43200-81-3

Basic information

• Product Name: 6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one
• Synonyms: 6-(5-CHLOROPYRIDIN-2-YL)-5-HYDROXY-7-OXO-5,6-DIHYDROPROLO(3,4B)PYRAZINE;6-(5-CHLORO-PYRIDIN-2-YL)-7-HYDROXY-6,7-DIHYDRO-PYRROLO3,4-BPYRAZIN-5-ONE;6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one;6-(5-Chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-pyrrolo-(3,4b) Pyrazime;Zopiclone6-(5-Chloropyrid-2-Yl)-5-Hydroxy-7-Oxo-6,7-Dihydro-5H-Pyrrolo-[3,4-B]-Pyrazine;6-(5-Chloro-2-pyridin-2-yl)-7-hydroxy-6,7-dihydro-pyrrolo[3,4-b]pyrazin-5-one;Intermediate for Zopiclone II;6-(5-Chloro-2-pyridin-2-yl)-7-hydroxy-6,7-dihydro-pyrrolo[3,4-β]pyrazin-5-one
• CAS NO: 43200-81-3
• Molecular Formula: C₁₁H₇ClN₄O₂
• Molecular Weight: 262.65
• EINECS: 256-139-4
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 43200-81-3.mol
• Article Data: 10

Chemical Properties

• Melting Point: 240.5-241.50C
• Boiling Point: 525.2 °C at 760 mmHg
• Flash Point: 271.5 °C
• Appearance: Yellow crystalline powder
• Density: 1.653 g/cm³
• Vapor Pressure: 7.35E-12mmHg at 25°C
• Refractive Index: 1.719
• Storage Temp.: -20°C Freezer
• PKA: 8.62±0.20(Predicted)
• CAS DataBase Reference: 6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one(CAS DataBase Reference)
• NIST Chemistry Reference: 6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one(43200-81-3)
• EPA Substance Registry System: 6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one(43200-81-3)

Safety Data

• Hazardous Substances Data: 43200-81-3(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Crystalline Powder

Uses

Different sources of media describe the Uses of 43200-81-3 differently. You can refer to the following data:
1. Eszopiclone intermediate
2. Eszopiclone Impurity B.

InChI:InChI=1/C11H7ClN4O2/c12-6-1-2-7(15-5-6)16-10(17)8-9(11(16)18)14-4-3-13-8/h1-5,10,17H

Synthetic route

6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3.4-b]pyrazin-5-yl acetate → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
With sulfuric acid In ethanol for 3h; Reflux;	88.7%

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;

(-)-Zopiclone (138680-08-7) → 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: (-)-Zopiclone With trifluoroacetic acid In dichloromethane for 18h; Heating / reflux; Stage #2: With water; sodium hydrogencarbonate In dichloromethane at 0℃; pH=7.5 - 8; Product distribution / selectivity;	70%
Stage #1: (-)-Zopiclone With trifluoroacetic acid In dichloromethane for 18h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 0℃; pH=7.5 - 8; Product distribution / selectivity;	70%
Stage #1: (-)-Zopiclone With hydrogenchloride; water In methanol at 41℃; for 11h; Stage #2: With sodium hydrogencarbonate In methanol; water at 10 - 15℃; Product distribution / selectivity;	41.24%
Stage #1: (-)-Zopiclone With hydrogenchloride; water In methanol at 41℃; for 11h; Stage #2: With sodium hydrogencarbonate In methanol; water at 10 - 15℃; Product distribution / selectivity;	41.24%
With hydrogenchloride; water at 70℃; for 3h;

(+/-)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-18-4) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) + (S)-(+)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-20-8)

Conditions	Yield
With phosphate buffer; Candida antarctica lipase B Chirazyme-L2; triethylamine In water; toluene at 60℃; for 96h; pH=7;

(+/-)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-17-3) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) + (S)-(+)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-19-5)

Conditions	Yield
With phosphate buffer; Candida antarctica lipase B Novozym 435 In water; toluene at 60℃; for 96h; pH=7;

(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) → 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: (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 With water; sodium hydrogencarbonate In dichloromethane; acetonitrile at 25 - 30℃; for 0.75h; Stage #2: With hydrogenchloride; formic acid; water at 0 - 68℃; for 4h; Product distribution / selectivity;

(+/-)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-18-4) → (R)-5-(chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (1151528-25-4) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) + (S)-(+)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-20-8)

Conditions	Yield
With propan-1-ol; triethylamine; Novozyme 435 In toluene at 45℃; for 16 - 24h; Purification / work up; Enzymatic reaction; Resolution of racemate;	A n/a B n/a C n/a

2,3-pyrazinedicarboxylic anhydride (4744-50-7) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / 5,5-dimethyl-1,3-cyclohexadiene / 13 h / 0 °C / Reflux 2.1: potassium borohydride / 1,4-dioxane / 0.5 h / 10 - 15 °C 2.2: 6 h View Scheme
Multi-step reaction with 3 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 3.1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C View Scheme
Multi-step reaction with 2 steps 1: propionic acid anhydride / 1 h / 60 - 105 °C 2: potassium borohydride; water / tetrahydrofuran / 3 h / -10 - 5 °C / Large scale View Scheme

5-chloro-2-pyridylamine (1072-98-6) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / 5,5-dimethyl-1,3-cyclohexadiene / 13 h / 0 °C / Reflux 2.1: potassium borohydride / 1,4-dioxane / 0.5 h / 10 - 15 °C 2.2: 6 h View Scheme
Multi-step reaction with 3 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 3.1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: isopropyl alcohol / 5 h / Reflux; Large scale 2: 1 h / Reflux; Large scale 3: sulfuric acid / ethanol / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: propionic acid anhydride / 1 h / 60 - 105 °C 2: potassium borohydride; water / tetrahydrofuran / 3 h / -10 - 5 °C / Large scale View Scheme

zopiclon (43200-80-2) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water; acetonitrile / 3 - 4.5 h / 25 - 80 °C / Resolution of racemate 2.1: water; sodium hydrogencarbonate / dichloromethane; acetonitrile / 0.75 h / 25 - 30 °C 2.2: 4 h / 0 - 68 °C View Scheme

3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid (43200-83-5) → 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / 1 h / Heating / reflux 1.2: 0.75 - 1 h / 25 - 30 °C / Heating / reflux 2.1: sodium hydroxide; sodium tetrahydroborate / water / 4 - 5 h / 0 - 5 °C View Scheme

2-Chloroethyl chloroformate (627-11-2) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-17-3)

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 7h;	98%
With pyridine In dichloromethane at 0 - 20℃; for 7h;	98%
With pyridine In dichloromethane at 20℃; for 7h;

carbonochloridic acid 1-chloro-ethyl ester (50893-53-3) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(1-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 4h;	98%
With pyridine

2,2,2-trichloro-1,1-dimethylethoxychloroformate (66270-36-8) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(1,1-dimethyl-2,2,2-trichloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 2h;	98%
With pyridine

6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) + 2,2,2-Trichloroethyl chloroformate (17341-93-4) → (+/-)-6-(5-chloropyridin-2-yl)-7-oxo-5-(2,2,2-trichloroethyloxycarbonyloxy)-5,6-dihydropyrrolo[3,4b]pyrazine

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 5h;	98%
With pyridine In dichloromethane at 0 - 20℃; for 5h;	98%

4-methylpiperazine-1-carbonyl chloride monohydrochloride (55112-42-0) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → zopiclon (43200-80-2)

Conditions	Yield
Stage #1: 4-methylpiperazine-1-carbonyl chloride monohydrochloride With triethylamine In dichloromethane at 5℃; for 0.416667h; Stage #2: dmap In dichloromethane for 0.0166667 - 0.0333333h; Stage #3: 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one In dichloromethane at 20℃; for 7h; Product distribution / selectivity; Heating / reflux;	95%
With triethylamine; dmap In 2-methylpropyl acetate at 80℃; for 5.5h; Product distribution / selectivity;	91.7%
Stage #1: 4-methylpiperazine-1-carbonyl chloride monohydrochloride With triethylamine In ethyl acetate for 0.166667h; Stage #2: 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one; dmap In ethyl acetate at 60℃; for 7.5h; Product distribution / selectivity;	90%

Isopropenyl chloroformate (57933-83-2) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → 6-(5-chloropyridin-2-yl)-7-oxo-5-(2-propenyloxycarbonyloxy)-5,6-dihydropyrrolo[3,4b]pyrazine (862210-86-4)

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 6h;	93%

6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → 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 -15℃; for 2h; Temperature;	92.6%

benzoyl chloride (98-88-4) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → benzoic acid 6-(5-chloro-pyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl ester

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 4h;	89%

butyryl chloride (141-75-3) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → butyric acid 6-(5-chloro-pyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl ester

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 5h;	87%

carbonochloridic acid, chloromethyl ester (22128-62-7) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-18-4)

Conditions	Yield
With pyridine In dichloromethane at 20℃; for 17h;	86%
With pyridine In dichloromethane at 25℃; for 17h;	86%
With pyridine In dichloromethane at 0 - 20℃; for 17h;	86%

acetyl chloride (75-36-5) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → 6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3.4-b]pyrazin-5-yl acetate

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 5h;	85%

4-methyl-piperazine-1-carbonyl chloride (39539-66-7) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → zopiclon (43200-80-2)

Conditions	Yield
With dmap; triethylamine In dichloromethane at 20℃; for 3h; Reflux;	80%
With dmap; triethylamine In acetonitrile at 60 - 65℃; for 1.5h; Large scale;	80.9%
Stage #1: 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at -10 - 35℃; Stage #2: 4-methyl-piperazine-1-carbonyl chloride In N,N-dimethyl-formamide; mineral oil at -10 - 20℃; Product distribution / selectivity;	78.81%
Stage #1: 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With sodium hydride In N,N-dimethyl-formamide at -10℃; Stage #2: 4-methyl-piperazine-1-carbonyl chloride In N,N-dimethyl-formamide at -10 - 20℃; for 3h; Product distribution / selectivity;	78.81%
With sodium hydride In N,N-dimethyl-formamide Product distribution / selectivity;

6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → 3-hydroxymethyl-pyrazine-2-carboxylic acid N-(5-chloro-pyridin-2-yl)-amide (1122549-43-2)

Conditions	Yield
With sodium tetrahydroborate In 1,4-dioxane; water at 10 - 15℃; for 2h;	75.2%

Vinyl chloroformate (5130-24-5) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-6-(5-chloropyridin-2-yl)-7-oxo-5-(vinyloxycarbonyloxy)-5,6-dihydropyrrolo[3,4b]pyrazine (190369-20-1)

Conditions	Yield
With pyridine In dichloromethane at 25℃; for 10h;	75%

4-Nitrophenyl chloroformate (7693-46-1) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(p-nitrophenyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 21h;	55%
With pyridine

di(succinimido) carbonate (74124-79-1) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → 6-(5-chloropyridin-2-yl)-7-oxo-5-(N-succinimidyloxycarbonyloxi)-5,6-dihydropyrrolo[3,4b]pyrazine

Conditions	Yield
With pyridine; triethylamine In acetonitrile at 0 - 20℃; for 18h;	40%

phenyl chloroformate (1885-14-9) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → C18H11ClN4O4

Conditions	Yield
With (R)-6-benzyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole; triethylamine In dichloromethane at 20℃; Catalytic behavior; enantioselective reaction;	35%

2-nitrophenyl chloroformate (50353-00-9) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (+/-)-7-(o-nitrophenyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

Conditions	Yield
With pyridine

carbonochloridic acid, chloromethyl ester (22128-62-7) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (S)-(+)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-20-8) + (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine

Conditions	Yield
Stage #1: carbonochloridic acid, chloromethyl ester; 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With pyridine In dichloromethane at 25℃; for 17h; Stage #2: With Candida antarctica lipase (fraction B) - octadecyl-Sepabeads; sodium phosphate In 1,4-dioxane; water at 25℃; pH=7;

2-Chloroethyl chloroformate (627-11-2) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (S)-(+)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (508169-19-5) + (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine

Conditions	Yield
Stage #1: 2-Chloroethyl chloroformate; 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With pyridine In dichloromethane at 25℃; for 7h; Stage #2: With Candida antarctica lipase (fraction B) - octadecyl-Sepabeads; sodium phosphate In 1,4-dioxane; water at 25℃; pH=7;

acetyl chloride (75-36-5) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine + acetic acid 6-(5-chloro-pyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl ester

Conditions	Yield
Stage #1: acetyl chloride; 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With pyridine In dichloromethane at 25℃; for 5h; Stage #2: With Candida antarctica lipase (fraction B) - octadecyl-Sepabeads; sodium phosphate In 1,4-dioxane; water at 37℃; pH=7;

butyryl chloride (141-75-3) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine + (7S)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one + butyric acid 6-(5-chloro-pyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl ester + butyric acid 6-(5-chloro-pyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl ester

Conditions	Yield
Stage #1: butyryl chloride; 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With pyridine In dichloromethane at 25℃; for 5h; Stage #2: With Candida antarctica lipase (fraction B) - octadecyl-Sepabeads; sodium phosphate In 1,4-dioxane; water at 25℃; pH=7; Title compound not separated from byproducts;

Vinyl chloroformate (5130-24-5) + 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine + (S)-6-(5-chloropyridin-2-yl)-7-oxo-5-(vinyloxycarbonyloxy)-5,6-dihydropyrrolo[3,4b]pyrazine

Conditions	Yield
Stage #1: Vinyl chloroformate; 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one With pyridine In dichloromethane at 25℃; for 10h; Stage #2: With Candida antarctica lipase (fraction B) - octadecyl-Sepabeads; sodium phosphate In 1,4-dioxane; water at 25℃; pH=7;

6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (43200-81-3) → eszopiclone (138729-47-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / pyridine / CH2Cl2 / 17 h / 20 °C 2: Candida antarctica lipase B Chirazyme-L2; phosphate buffer; triethylamine / toluene; H2O / 96 h / 60 °C / pH 7 3: 90 percent / acetone / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: (R)-6-tert-butyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole; triethylamine / dichloromethane / 0 °C 2: acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: dmap; calcium oxide / dichloromethane; N,N-dimethyl-formamide / 10 - 30 °C 2: water; acetonitrile / 3 - 4.5 h / 25 - 80 °C / Resolution of racemate 3: 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 
• 43200-80-2 zopiclon 
• 508169-18-4 (+/-)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 43200-82-4 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine 
• 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 
• 138680-08-7 (-)-Zopiclone 
• 508169-17-3 (+/-)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 1072-98-6 5-chloro-2-pyridylamine 
• 4744-50-7 2,3-pyrazinedicarboxylic anhydride 

Downstream Products

• 1122549-43-2 3-hydroxymethyl-pyrazine-2-carboxylic acid N-(5-chloro-pyridin-2-yl)-amide 
• 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 
• 148891-53-6 6-(5-chloropyridin-2-yl)-6,7-dihydropyrrolo[3,4-b]pyrazin-5-one 
• 43200-88-0 6-(5-chloro-pyridin-2-yl)-7-phenoxycarbonyloxy-6,7-dihydro-pyrrolo[3,4-b]pyrazin-5-one 
• 43200-80-2 zopiclon 
• 138729-47-2 eszopiclone 
• 537036-14-9 (R)-6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine 
• 537036-14-9 (7S)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 508169-19-5 (S)-(+)-7-(2-chloroethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 508169-20-8 (S)-(+)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 508169-18-4 (+/-)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 

Relevant articles and documents

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.

Process for synthesis and purification of anhydrous crystalline S-zopiclone

Process for synthesis and purification of anhydrous crystalline S-zopiclone for the preparation of enantiomerically pure {S)-5-{chloromethyloxycarbonyloxy)-6-{5-chloropyrid-2-yl)-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine (S)-(I).