JPH083161A - Method for separating 6-(1-h-imidazol-1-yl)-7-nitro-2,3(1h,4h)-quinoxalinedione - Google Patents
Method for separating 6-(1-h-imidazol-1-yl)-7-nitro-2,3(1h,4h)-quinoxalinedioneInfo
- Publication number
- JPH083161A JPH083161A JP16293694A JP16293694A JPH083161A JP H083161 A JPH083161 A JP H083161A JP 16293694 A JP16293694 A JP 16293694A JP 16293694 A JP16293694 A JP 16293694A JP H083161 A JPH083161 A JP H083161A
- Authority
- JP
- Japan
- Prior art keywords
- quinoxalinedione
- nitro
- imidazol
- isomer mixture
- mixture
- 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.)
- Pending
Links
- UMLFDVOHVJPDIZ-UHFFFAOYSA-N hydron;6-imidazol-1-yl-7-nitro-1,4-dihydroquinoxaline-2,3-dione;chloride Chemical compound Cl.[O-][N+](=O)C1=CC=2NC(=O)C(=O)NC=2C=C1N1C=CN=C1 UMLFDVOHVJPDIZ-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 12
- 239000000203 mixture Substances 0.000 claims abstract description 43
- 239000002244 precipitate Substances 0.000 claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 7
- 239000012452 mother liquor Substances 0.000 claims abstract description 7
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 24
- 238000000926 separation method Methods 0.000 claims description 15
- 239000012736 aqueous medium Substances 0.000 claims description 11
- ABJFBJGGLJVMAQ-UHFFFAOYSA-N 1,4-dihydroquinoxaline-2,3-dione Chemical compound C1=CC=C2NC(=O)C(=O)NC2=C1 ABJFBJGGLJVMAQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000006396 nitration reaction Methods 0.000 claims description 7
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 4
- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical class C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 claims 2
- 239000000126 substance Substances 0.000 abstract description 2
- CSJLKCCGNKAAJZ-UHFFFAOYSA-N 7-imidazol-1-yl-5-nitro-1,4-dihydroquinoxaline-2,3-dione Chemical compound C=1C([N+]([O-])=O)=C2N=C(O)C(O)=NC2=CC=1N1C=CN=C1 CSJLKCCGNKAAJZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 239000003125 aqueous solvent Substances 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WHCRZZIBXAGFLY-UHFFFAOYSA-N 4-nitro-1h-quinoxaline-2,3-dione Chemical class C1=CC=C2NC(=O)C(=O)N([N+](=O)[O-])C2=C1 WHCRZZIBXAGFLY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は，医薬用中間体の分離法
に関する。更に詳しくは６−（１−Ｈ−イミダゾ−ル−
１−イル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キ
ノキサリンジオンのその異性体混合物からの分離法に関
する。FIELD OF THE INVENTION The present invention relates to a method for separating pharmaceutical intermediates. More specifically, 6- (1-H-imidazole-
1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione separation method from its isomer mixture.
【０００２】[0002]
【従来の技術】医薬用中間体として有用な６−（１−Ｈ
−イミダゾ−ル−１−イル）−７−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンは国際公開特許Ｗ
Ｏ９２／０７８４７に記載された化合物である。又その
精製法についてはＤＭＦと水の混合溶媒から再結晶する
方法ががＷＯ９２／０７８４７に記載されている。６−
（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−
２，３−（１Ｈ，４Ｈ）−キノキサリンジオン（以下７
−ニトロ化物という）を製造する通常の方法は、例えば
６−（１−Ｈ−イミダゾ−ル−１−イル）−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンをニトロ化する方
法であるが、この様なニトロ化においては６−（１−Ｈ
−イミダゾ−ル−１−イル）−８−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオン（以下８−ニトロ
化物という）が副生し目的物は異性体混合物（例えば７
−ニトロ化物７０〜８０％、８−ニトロ化物２０〜３０
％混合物となる）として取得される。これを従来の方法
に従い，ＤＭＦと水の混合溶媒により分離精製しようと
すると，８−ニトロ化物の溶解度が低いため非常に多量
のＤＭＦを使用する必要があり，分離精製の効率が低い
ばかりでなく，溶媒の回収等の問題も含んでいる。従っ
て純度の良好な６−（１−Ｈ−イミダゾ−ル−１−イ
ル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサ
リンジオンを効率よく得るためには異性体混合物から目
的物を純度よく取り出す方法の確立が重要である。BACKGROUND OF THE INVENTION 6- (1-H, which is useful as a pharmaceutical intermediate,
-Imidazol-1-yl) -7-nitro-2,3-
(1H, 4H) -Quinoxalinedione is an International Patent Publication W
It is the compound described in O92 / 07847. As for the purification method, WO92 / 07847 describes a method of recrystallization from a mixed solvent of DMF and water. 6-
(1-H-imidazol-1-yl) -7-nitro-
2,3- (1H, 4H) -quinoxalinedione (7 below)
-Nitride) is a conventional method for producing 6- (1-H-imidazol-1-yl) -2,3-
This is a method of nitrating (1H, 4H) -quinoxalinedione, and in such nitration, 6- (1-H
-Imidazol-1-yl) -8-nitro-2,3-
(1H, 4H) -quinoxalinedione (hereinafter referred to as 8-nitride) is a by-product, and the target product is an isomer mixture (for example, 7
-Nitride 70-80%, 8-nitride 20-30
% Mixture). If it is attempted to separate and purify this using a mixed solvent of DMF and water according to the conventional method, it is necessary to use a very large amount of DMF because the solubility of 8-nitride is low, and not only the efficiency of separation and purification is low. It also includes problems such as solvent recovery. Therefore, in order to efficiently obtain 6- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione having a good purity, the desired product can be obtained from the isomer mixture. It is important to establish a method for taking out the product in high purity.
【０００３】[0003]
【発明が解決しようとする課題】６−（１−Ｈ−イミダ
ゾ−ル−１−イル）−７−ニトロ−２，３−（１Ｈ，４
Ｈ）−キノキサリンジオンをその異性体混合物から簡便
な方法により分離精製する事を目的とする。SUMMARY OF THE INVENTION 6- (1-H-Imidazol-1-yl) -7-nitro-2,3- (1H, 4)
The purpose is to separate and purify H) -quinoxalinedione from its isomer mixture by a simple method.
【０００４】[0004]
【課題を解決するための手段】本発明者らは，上記課題
を解決すべく鋭意検討の結果本発明に到達した。The present inventors have arrived at the present invention as a result of extensive studies to solve the above problems.
【０００５】即ち本発明は， （１）６−（１−Ｈ−イミダゾ−ル−１−イル）−７−
ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオン
と６−（１−Ｈ−イミダゾ−ル−１−イル）−８−ニト
ロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンの異
性体混合物を水性媒体中に加え、そのｐＨを７．５〜１
１に調整し、不溶性の沈澱を除去した後その母液のｐＨ
を０．１〜７．５とし，生成する結晶を分離する事を特
徴とする６−（１−Ｈ−イミダゾ−ル−１−イル）−７
−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオ
ンのその異性体混合物からの分離法 （２）前記（１）において異性体混合物が（１−Ｈ−イ
ミダゾ−ル−１−イル）−２，３−（１Ｈ，４Ｈ）−キ
ノキサリンジオンのニトロ化により生成する異性体混合
物である６−（１−Ｈ−イミダゾ−ル−１−イル）−７
−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオ
ンのその異性体混合物からの分離法 （３）前記（１）又は（２）において，異性体混合物を
水性媒体中に加えた後のｐＨを７．８〜９．５に調整す
る６−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニト
ロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンのそ
の異性体混合物からの分離法 （４）前記（１）、（２）又は（３）において，不溶性
の沈澱を除去した後の母液のｐＨが４〜７．２である６
−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−
２，３−（１Ｈ，４Ｈ）−キノキサリンジオンのその異
性体混合物からの分離法 （５）前記（１）、（２）又は（３）において，不溶性
沈澱を濾別する時の温度が０〜９０℃である６−（１−
Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンのその異性体混合
物からの分離法（６）前記（１）、（２）、（３）、
（４）、（５）又は（６）において水性媒体の使用量
が，６−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニ
トロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンと
６−（１−Ｈ−イミダゾ−ル−１−イル）−８−ニトロ
−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンの異性
体混合物に対して２〜２００重量倍である６−（１−Ｈ
−イミダゾ−ル−１−イル）−７−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンのその異性体混合
物からの分離法 を提供する。That is, the present invention provides (1) 6- (1-H-imidazol-1-yl) -7-
Isomers of nitro-2,3- (1H, 4H) -quinoxalinedione and 6- (1-H-imidazol-1-yl) -8-nitro-2,3- (1H, 4H) -quinoxalinedione The mixture is added to an aqueous medium and its pH is adjusted to 7.5-1.
The pH of the mother liquor was adjusted to 1 and the insoluble precipitate was removed.
6- (1-H-imidazol-1-yl) -7, characterized in that the crystal formed is separated from 0.1 to 7.5.
-Separation of nitro-2,3- (1H, 4H) -quinoxalinedione from its isomer mixture (2) In (1) above, the isomer mixture is (1-H-imidazol-1-yl)- 6- (1-H-Imidazol-1-yl) -7, an isomer mixture formed by nitration of 2,3- (1H, 4H) -quinoxalinedione.
Method for separating nitro-2,3- (1H, 4H) -quinoxalinedione from its isomer mixture (3) In the above (1) or (2), the pH after adding the isomer mixture to an aqueous medium From isomer mixtures of 6- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione, which is adjusted to 7.8-9.5. Separation method (4) In the above (1), (2) or (3), the pH of the mother liquor after removing the insoluble precipitate is 4 to 7.2 6
-(1-H-imidazol-1-yl) -7-nitro-
Separation method of 2,3- (1H, 4H) -quinoxalinedione from its isomer mixture (5) In the above (1), (2) or (3), the temperature at which the insoluble precipitate is filtered is 0 to 6- (1-
H-imidazol-1-yl) -7-nitro-2,3-
Separation method of (1H, 4H) -quinoxalinedione from its isomer mixture (6) The above (1), (2), (3),
In (4), (5) or (6), the amount of the aqueous medium used is 6- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxaline. 2 to 200 times by weight based on the isomer mixture of dione and 6- (1-H-imidazol-1-yl) -8-nitro-2,3- (1H, 4H) -quinoxalinedione 6- (1-H
-Imidazol-1-yl) -7-nitro-2,3-
A method of separating (1H, 4H) -quinoxalinedione from its isomer mixture is provided.
【０００６】以下に本発明を詳細に説明する。本発明の
分離法を実施するに当たり，溶媒としては水性媒体が用
いられる。水性媒体としては水が最も好ましいが、水と
メタノ−ル，エタノ−ル，イソプロパノ−ル等のアルコ
−ル類，アセトン，アセトニトリル，ジメチルフォルム
アミド，ジメチルスルフォキサイド等の水溶性有機溶媒
の混合物も使用できる。水性媒体の使用量は，６−（１
−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−２，３
−（１Ｈ，４Ｈ）−キノキサリンジオンと６−（１−Ｈ
−イミダゾ−ル−１−イル）−８−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンの異性体混合物に
対して２〜２００重量倍，好ましくは２０〜１２０重量
倍である。The present invention will be described in detail below. When carrying out the separation method of the present invention, an aqueous medium is used as a solvent. Water is most preferable as the aqueous medium, but water and alcohols such as methanol, ethanol and isopropanol, water-soluble organic solvents such as acetone, acetonitrile, dimethylformamide and dimethylsulfoxide are preferred. Mixtures can also be used. The amount of the aqueous medium used is 6- (1
-H-imidazol-1-yl) -7-nitro-2,3
-(1H, 4H) -quinoxalinedione and 6- (1-H
-Imidazol-1-yl) -8-nitro-2,3-
The amount is 2-200 times by weight, preferably 20-120 times by weight, with respect to the isomer mixture of (1H, 4H) -quinoxalinedione.
【０００７】本発明の分離法は例えばつぎのように実施
される。所定量の水媒体中に６−（１−Ｈ−イミダゾ−
ル−１−イル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）
−キノキサリンジオンと６−（１−Ｈ−イミダゾ−ル−
１−イル）−８−ニトロ−２，３−（１Ｈ，４Ｈ）−キ
ノキサリンジオンの異性体混合物を溶解または分散せし
め，攪拌しつつ苛性ソ−ダ，苛性カリ，炭酸ソ−ダ，重
曹，炭酸カリ，アンモニア等のアルカリ性化合物を添加
し液のｐＨを７．５〜１１，好ましくは７．８〜９．５
とする。酸性の状態の低いｐＨより上記アルカリ性化合
物を加えることにより所定のｐＨに調節することもでき
る。所望により０〜９０℃にて攪拌を行う。間もなく不
溶性の沈澱が析出するが，好ましくは液の温度を５〜７
０℃として，析出している不溶性の沈澱を濾別する。こ
の沈澱の組成は６−（１−Ｈ−イミダゾ−ル−１−イ
ル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサ
リンジオンと６−（１−Ｈ−イミダゾ−ル−１−イル）
−８−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンのほぼ１：１の混合物であり，コンプレックスを
形成している可能性もある。The separation method of the present invention is carried out, for example, as follows. 6- (1-H-imidazo-in a predetermined amount of aqueous medium
L-1-yl) -7-nitro-2,3- (1H, 4H)
-Quinoxalinedione and 6- (1-H-imidazole-
1-yl) -8-nitro-2,3- (1H, 4H) -quinoxalinedione isomer mixture was dissolved or dispersed and stirred with caustic soda, caustic potash, sodium carbonate, baking soda, potassium carbonate. , An alkaline compound such as ammonia is added to adjust the pH of the solution to 7.5 to 11, preferably 7.8 to 9.5.
And It is also possible to adjust to a predetermined pH by adding the above alkaline compound from a low acidic pH. Stir at 0-90 ° C if desired. An insoluble precipitate will precipitate soon, but the temperature of the liquid is preferably 5 to 7
The temperature is set to 0 ° C., and the insoluble precipitate that has precipitated is filtered off. The composition of this precipitate was 6- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione and 6- (1-H-imidazol-1). -Ill)
It is an approximately 1: 1 mixture of -8-nitro-2,3- (1H, 4H) -quinoxalinedione and may also form a complex.
【０００８】濾液をかくはんしつつ，塩酸，硫酸，燐
酸，酢酸等の酸性物質を加えて，ｐＨを０．１〜７．
５，好ましくは４〜７．２とすることにより６−（１−
Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンの結晶が析出す
る。ついで、好ましくは５〜５０℃において濾別する。
本発明の分離法は硫酸中におけるニトロ化反応にひきつ
ずき実施するのが好都合である、即ち、ニトロ化反応終
了後、氷水中に反応物を滴下し，上記のアルカリ化合物
を加えて硫酸を中和し所定のｐＨに調整することが出来
る。なお，アルカリ性化合物を加える前に不溶物が存在
する場合には，ニトロ化の副生物であるので濾別してお
いたほうがよい。後の処理は前記同様に実施し目的の６
−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−
２，３−（１Ｈ，４Ｈ）−キノキサリンジオンを得るこ
とが出来る。While stirring the filtrate, an acidic substance such as hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid was added to adjust the pH to 0.1 to 7.
5 and preferably 6- (1-
H-imidazol-1-yl) -7-nitro-2,3-
Crystals of (1H, 4H) -quinoxalinedione precipitate. Then, it is preferably filtered at 5 to 50 ° C.
The separation method of the present invention is conveniently carried out after the nitration reaction in sulfuric acid, that is, after completion of the nitration reaction, the reaction product is added dropwise to ice water, and the above alkaline compound is added to add sulfuric acid. Can be neutralized and adjusted to a predetermined pH. If any insoluble matter is present before adding the alkaline compound, it is a by-product of nitration and should be filtered off. Subsequent processing is performed in the same manner as described above, and the target 6
-(1-H-imidazol-1-yl) -7-nitro-
2,3- (1H, 4H) -quinoxalinedione can be obtained.
【０００９】６−（１−Ｈ−イミダゾ−ル−１−イル）
−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンの純度の測定は、例えば液体クロマトグラフィ−
により容易に実施出来る。6- (1-H-imidazol-1-yl)
The purity of -7-nitro-2,3- (1H, 4H) -quinoxalinedione can be measured by, for example, liquid chromatography.
Can be implemented easily.
【００１０】本発明の分離法で得られる６−（１−Ｈ−
イミダゾ−ル−１−イル）−７−ニトロ−２，３−（１
Ｈ，４Ｈ）−キノキサリンジオンは医薬品の原料として
重要な中間体である。6- (1-H-obtained by the separation method of the present invention
Imidazol-1-yl) -7-nitro-2,3- (1
(H, 4H) -quinoxalinedione is an important intermediate as a raw material for pharmaceuticals.
【００１１】[0011]
【実施例】以下参考例及び実施例により本発明の分離法
をより詳しく説明する。EXAMPLES The separation method of the present invention will be described in more detail with reference to the following Reference Examples and Examples.
【００１２】参考例１ ５０ｍｌ容量のガラス製フラスコに９７％硫酸２０ｇを
取り，オイルバスにて７０℃に加熱した。ここに攪拌し
つつ，６−（１−Ｈ−イミダゾ−ル−１−イル）−２，
３−（１Ｈ，４Ｈ）−キノキサリンジオン２ｇを徐々に
仕込んだ。均一の溶液が得られた。ここに７０℃にて約
３０分かけて硝酸ソ−ダ０．８３ｇを粉末にて仕込みニ
トロ化反応を実施した。この後７０℃にて更に３０分攪
拌を行い反応させ完結させた。これを室温まで冷却し，
氷２５ｇ，水１０ｇの入った１００ｍｌのビ−カ−中に
攪拌下に注いだ。ここに４８％苛性ソ−ダ水溶液約３３
ｇを加えてｐＨを４〜５とした。黄色の沈澱が生成した
ので濾過し，水洗，乾燥させた。２．４２ｇの黄色粉末
が得られた。これは，液体クロマトグラフィ−によると
７−ニトロ体７８％，８−ニトロ体２２％の二異性体混
合物であった。Reference Example 1 20 g of 97% sulfuric acid was placed in a glass flask having a capacity of 50 ml and heated to 70 ° C. in an oil bath. While stirring here, 6- (1-H-imidazol-1-yl) -2,
2 g of 3- (1H, 4H) -quinoxalinedione was gradually charged. A homogeneous solution was obtained. 0.83 g of sodium nitrate was charged as powder at 70 ° C. for about 30 minutes to carry out a nitration reaction. After that, the mixture was further stirred at 70 ° C. for 30 minutes to cause a reaction and complete. Cool it to room temperature,
The mixture was poured into a 100 ml beaker containing 25 g of ice and 10 g of water with stirring. About 48% caustic soda solution
g was added to bring the pH to 4-5. A yellow precipitate was formed, which was filtered, washed with water and dried. 2.42 g of yellow powder was obtained. According to liquid chromatography, this was a diisomer mixture of 78% of 7-nitro compound and 22% of 8-nitro compound.
【００１３】実施例１ 参考例１で得られた６−（１−Ｈ−イミダゾ−ル−１−
イル）−２，３−（１Ｈ，４Ｈ）−キノキサリンジオン
のニトロ化物（異性体混合物）１．０ｇ，水７５ｇを２
００ｍｌ容量のビ−カ−に取り，攪拌しつつ約１０％苛
性ソ−ダ水溶液を加え，ｐＨを８．５とした。４０℃に
て１時間攪拌した後，析出した不溶性の沈澱を濾別、乾
燥した。得られた結晶は０．１７ｇの重量を有し，液体
クロマトグラフィ−によると７−ニトロ化物４５．３
％，８−ニトロ化物５４．０％（２５４ｎｍの吸光度検
出器，感度補正無し）の混合物であった。不溶物を濾別
した後の母液をさらに攪拌しつつ約１０％の苛性ソ−ダ
水溶液にてｐＨを７．０とした。ここで生成した結晶を
濾過、乾燥したところ０．５８ｇの黄白色の６−（１−
Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−２，３−
（１Ｈ，４Ｈ）−キノキサリンジオンが得られた。液体
クロマトグラフィ−による純度は９７．１％であった。
プロトンＮＭＲスペクトルを測定したところ，７．１ｐ
ｐｍ，７．４５ｐｐｍ，７．８９ｐｐｍにイミダゾ−ル
基の水素に基づくトリプレット吸収がみられ，７．１４
ｐｐｍ，と７．９３ｐｐｍにそれぞれ５位と８位のベン
ゼン核についた水素の吸収がシングレットで検出され
た。Example 1 6- (1-H-imidazole-1-obtained in Reference Example 1
Yl) -2,3- (1H, 4H) -quinoxalinedione nitrate (mixture of isomers) 1.0 g, water 75 g 2
The mixture was taken in a beaker having a volume of 00 ml and about 10% aqueous caustic soda solution was added with stirring to adjust the pH to 8.5. After stirring at 40 ° C. for 1 hour, the insoluble precipitate that had precipitated was filtered off and dried. The crystals obtained weigh 0.17 g, and according to liquid chromatography 7-nitride 45.3.
%, 8-nitride 54.0% (absorbance detector at 254 nm, no sensitivity correction). After the insoluble matter was filtered off, the mother liquor was adjusted to pH 7.0 with an approximately 10% aqueous solution of caustic soda while further stirring. The crystals formed here were filtered and dried to give 0.58 g of yellowish white 6- (1-
H-imidazol-1-yl) -7-nitro-2,3-
(1H, 4H) -quinoxalinedione was obtained. The purity by liquid chromatography was 97.1%.
The proton NMR spectrum was measured and found to be 7.1 p.
Triplet absorption based on hydrogen of the imidazole group was observed at pm, 7.45 ppm, 7.89 ppm, and 7.14 ppm.
The absorption of hydrogen on the benzene nucleus at the 5th and 8th positions was detected by the singlet at ppm and 7.93ppm, respectively.
【００１４】実施例２ ５０ｍｌのガラス製フラスコに，９７％硫酸３５ｇを取
り，２５℃にて，攪拌しつつ，６−（１−Ｈ−イミダゾ
−ル−１−イル）−２，３−（１Ｈ，４Ｈ）−キノキサ
リンジオン５ｇを仕込んだ。ここに発煙硝酸（比重１．
５２）１．６２ｇと９７％硫酸５ｇの混合物を３０分で
攪拌下に滴下して，さらに２５℃で３０分攪拌した。反
応液を氷５０ｇ及び１５０ｇの入った３００ｍｌのビ−
カ−に攪拌下に注いだ。微量の不溶物が存在したので濾
別し，濾液に２５％苛性ソ−ダ約１１０ｇを冷却しつつ
加えた。温度は最高６０℃まで上昇した。ｐＨを８．６
に調整し、析出した沈澱を４５℃にて濾別した。不溶物
を濾別した後の母液をさらに攪拌しつつ約１０％の苛性
ソ−ダ水溶液を滴下し、そのｐＨを７．０とした。生成
した結晶を濾過、乾燥したところ２．８５ｇの黄白色の
６−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ
−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンが得ら
れた。液体クロマトグラフィ−による純度は９６．２％
であった。プロトンＮＭＲスペクトルを測定したとこ
ろ，７．１ｐｐｍ，７．４５ｐｐｍ，７．８９ｐｐｍに
イミダゾ−ル基の水素に基づくトリプレット吸収がみら
れ，７．１４ｐｐｍ，と７．９３ｐｐｍにそれぞれ５位
と８位のベンゼン核についた水素の吸収がシングレット
で検出された。Example 2 35 g of 97% sulfuric acid was placed in a 50 ml glass flask and stirred at 25 ° C. with 6- (1-H-imidazol-1-yl) -2,3- (). 1H, 4H) -quinoxalinedione 5g was charged. Fuming nitric acid (specific gravity 1.
52) A mixture of 1.62 g and 97% sulfuric acid 5 g was added dropwise with stirring over 30 minutes, and the mixture was further stirred at 25 ° C. for 30 minutes. The reaction solution was added to a 300 ml beer containing 50 g and 150 g of ice.
It was poured into the car with stirring. Since a trace amount of insoluble matter was present, it was filtered off, and about 110 g of 25% caustic soda was added to the filtrate while cooling. The temperature rose up to 60 ° C. pH 8.6
The resulting precipitate was filtered off at 45 ° C. After the insoluble matter was filtered off, the mother liquor was further stirred and a caustic soda aqueous solution of about 10% was added dropwise to adjust the pH to 7.0. The formed crystals were filtered and dried to obtain 2.85 g of yellowish white 6- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione. Was given. 96.2% purity by liquid chromatography
Met. When the proton NMR spectrum was measured, triplet absorption based on hydrogen of the imidazole group was observed at 7.1 ppm, 7.45 ppm, and 7.89 ppm, and at 714 ppm and 7.93 ppm, 5th and 8th positions, respectively. The absorption of hydrogen on the benzene nucleus was detected in the singlet.
【００１５】[0015]
【発明の効果】６−（１−Ｈ−イミダゾ−ル−１−イ
ル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサ
リンジオンと６−（１−Ｈ−イミダゾ−ル−１−イル）
−８−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンを含有する異性体混合物を含む水媒体のｐＨを調
整するだけの簡便な操作により，６−（１−Ｈ−イミダ
ゾ−ル−１−イル）−７−ニトロ−２，３−（１Ｈ，４
Ｈ）−キノキサリンジオンをその異性体混合物から純度
よく分離することが出来るようになった。EFFECT OF THE INVENTION 6- (1-H-Imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione and 6- (1-H-imidazole-1) -Ill)
6- (1-H-imidazole) was prepared by a simple operation of adjusting pH of an aqueous medium containing an isomer mixture containing -8-nitro-2,3- (1H, 4H) -quinoxalinedione. 1-yl) -7-nitro-2,3- (1H, 4
It has become possible to separate H) -quinoxalinedione from its isomer mixture in good purity.
Claims (6)
−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンと６−（１−Ｈ−イミダゾ−ル−１−イル）−８
−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオ
ンの異性体混合物を水性媒体中に加えそのｐＨを７．５
〜１１に調整し、不溶性の沈澱を除去した後その母液の
ｐＨを０．１〜７．５とし，生成する結晶を分離する事
を特徴とする６−（１−Ｈ−イミダゾ−ル−１−イル）
−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンのその異性体混合物からの分離法1. 6- (1-H-Imidazol-1-yl)
-7-Nitro-2,3- (1H, 4H) -quinoxalindione and 6- (1-H-imidazol-1-yl) -8
A mixture of isomers of -nitro-2,3- (1H, 4H) -quinoxalinedione was added to an aqueous medium and its pH was 7.5.
The pH of the mother liquor is adjusted to 0.1 to 7.5 after the insoluble precipitate is removed, and the resulting crystals are separated to give 6- (1-H-imidazole-1). -Ill)
Separation of -7-nitro-2,3- (1H, 4H) -quinoxalinedione from its isomer mixture
−イミダゾ−ル−１−イル）−２，３−（１Ｈ，４Ｈ）
−キノキサリンジオンのニトロ化により生成する異性体
混合物である６−（１−Ｈ−イミダゾ−ル−１−イル）
−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサリン
ジオンのその異性体混合物からの分離法2. The mixture of isomers according to claim 1 is (1-H
-Imidazol-1-yl) -2,3- (1H, 4H)
6- (1-H-imidazol-1-yl), a mixture of isomers produced by nitration of quinoxalinediones
Separation of -7-nitro-2,3- (1H, 4H) -quinoxalinedione from its isomer mixture
加えた後の水性媒体のｐＨを７．８〜９．５に調整する
６−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ
−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンのその
異性体混合物からの分離法3. The 6- (1-H-imidazol-1-yl) according to claim 1 or 2, wherein the pH of the aqueous medium after adding the isomer mixture is adjusted to 7.8 to 9.5. Separation of -7-nitro-2,3- (1H, 4H) -quinoxalinedione from its isomer mixture
澱を除去した後の母液のｐＨを４〜７．２に調整する６
−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニトロ−
２，３−（１Ｈ，４Ｈ）−キノキサリンジオンのその異
性体混合物からの分離法4. The method according to claim 1, 2 or 3, wherein the pH of the mother liquor after removing the insoluble precipitate is adjusted to 4 to 7.2.
-(1-H-imidazol-1-yl) -7-nitro-
Method for separating 2,3- (1H, 4H) -quinoxalinedione from its isomer mixture
を濾別する時の温度が０〜９０℃である６−（１−Ｈ−
イミダゾ−ル−１−イル）−７−ニトロ−２，３−（１
Ｈ，４Ｈ）−キノキサリンジオンのその異性体混合物か
らの分離法5. The method according to claim 1, wherein the temperature at which the insoluble precipitate is filtered off is 0 to 90 ° C. 6- (1-H-
Imidazol-1-yl) -7-nitro-2,3- (1
H, 4H) -Quinoxalinedione from its isomer mixture
水性媒体の使用量が，６−（１−Ｈ−イミダゾ−ル−１
−イル）−７−ニトロ−２，３−（１Ｈ，４Ｈ）−キノ
キサリンジオンと６−（１−Ｈ−イミダゾ−ル−１−イ
ル）−８−ニトロ−２，３−（１Ｈ，４Ｈ）−キノキサ
リンジオンの異性体混合物に対して２〜２００重量倍で
ある６−（１−Ｈ−イミダゾ−ル−１−イル）−７−ニ
トロ−２，３−（１Ｈ，４Ｈ）−キノキサリンジオンの
その異性体混合物からの分離法6. The amount of the aqueous medium used in claim 1, 2, 3, 4, 5 or 6 is 6- (1-H-imidazole-1).
-Yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione and 6- (1-H-imidazol-1-yl) -8-nitro-2,3- (1H, 4H) Of 2- (1-H-imidazol-1-yl) -7-nitro-2,3- (1H, 4H) -quinoxalinedione, which is 2-200 times by weight based on the isomer mixture of quinoxalinedione Separation method from its isomer mixture
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16293694A JPH083161A (en) | 1994-06-22 | 1994-06-22 | Method for separating 6-(1-h-imidazol-1-yl)-7-nitro-2,3(1h,4h)-quinoxalinedione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16293694A JPH083161A (en) | 1994-06-22 | 1994-06-22 | Method for separating 6-(1-h-imidazol-1-yl)-7-nitro-2,3(1h,4h)-quinoxalinedione |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH083161A true JPH083161A (en) | 1996-01-09 |
Family
ID=15764064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16293694A Pending JPH083161A (en) | 1994-06-22 | 1994-06-22 | Method for separating 6-(1-h-imidazol-1-yl)-7-nitro-2,3(1h,4h)-quinoxalinedione |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH083161A (en) |
-
1994
- 1994-06-22 JP JP16293694A patent/JPH083161A/en active Pending
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