WO1998047878A1 - Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete - Google Patents

Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete Download PDF

Info

Publication number
WO1998047878A1
WO1998047878A1 PCT/US1998/007966 US9807966W WO9847878A1 WO 1998047878 A1 WO1998047878 A1 WO 1998047878A1 US 9807966 W US9807966 W US 9807966W WO 9847878 A1 WO9847878 A1 WO 9847878A1
Authority
WO
WIPO (PCT)
Prior art keywords
water
dichloro
dione
nitro
dihydroquinoxaline
Prior art date
Application number
PCT/US1998/007966
Other languages
English (en)
Inventor
Bruce Gaede
Original Assignee
Abbott Laboratories
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA002286797A priority Critical patent/CA2286797C/fr
Priority to JP54625298A priority patent/JP2001522358A/ja
Priority to EP98919820A priority patent/EP0975607A1/fr
Publication of WO1998047878A1 publication Critical patent/WO1998047878A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • This invention relates to a process for the purification of 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione.
  • 6,7-Dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione (CAS 153504-81 -5; ACEA- 1021 ) has the following structure:
  • ACEA 1021 is being developed as a glycine site antagonist of the N-methyl-D-aspartate receptor for the treatment of head trauma and stroke.
  • a suitable procedure for purification and isolation of the product was required.
  • a method for producing 6,7-dichloro-5-nitro- 2,3-dihydroquinoxaline-2,3-dione Also provided is 6,7-dichloro- 5-nitro-2,3-dihydroquinoxaline-2,3-dione free of sodium salt wherein the crude 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline- 2,3-dione is recrystallized from a solution of highly polar solvents and water.
  • the solution is comprised of dimethylsulfoxide or dimethylformamide in water. More preferably, the solution is one part DMSO to three parts water. Most preferably, the solution is at an elevated temperature in the range of 80 to 95 °C .
  • composition of 6,7-dichloro-5-nitro-2,3- dihydroquinoxaline-2,3 -dione produced by the process of the invention.
  • Figure 1 shows the increase in ACEA 1021 purity and decrease in impurity levels at each stage of purification.
  • Figure 2 shows the dependence of per cent residual DMSO on stir time and precipitation temperature at two ratios of water.DMSO.
  • Figure 3 shows the dependence of per cent residual DMSO on temperature and ratio of water.DMSO.
  • Crude 1 was taken up in DMSO, filtered to remove filter aid and insoluble impurities, and diluted with water until crystallization ensued. Cooling and filtration gave purified 1 as a 1 : 1 solvate with DMSO.
  • the mixture is cooled to 0° to 25° C, preferably 0° to 5°C.
  • the mixture should not be cooled to less than 0°C in order to avoid freezing the solvent.
  • the cooling can be carried out over a period of not less than about 0.1 hour and not more than about 24 hr.
  • the recrystallization can be repeated as often as necessary until the desired degree of purity is attained, typically twice, and this results in product purity comparable to that attained previously using acid-base partition.
  • Example 1 Synthesis and Isolation of Crude 6,7-Dichloro-l ,4- dihydro-5-nitro-quinoxaline-2,3-dione ( 1 ).
  • the mixture was stirred at 0-5° for 1 hr and quenched by pouring into 3000 ml water with external ice-salt bath cooling at a rate such that the internal temperature of the mixture did not exceed 30°.
  • To the slurry of yellow product was added 64 g diatomaceous earth filter aid and the product isolated by centrifugation or filtration using a filter medium coated with filter aid. The product cake was washed with water until the filtrate or centrate was colorless.
  • the crude product was taken up in 2000 g dimethylsulfoxide at 90° and filtered to remove filter aid, and the cake was washed with 500 g additional dimethylsulfoxide.
  • the filtrate was heated to 90° and 500 ml water was added with stirring.
  • the product began to precipitate and the mixture was cooled in an ice bath to ⁇ 5°.
  • the solid product was isolated by filtration and washed with water. If the desired degree of purity was not attained a second recrystallization was carried out from 1000 g dimethylsulfoxide and 200 ml water under the same conditions.
  • the purified product wet cake was taken up in 750 g dimethylsulfoxide at 90° and treated with 55 g Darco G60 charcoal _ for 15 min.
  • the solution was filtered through a pad of filter aid and the cake was washed with 250 g dimethylsulfoxide.
  • the filtrate was reheated to 90° and added to 3000 ml water at 90° with stirring.
  • the resulting yellow slurry was stirred 30 min. at 90°, then cooled to ⁇ 5°, and the solid product was isolated by filtration and washed with water.
  • the solid was dried overnight under vacuum at 90-95° with a slow nitrogen purge.
  • the dried solid was a pure yellow color and contained ⁇ 0.1 % dimethylsulfoxide and ⁇ 0.1 % water. HPLC purity was >99.5%.
  • Equation (2) was used to generate the surface.
  • % DMSO -0.04 W - 0.00357 T + 0.508952 (2)
  • W Parts Water : 1 Part DMSO
  • T Temperature in °C. Agreement between the plotted function and the data was better in this graph. Temperature was the most significant determinant of residual DMSO content with the amount of water being barely significant.
  • Residual solvent was determined by gas chromatography.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione de haute pureté, qui consiste à recristalliser l2 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione brut à partir d'une solution d'eau et de solvants fortement polaires.
PCT/US1998/007966 1997-04-18 1998-04-20 Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete WO1998047878A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002286797A CA2286797C (fr) 1997-04-18 1998-04-20 Procede de preparation de 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete
JP54625298A JP2001522358A (ja) 1997-04-18 1998-04-20 高純度６，７−ジクロロ−５−ニトロ−２，３−ジヒドロキノキサリン−２，３−ジオンの調製方法
EP98919820A EP0975607A1 (fr) 1997-04-18 1998-04-20 Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84447597A 1997-04-18 1997-04-18
US08/844,475 1997-04-18

Publications (1)

Publication Number Publication Date
WO1998047878A1 true WO1998047878A1 (fr) 1998-10-29

Family

ID=25292811

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/007966 WO1998047878A1 (fr) 1997-04-18 1998-04-20 Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete

Country Status (4)

Country Link
EP (1) EP0975607A1 (fr)
JP (1) JP2001522358A (fr)
CA (1) CA2286797C (fr)
WO (1) WO1998047878A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6562873B2 (en) 2000-07-14 2003-05-13 Allergan, Inc. Compositions containing therapeutically active components having enhanced solubility
US6627210B2 (en) 2000-07-14 2003-09-30 Allergan, Inc. Compositions containing α-2-adrenergic agonist components
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
US8858961B2 (en) 2000-07-14 2014-10-14 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000124A1 (fr) * 1992-06-22 1994-01-06 Eckard Weber Antagonistes des recepteurs de glycine et leur utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000124A1 (fr) * 1992-06-22 1994-01-06 Eckard Weber Antagonistes des recepteurs de glycine et leur utilisation

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6562873B2 (en) 2000-07-14 2003-05-13 Allergan, Inc. Compositions containing therapeutically active components having enhanced solubility
US6627210B2 (en) 2000-07-14 2003-09-30 Allergan, Inc. Compositions containing α-2-adrenergic agonist components
US6641834B2 (en) 2000-07-14 2003-11-04 Allergan Sales, Inc. Compositions containing alpha-2-adrenergic agonist components
US6673337B2 (en) 2000-07-14 2004-01-06 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
US8858961B2 (en) 2000-07-14 2014-10-14 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
US9295641B2 (en) 2000-07-14 2016-03-29 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
US9687443B2 (en) 2000-07-14 2017-06-27 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
US10307368B2 (en) 2000-07-14 2019-06-04 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
EP3263108A1 (fr) 2012-07-12 2018-01-03 Glytech LLC Composition et procédé de traitement de la dépression et de psychoses chez les humains
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

Also Published As

Publication number Publication date
CA2286797C (fr) 2008-07-15
CA2286797A1 (fr) 1998-10-29
JP2001522358A (ja) 2001-11-13
EP0975607A1 (fr) 2000-02-02

Similar Documents

Publication Publication Date Title
JP3854765B2 (ja) 長鎖ジカルボン酸の精製方法
CA2286797C (fr) Procede de preparation de 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete
JP2013508377A (ja) ５−スルホイソフタル酸から、低硫酸塩の５−スルホイソフタル酸・モノ−リチウム塩を調製するための、酢酸／水混合溶媒の使用
US3864400A (en) Production of aryl-(4,4{40 -bis-(dialkylamino)-benzhydryl)-sulfones
RU2104271C1 (ru) Способ получения замещенных или незамещенных 1,4-дигидро-4-оксо-2- или -3-хинолинкарбоновых кислот
MXPA99009559A (en) A process for the preparation of highly pure 6,7-dichloro-5- nitro-2, 3-dihydroquinoxaline-2,3-dione
US5786479A (en) Process for producing a 6-subsitituted 2(1H)-quinoxalinone
JP3486633B2 (ja) ２，４′−ジヒドロキシジフェニルスルホンの精製法
JP2007015967A (ja) 低金属高純度３，３’−ジアミノ−４，４’−ジヒドロキシジフェニルスルフォンとその製造方法。
Scott et al. CCXLV.—The condensation of aromatic o-aminosulphonic acids with iso cyanic acid
SU1068417A1 (ru) Способ получени производных 1,2-диоксо-3-хлорнафталина или 4,5-диоксоиндола
JPS5949265A (ja) ４，４′，７，７′−テトラクロルチオインジゴを基剤とする有機顔料の製法
SU1104136A1 (ru) Способ получени бенз/ @ /изатинов
EP0927714B1 (fr) Procede pour la separation d'isomeres de l'acide nitrotoluique
JP2022024937A (ja) ビオチン及びその製造方法、並びに、ビオチン・アミン類塩の製造方法
Morgan et al. LXVI.—Researches on residual affinity and coordination. Part III. Reactions of selenium and tellurium acetylacetones
JP2021024814A (ja) ビオチンの製造方法
JPH03127788A (ja) ２，４‐ジアミノ‐６‐（１‐ピペリジニル）‐ピリミジン‐３‐オキサイドの新規な精製方法
RU2269530C1 (ru) Способ получения тетра-(2,3-хиноксалино) порфиразина
JPH055825B2 (fr)
JPH09194443A (ja) ４，６−ジアミノレゾルシノールの製造方法
Jackson et al. ON THE ACTION OF SODIUM HYDROXIDE ON IODOANIL.
JACKSON et al. I. CONTRIBUTIONS FROM THE CHEMICAL LABORATORY OF HARVARD COLLEGE.
JP2000319239A (ja) 高純度アスパラギン酸ジベンジルエステル・スルホン酸塩の製造法および高純度アスパラギン酸ジベンジルエステル・スルホン酸塩
JPS6191166A (ja) Ｎ”置換−ｎ，ｎ′−ジシクロヘキシルグアニジン誘導体の製造方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP MX

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 1998 546252

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2286797

Country of ref document: CA

Kind code of ref document: A

Country of ref document: CA

WWE Wipo information: entry into national phase

Country of ref document: MX

Ref document number: PA/a/1999/009559

Ref document number: 1998919820

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1998919820

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998919820

Country of ref document: EP