EP0975607A1 - 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

Info

Publication number
EP0975607A1
EP0975607A1 EP98919820A EP98919820A EP0975607A1 EP 0975607 A1 EP0975607 A1 EP 0975607A1 EP 98919820 A EP98919820 A EP 98919820A EP 98919820 A EP98919820 A EP 98919820A EP 0975607 A1 EP0975607 A1 EP 0975607A1
Authority
EP
European Patent Office
Prior art keywords
water
dichloro
dione
nitro
dihydroquinoxaline
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.)
Withdrawn
Application number
EP98919820A
Other languages
German (de)
English (en)
Inventor
Bruce Gaede
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
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
Publication of EP0975607A1 publication Critical patent/EP0975607A1/fr
Withdrawn legal-status Critical Current

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.
EP98919820A 1997-04-18 1998-04-20 Procede de preparation de 6,7-dichloro-5- nitro-2,3-dihydroquinoxaline-2,3-dione de haute purete Withdrawn EP0975607A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US84447597A 1997-04-18 1997-04-18
US844475 1997-04-18
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

Publications (1)

Publication Number Publication Date
EP0975607A1 true EP0975607A1 (fr) 2000-02-02

Family

ID=25292811

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98919820A Withdrawn 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

Country Status (4)

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

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8858961B2 (en) 2000-07-14 2014-10-14 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
MXPA02012206A (es) 2000-07-14 2003-06-04 Allergan Inc Composiciones que contienen componentes terapeuticamente activos que tienen solubilidad mejorada.
CA2402405C (fr) 2000-07-14 2008-02-12 Allergan Sales, Inc. Compositions contenant des composants agonistes alpha-2 adrenergiques
US9737531B2 (en) 2012-07-12 2017-08-22 Glytech, Llc Composition and method for treatment of depression and psychosis in humans
KR102609676B1 (ko) 2017-06-12 2023-12-05 글리테크 엘엘씨. Nmda 길항제 및 d2/5ht2a 또는 선택적 5ht2a 길항제를 이용한 우울증의 치료

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0647137B1 (fr) * 1992-06-22 2008-08-13 The Regents Of The University Of California Antagonistes des recepteurs de glycine et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9847878A1 *

Also Published As

Publication number Publication date
CA2286797A1 (fr) 1998-10-29
WO1998047878A1 (fr) 1998-10-29
JP2001522358A (ja) 2001-11-13
CA2286797C (fr) 2008-07-15

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