによりβ−
シクロデキストリン硫酸エステルアルカリ金属塩を含有
する反応液が得られる。For example, by sulfonating β-cyclodextrin with a sulfonating agent and subjecting it to a salt exchange reaction if necessary, β-cyclodextrin is
A reaction solution containing a cyclodextrin sulfate alkali metal salt is obtained.
β−シクロデキストリンのスルホン化剤としては、三酸
化硫黄ピリジン錯塩、三酸化硫黄トリメチルアミン錯塩
、三酸化硫黄トリエチルアミン錯塩、三酸化硫黄ジメチ
ルホルムアミド錯塩等の無水硫酸−有機アミン錯体、ま
たはクロルスルホン酸が用いられる。As the sulfonating agent for β-cyclodextrin, sulfuric anhydride-organic amine complexes such as sulfur trioxide pyridine complex salt, sulfur trioxide trimethylamine complex salt, sulfur trioxide triethylamine complex salt, sulfur trioxide dimethylformamide complex salt, or chlorosulfonic acid are used. It will be done.
無水硫酸−有機アミン錯体は、通常β−シクロデキスト
リンの無水グルコース単位あたり約３から５倍モルを用
いる。The sulfuric anhydride-organic amine complex is usually used in an amount of about 3 to 5 times the mole per anhydroglucose unit of β-cyclodextrin.
反応は溶媒中で行なわれる。溶媒はジメチルホルムアミ
ド、ジメチルスルホキシド、ピリジンまたはへ牛サメチ
ルホスホルアミド等が用いられる。The reaction is carried out in a solvent. As the solvent, dimethylformamide, dimethylsulfoxide, pyridine, samethylphosphoramide, or the like is used.
溶媒の使用量はβ−シクロデキストリンに対して約ｌＯ
から５０重量倍が好ましい。The amount of solvent used is approximately 1O per β-cyclodextrin.
50 times by weight is preferred.
反応温度は、約４０から８０℃である。反応時間は約５
から２４時間である。The reaction temperature is about 40 to 80°C. The reaction time is about 5
24 hours.
クロルスルホン酸を用いる場合、有機３級アミン（例、
ピリジ石トリエチルアミン）の存在下に行なわれる。例
えばピリジン中クロルスルホン酸を用いる場合にはβ−
シクロデキストリンに対しピリジンは約１５から２５重
量倍を用いる。クロルスルホン酸はβ−シクロデキスト
リンの無水グルコース単位当り約３から５倍モルを用い
る。反応に際しては、まずピリジンを約−１０から一２
０℃に冷却する。ついで同温度でクロルスルホン酸を加
えたのち、７０℃に加温し均一溶液とする。ついでβ−
シクロデキストリンを加え約４０から８０°Ｃで約５か
ら２４時間かくはん下反応させる。When using chlorosulfonic acid, organic tertiary amines (e.g.
pyridite triethylamine). For example, when using chlorosulfonic acid in pyridine, β-
Pyridine is used in an amount of about 15 to 25 times the weight of cyclodextrin. Chlorsulfonic acid is used in an amount of about 3 to 5 times the mole per anhydroglucose unit of β-cyclodextrin. During the reaction, first add pyridine to about -10 to -12
Cool to 0°C. Then, after adding chlorosulfonic acid at the same temperature, the mixture was heated to 70°C to form a homogeneous solution. Then β-
Add cyclodextrin and react at about 40 to 80°C for about 5 to 24 hours with stirring.
ついでこの溶液を酢酸ナトリウムまたは酢酸カリウム、
水酸化ナトリウムまたは水酸化カリウムなどの塩交換試
薬と処理（塩交換反応）することによりβ−シクロデキ
ストリン硫酸エステルアルカリ金属塩を含有する反応液
が得られる。塩交換試薬は、用いたスルホン化剤の約２
から４倍モル用いる。この塩交換反応は通常含水溶媒中
でおこなわれる。反応温度は約ｌＯから５０°Ｃ１好ま
しくは室温（約２０から３０°Ｃ）である。通常室温で
約１から１０時間かきまぜると塩交換反応は終了する。This solution was then diluted with sodium acetate or potassium acetate,
A reaction solution containing a β-cyclodextrin sulfate alkali metal salt is obtained by treatment (salt exchange reaction) with a salt exchange reagent such as sodium hydroxide or potassium hydroxide. The salt exchange reagent is about 2 times the amount of the sulfonating agent used.
4 times the molar amount is used. This salt exchange reaction is usually carried out in an aqueous solvent. The reaction temperature is about 10 to 50°C, preferably room temperature (about 20 to 30°C). The salt exchange reaction is usually completed by stirring at room temperature for about 1 to 10 hours.
この際、含水溶媒中で１時間かきまぜると、β−シクロ
デキストリンの１級水酸基の硫酸エステルのみが加水分
解されたβ−シクロデキストリンテトラデカ硫酸エステ
ルアルカリ金属塩を含Ｈする溶液が得られる。At this time, by stirring in a water-containing solvent for 1 hour, a solution containing H containing β-cyclodextrin tetradeca sulfate alkali metal salt in which only the sulfate ester of the primary hydroxyl group of β-cyclodextrin is hydrolyzed is obtained.
この場合、β−シクロデキストリンをスルホン化剤でス
ルホン化して得られる溶液からβ−シクロデキストリン
の硫酸エステル有機アミン塩を一旦単離し、ついで上記
した塩交換試薬と処理し、β−シクロデキストリン硫酸
エステルアルカＨＪｔ塩を含有する反応液を得てもよい
。In this case, the sulfate ester organic amine salt of β-cyclodextrin is once isolated from the solution obtained by sulfonating β-cyclodextrin with a sulfonating agent, and then treated with the above-mentioned salt exchange reagent to form the β-cyclodextrin sulfate ester. A reaction solution containing an alkali HJt salt may also be obtained.
β−シクロデキストリン硫酸エステル有機アミン塩を析
出させるためには、スルホン化反応に用いた溶液と同容
量の溶媒、例えば、エーテル、アセトン、メチレンクロ
リド、エチルアルコール、メチルアルコールなどを加え
るとよい。析出したβ−シクロデキストリンの硫酸エス
テル有機アミン塩は通常の単離、精製法で採取したのち
、上記した塩交換反応試薬と処理（塩交換反応）するこ
とによりβ−シクロデキストリン硫酸エステルアルカリ
金属塩を含有する溶液を得ることができる。塩交換試薬
の世は使用したスルホン化剤の約２から４倍モルが適当
である。In order to precipitate the β-cyclodextrin sulfate ester organic amine salt, it is preferable to add a solvent in the same volume as the solution used in the sulfonation reaction, such as ether, acetone, methylene chloride, ethyl alcohol, methyl alcohol, etc. The precipitated β-cyclodextrin sulfate ester organic amine salt is collected by a conventional isolation and purification method, and then treated with the above-mentioned salt exchange reaction reagent (salt exchange reaction) to obtain the β-cyclodextrin sulfate ester alkali metal salt. A solution containing . In the world of salt exchange reagents, the appropriate amount is about 2 to 4 times the molar amount of the sulfonating agent used.
この塩交換反応は通常水溶媒中でおこなわれる。This salt exchange reaction is usually carried out in an aqueous solvent.
通常室温で約１から１０時間かきまぜる。この際、水中
で１時間かき゛まぜると、β−シクロデキストリンの１
級水酸基の硫酸エステルのみが加水分解されたβ−シク
ロデキストリンテトラデカ硫、酸エステルアルカリ金属
塩を含有する溶液が得られる。Stir for about 1 to 10 hours, usually at room temperature. At this time, when stirred in water for 1 hour, 1 of the β-cyclodextrin
A solution containing β-cyclodextrin tetradeca sulfate and acid ester alkali metal salt in which only the sulfate ester of the hydroxyl group is hydrolyzed is obtained.
以下実施例を示し、本発明の精製方法を具体的に説明す
る。The purification method of the present invention will be specifically explained below with reference to Examples.
実施例１ β−シクロデキストリンテトラデカ硫酸エス
テルナトリウム塩
（ａ） β−シクロデキストリン５ｇをジメチルホル
ムアミド２５０−に溶解し、７０℃でかきまぜながら三
酸化硫黄トリメチルアミン錯塩１５ｇを５分間で加えた
のち、同温度で１６時間かきまぜた。Example 1 β-Cyclodextrin tetradeca sulfate ester sodium salt (a) 5 g of β-cyclodextrin was dissolved in 250% dimethylformamide, and 15 g of sulfur trioxide trimethylamine complex salt was added over 5 minutes while stirring at 70°C. Stir at temperature for 16 hours.
冷却後、エタノール２５０鑓を加え、デカンチーシコン
により不溶物を得、不溶物は少量のエタノールで洗浄し
た。残渣を水２５０ｄに溶解し不溶物をろ去、ろ液に３
０ｗ／ｖ％酢酸ソーダ水溶液７５蔵を加え、室温で１時
間かきまぜた。After cooling, 250 g of ethanol was added, and the insoluble matter was obtained by decanting and washed with a small amount of ethanol. Dissolve the residue in 250 d of water, remove insoluble matter by filtration, and add 3 ml to the filtrate.
Seventy five centimeters of a 0w/v% sodium acetate aqueous solution was added, and the mixture was stirred at room temperature for 1 hour.
（ｂ） 上記で得られるβ−シクロデキストリンテト
ラデカ硫酸エステルナトリウム塩を含有する反応液を減
圧下（２０〜２５ ｓａＨｇ）に〜６０℃の湯浴上で濃
縮乾固した。濃縮物を水７５−に溶解し、エタノール１
５０−を加え析出するガム状固形物をデカンテーション
して採取し、さらにエタノール３０ＭＬを加えて粉末化
後、ろ取、乾燥すると無色粉末状の標記化合物１０．３
ｇが得られた。(b) The reaction solution containing β-cyclodextrin tetradeca sulfate sodium salt obtained above was concentrated to dryness under reduced pressure (20 to 25 saHg) on a water bath at ~60°C. Dissolve the concentrate in 75 ml of water and 1 ml of ethanol.
50- was added and the precipitated gummy solid was collected by decantation, further added with 30 mL of ethanol to powder, filtered, and dried to yield the title compound 10.3 in the form of a colorless powder.
g was obtained.
元素分析値 Ｃ＊ｔＨｓ＊０ｔｔＳ ＋４Ｎａ＋＊とし
て計算値：Ｃ１９，６８； Ｈ２，２０； Ｓ
１７．５１（％）実測値：Ｃ２０，６７； Ｈ３，４
０； Ｓ １６．２９（％）［α都 ＋８３．５°
（ｃ＝ １．５５． 水）含水量 １ 、５ ｗ／ｗ
％（カールフィッシャー法）実施例２ β−シクロデキ
ストリンテトラデカ硫酸エステルナトリウム塩
（ａ） ピリジン１４０ＰＲ１を一２０℃に冷却し、
かきまぜながらクロルスルホン酸２２ＩＩ＆を徐々に滴
下後、加温して均一溶液としたのち、β−シクロデキス
トリン５．６ｇを加え、７０℃で１５時間反応させた。Elemental analysis value C*tHs*0ttS +4Na+* Calculated value: C19,68; H2,20; S
17.51 (%) Actual value: C20,67; H3,4
0; S 16.29 (%) [α capital +83.5°
(c= 1.55. water) water content 1,5 w/w
% (Karl Fischer method) Example 2 β-cyclodextrin tetradeca sulfate sodium salt (a) Pyridine 140PR1 was cooled to -20°C,
Chlorsulfonic acid 22II& was gradually added dropwise while stirring, and after heating to form a homogeneous solution, 5.6 g of β-cyclodextrin was added and reacted at 70° C. for 15 hours.
冷却後、エタノール５００）！ｌ！を加えデカンテーシ
ョンし、ピリジニウム塩をエタノールで洗浄した。残渣
を水２５０Ｍ１に溶解、ろ過したのちる液に３０ｖ／ｖ
％酢酸ソーダ水溶液７５−を加え室温で１時間かきまぜ
た。After cooling, ethanol 500)! l! was added and decanted, and the pyridinium salt was washed with ethanol. Dissolve the residue in 250M1 water, filter it, and add 30v/v to the filtered liquid.
A 75% aqueous solution of sodium acetate was added and stirred at room temperature for 1 hour.
（ｂ） β−シクロデキストリンテトラデカ硫酸エス
テルナトリウム塩を含有する反応液を減圧下（６０℃、
２０〜２５ ｍｓＨｇ）に濃縮乾固する。残渣に水８０
−を加えて溶解し、エタノール１６〇−を加え析出する
固形物をデカンチーシコンにより得、さらにエタノール
４０ｔｌ！を加えて粉末化後、ろ取乾燥すると無色粉末
状の標記化合物１１．７ｇが得られた。(b) The reaction solution containing β-cyclodextrin tetradeca sulfate sodium salt was heated under reduced pressure (60°C,
20-25 msHg). 80% water to the residue
- was added and dissolved, 160 - of ethanol was added and a precipitated solid was obtained by decanting, and then 40 tl of ethanol was added! The mixture was powdered, filtered and dried to obtain 11.7 g of the title compound as a colorless powder.
元素分析値 Ｃａ＊Ｈｓ＊ｏｔｔｓ ＋４Ｎａ＋ａとし
て計算値二Ｃ１９，６８； Ｈ２，２０； Ｓ １
７．５１（％）実測値：Ｃ２１，０７，Ｈ３，５６；
Ｓ １５．９５（％）［αｌＤ＋８４．２°（ｃ＝
１．２２５． 水）含水量１ 、４ ｗ／ｗ％（カ
ールフィッシャー法）〔発明の効果〕
本発明の精製方法は、操作法が簡単で、析出物の単窄も
容易かつ純度のよいβ−シクロデ牛ストリン硫酸エステ
ルアルカリ金属塩が得られる。Elemental analysis value Calculated value as Ca*Hs*otts +4Na+a 2C19,68; H2,20; S 1
7.51 (%) Actual value: C21,07, H3,56;
S 15.95 (%) [αlD+84.2° (c=
1.225. Water) Water content: 1, 4 w/w% (Karl Fischer method) [Effects of the invention] The purification method of the present invention is simple in operation, easy to narrow the precipitate, and has a high purity β-cyclodecorate A sulfate ester alkali metal salt is obtained.
代理人 弁理士 岩 １） 弘Agent Patent Attorney Iwa 1) Hiroshi
Claims (1)
含有する反応液を濃縮乾固し、濃縮物を水に溶解しこの
水溶液を親水性溶媒と混合して目的物を析出させること
を特徴とするβ−シクロデキストリン硫酸エステルアル
カリ金属塩の精製方法。β-cyclodextrin sulfate ester alkali metal salt-containing reaction solution is concentrated to dryness, the concentrate is dissolved in water, and this aqueous solution is mixed with a hydrophilic solvent to precipitate the target product. Method for purifying dextrin sulfate ester alkali metal salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6125489A JP2751344B2 (en) | 1988-03-18 | 1989-03-13 | Purification method of β-cyclodextrin sulfate |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-67003 | 1988-03-18 | ||
| JP6700388 | 1988-03-18 | ||
| JP6125489A JP2751344B2 (en) | 1988-03-18 | 1989-03-13 | Purification method of β-cyclodextrin sulfate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01315401A true JPH01315401A (en) | 1989-12-20 |
| JP2751344B2 JP2751344B2 (en) | 1998-05-18 |
Family
ID=26402299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6125489A Expired - Lifetime JP2751344B2 (en) | 1988-03-18 | 1989-03-13 | Purification method of β-cyclodextrin sulfate |
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| Country | Link |
|---|---|
| JP (1) | JP2751344B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5441944A (en) * | 1989-04-23 | 1995-08-15 | The Trustees Of The University Of Pennsylvania | Substituted cyclodextrin sulfates and their uses as growth modulating agents |
| US5446030A (en) * | 1991-09-19 | 1995-08-29 | Weisz; Paul B. | Prevention of hemolysis |
| US5637575A (en) * | 1988-01-19 | 1997-06-10 | The Trustees Of The University Of Pennsylvania | Methods of inhibiting restenosis |
| US5658894A (en) * | 1989-04-23 | 1997-08-19 | The Trustees Of The University Of Pennsylvania | Compositions for inhibiting restenosis |
| US5760015A (en) * | 1988-01-19 | 1998-06-02 | The Trustees Of The University Of Pennsylvania | Cyclodextrin compounds and methods of making and use thereof |
| JPH11100402A (en) * | 1997-07-25 | 1999-04-13 | Beckman Coulter Inc | Chiral separation of pharmaceutical compound with charged cyclodextrins by capillary electrophoresis |
-
1989
- 1989-03-13 JP JP6125489A patent/JP2751344B2/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5637575A (en) * | 1988-01-19 | 1997-06-10 | The Trustees Of The University Of Pennsylvania | Methods of inhibiting restenosis |
| US5760015A (en) * | 1988-01-19 | 1998-06-02 | The Trustees Of The University Of Pennsylvania | Cyclodextrin compounds and methods of making and use thereof |
| US5441944A (en) * | 1989-04-23 | 1995-08-15 | The Trustees Of The University Of Pennsylvania | Substituted cyclodextrin sulfates and their uses as growth modulating agents |
| US5658894A (en) * | 1989-04-23 | 1997-08-19 | The Trustees Of The University Of Pennsylvania | Compositions for inhibiting restenosis |
| US5874419A (en) * | 1989-04-23 | 1999-02-23 | The Trustees Of The University Of Pennsylvania | Compositions and methods for modulating growth of a tissue in a mammal |
| US5902799A (en) * | 1989-04-23 | 1999-05-11 | The Trustees Of The University Of Pennsylvania | Methods of modulating tissue growth and regeneration |
| US5935940A (en) * | 1989-04-23 | 1999-08-10 | Trustees Of The University Of Pennsylvania | Compositions and methods for modulating growth of a tissue in a mammal |
| US5446030A (en) * | 1991-09-19 | 1995-08-29 | Weisz; Paul B. | Prevention of hemolysis |
| US5776914A (en) * | 1991-09-19 | 1998-07-07 | The Trustees Of The University Of Pennsylvania | Prevention of hemolysis |
| JPH11100402A (en) * | 1997-07-25 | 1999-04-13 | Beckman Coulter Inc | Chiral separation of pharmaceutical compound with charged cyclodextrins by capillary electrophoresis |
| JP4503715B2 (en) * | 1997-07-25 | 2010-07-14 | ベックマン・コールター・インコーポレーテッド | Chiral separation of pharmaceutical compounds with charged cyclodextrins using capillary electrophoresis |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2751344B2 (en) | 1998-05-18 |
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