43200-82-4

Usage

Uses

Used in Pharmaceutical Research:
6-(5-Chloro-2-pyridyl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione is used as a potential drug candidate for various therapeutic applications, primarily due to its activity as a kinase inhibitor. This makes it a promising target for the development of new cancer treatments, as kinases are often implicated in the regulation of cell growth and have been identified as key players in cancer progression.
Used in Cancer Treatment Development:
In the field of oncology, 6-(5-Chloro-2-pyridyl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione is utilized as a kinase inhibitor for the development of cancer treatments. Its ability to target specific kinases involved in cancer cell growth and survival positions it as a candidate for creating more effective and targeted therapies against various types of cancer.
Used in Biological Mechanism Studies:
6-(5-Chloro-2-pyridyl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione also serves as a valuable tool in research for studying the mechanisms of various biological processes. Its unique chemical structure allows scientists to probe and understand intricate cellular functions, potentially leading to the discovery of new therapeutic targets and a deeper comprehension of disease pathways.

InChI:InChI=1/C11H5ClN4O2/c12-6-1-2-7(15-5-6)16-10(17)8-9(11(16)18)14-4-3-13-8/h1-5H

Synthetic route

bis(trichloromethyl) carbonate (32315-10-9) + 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid (43200-83-5) → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
With Triphenylphosphine oxide In dichloromethane at 20℃; for 0.0833333h; Temperature; Concentration;	98.5%

5-chloro-2-pyridylamine (1072-98-6) + 2,3-pyrazinedicarboxylic anhydride (4744-50-7) → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
With propionic acid anhydride at 60 - 105℃; for 1h; Temperature; Reagent/catalyst;	87%
With dmap; triethylamine In 5,5-dimethyl-1,3-cyclohexadiene at 0℃; for 13h; Reflux;	85%

3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid (43200-83-5) → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0 - 20℃; for 2h;
Stage #1: 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid In dichloromethane for 1h; Heating / reflux; Stage #2: With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 0.75 - 1h; Heating / reflux;

(7S)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
With manganese(IV) oxide In dichloromethane for 3h; Reflux;	12.5 g

5-chloro-2-pyridylamine (1072-98-6) → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 2.5 h / 20 - 52 °C 1.2: 1 h / 10 - 15 °C 2.1: dichloromethane / 1 h / Heating / reflux 2.2: 0.75 - 1 h / 25 - 30 °C / Heating / reflux View Scheme

2,3-pyrazinedicarboxylic anhydride (4744-50-7) → 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 2.5 h / 20 - 52 °C 1.2: 1 h / 10 - 15 °C 2.1: dichloromethane / 1 h / Heating / reflux 2.2: 0.75 - 1 h / 25 - 30 °C / Heating / reflux View Scheme

6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4) → 6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (148891-53-6)

Conditions	Yield
With diisobutylaluminium hydride In toluene at -25 - -10℃; for 2h; Temperature; Solvent;	91.1%

6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
Stage #1: 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine With potassium borohydride In 1,4-dioxane at 10 - 15℃; for 0.5h; Stage #2: With water In 1,4-dioxane for 6h;	87.4%
With potassium borohydride; water In tetrahydrofuran at -10 - 5℃; for 3h; Large scale;	70%
With potassium borohydride; potassium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide at 13℃; pH=11; Reagent/catalyst; Solvent; pH-value;	95.5 g
With sodium hydroxide; sodium tetrahydroborate In water at 0 - 5℃; for 4 - 5h; Product distribution / selectivity;

6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4) → (R)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate D-(+)-O,O'-dibenzoyltartaric acid salt (144025-94-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C 2: dmap; calcium oxide / dichloromethane; N,N-dimethyl-formamide / 10 - 30 °C 3: water; acetonitrile / 3 - 4.5 h / 25 - 80 °C / Resolution of racemate View Scheme

6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4) → eszopiclone dibenzoyl-D-tartrate (144025-93-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C 2: dmap; calcium oxide / dichloromethane; N,N-dimethyl-formamide / 10 - 30 °C 3: water; acetonitrile / 3 - 4.5 h / 25 - 80 °C / Resolution of racemate View Scheme

6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (43200-82-4) → eszopiclone (138729-47-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C 2: dmap; calcium oxide / dichloromethane; N,N-dimethyl-formamide / 10 - 30 °C 3: water; acetonitrile / 3 - 4.5 h / 25 - 80 °C / Resolution of racemate 4: water; sodium hydrogencarbonate / 3 - 4 h / 25 - 30 °C View Scheme

Upstream product

• 43200-83-5 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid 
• 4744-50-7 2,3-pyrazinedicarboxylic anhydride 
• 1072-98-6 5-chloro-2-pyridylamine 
• 32315-10-9 bis(trichloromethyl) carbonate 
• 537036-14-9 (7S)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one 

Downstream Products

• 43200-81-3 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 144025-94-5 (R)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate D-(+)-O,O'-dibenzoyltartaric acid salt 
• 144025-93-4 eszopiclone dibenzoyl-D-tartrate 
• 138729-47-2 eszopiclone 
• 148891-53-6 6-(5-chloropyridin-2-yl)-6,7-dihydropyrrolo[3,4-b]pyrazin-5-one 

Relevant academic research and scientific papers

Preparation method of zopiclone intermediate

The invention provides a preparation method of zopiclone. According to the method, anhydride is used as a reaction solvent, pyrazine-2,3-dianhydride and 2-amino-5-chloropyridine are synthesized into 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine in one step, so that the process is simplified, the obtained product is high in yield and purity, production conditions and environment friendliness are achieved, and the method is suitable for industrial production.

A method for producing zopiclone

The invention relates to a preparation method of zopiclone for improving sleeping, belonging to the field of medicines. In the preparation process of 6-(5-chlro-2-pyridyl)-5, 7-dioxo-5, 6-dihydropyrrolo[3, 4-b] pyrazine, namely a compound 3, by taking DMAP (dimethylaminopyridine) as a catalyst, in the presence of triethylamine, cyclization is directly carried out to synthesize an intermediate 3. The crude product yield is 85%, the yield is improved, the operation is simplified, and irritant reagents such as acetic anhydride, thionyl chloride, ethyl chloroformate and the like are not used, thereby facilitating production, facilitating recovery of xylene as a solvent and reducing emission of three wastes. Zopiclone is further synthesized by the compound 3. The method is concise in whole line, simple and convenient to operate and more suitable for industrialized production.

Preparation method for pyrrolo-pyrazine

The invention discloses a preparation method for pyrrolo-pyrazine. The preparation method comprises the following steps that 1, levo-zopiclone (I) is dissolved into organic solvent, the pH is regulated to 8-10, and heating reflux is performed; 2, water is added, stirring is performed, standing is performed for layering, and a water layer is separated out; 3, the step 2 is repeated; 4, a drying agent is added in an organic layer for drying, filtering is performed, and filtrate is concentrated under reduced pressure until the filtrate is dried into a compound (II); 5, the compound (II) is dissolved into the organic solvent, an oxidizing agent is added, heating reflux oxidation is performed, filtering is performed, filtrate is concentrated under reduced pressure, cooling and crystallizing are performed, filtering is performed, and solids are dried to obtain the pyrrolo-pyrazine (III). According to the method, the by-product levo-zopiclone generated in eszopiclone production can be taken as the raw material to generate the pyrrolo-pyrazine (III) through reacting, the pyrrolo-pyrazine (III) generates zopiclone according to a conventional technique, waste utilization is maximized on the premise that the quality is guaranteed, and discharge of three wastes is greatly reduced.

Preparing method for N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone

The invention relates to a preparing method for a dexzopiclone intermediate N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone, in particular to preparation of 6-(5-chloropyridine-2-yl)-5H-pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone. According to the preparation method, N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone is prepared with triphosgene/triphenylphosphine oxide serving as a reaction reagent, as the product is a crystalline solid and is slightly soluble in an organic solvent while a catalyst is soluble in the organic solvent, the product can be obtained through direct suction filtration, and posttreatment is convenient; besides, a mother solution can be directly and consecutively reused, cyclic use of aryl oxide phosphate and the solvent is achieved, and the preparing method has the advantages that operation is simple, the reaction conditions are mild, the yield is high, and the quantity of three wastes is small; use of highly-corrosive toxic reagents such as thionyl chloride and chloroformate is avoided from the source, and high implementation value and social and economic benefits are achieved.

Process for the preparation of eszopiclone

The invention relates to a process for making of 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b] pyrazin-5-yl-4-methyl piperazine-1-carboxylate, also known as zopiclone. The invention further describes an effective method for resolving of zopiclone into its enantiomers (eszopiclone and (R)-zopiclone) and also provides a method of recycling of (R)-zopiclone.

IMPROVED PROCESS FOR THE PREPARATION OF ZOPICLONE AND IT'S ENANTIOMERICALLY ENRICHED ISOMER

Present invention relates to an improved process for the preparation of Zopiclone and its enantiomerically enriched isomer (Eszopiclone). 6-(5-Chloropyridin-2- yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine is reacted with 1-chloro- carbonyl-4-methylpiperazine in the presence of alkali earth metal carbonates, hydroxides or oxides in a solvent medium to give Zopiclone. It is reacted with optically active acid in a mixture of water and water miscible organic solvent followed by work up to give Eszopiclone. The present invention also relates to process for the conversion of (R) or (S) Zopiclone to 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro- pyrrolo- [3,4-b] - pyrazine of the intermediate which can be converted to racemic Zopiclone.