Field of the invention

The present invention provides an improved process for the preparation of intermediate for the Zopiclone and it isomers, particularly Eszopiclone. More particularly the present invention relates to one pot process for the preparation of , 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) Formula (II)

Background of the invention

The compound of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) is one of the important key intermediate for preparation of zopiclone or its isomers. Eszopiclone (S-zopiclone), which is chemically known as (+)-(5S)-6-(chloropyridine-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolol[3,4-b]pyrazine-5-yl-4-methyl-piperazine-l-carboxylate, has the following structural formula (I): Eszopiclone is a non-benzodiazepine hypnotic drug used for the treatment of insomania. This drug is dextrorotatory isomer of zopiclone and is more active. It is marketed under the brand name LUNESTA as a tablet containing 1 mg, 2 mg, or 3 mg of Eszopiclone. US 3,862,149 patent claims Zopiclone and discloses the processes for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II), a key intermediate used in the preparation of zopiclone by heating a suspension of 2-amino-5-chloropyridine of formula (IV) with pyrazine-2,3-dicarboxylic acid anhydride of formula (III) in presence of acetonitrile to obtain 3-([(5-chloropyridin-2-yl)amino]carbonyl) pyrazine-2-carboxylic acid of formula (V), cyclizing the resulted compound of formula (V) by heating 3-([(5-chloropyridin-2-yl)amino]carbonyl) pyrazine-2-carboxylic acid of formula (V) in thionyl chloride to the reflux temperature to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine of formula (VI) and reducing the 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine of formula (VI) using potassium borohydride in presence of dioxan and water to obtain 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II).

This patent process has following drawbacks, i) This patent process involves the isolation of every step as a solid material which involves the workup procedures and purification methods which lowers the overall yield, ii) The product obtained in step-ii) i.e. 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6 dihydropyrrolo[3,4-b]-pyrazine of formula (VI) highly unstable and easily converted into its 3-(5-chloropyrid-2-yl)carbamoylpyrazine-2-carboxylic acid of formula (V) hence it is inconvenient for the commercial scale preparation and iii) this patent also uses hazardous material such as thionyl chloride for cyclization. CZ 288047 B6 describes process for the preparation of 6-(5-Chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) by reducing 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-bjpyrazine of formula (VI) using sodium borohydride in presence aqueous organic amide such as dimethylformamide. IN 1412/MUM/2005 A describes a process for the preparation of 6-(5-Chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) which involves the hazardous reagent like thionyl chloride for cyclization.

IN 247051A (IN 645/MUM/2004) disclosed an one pot process for the preparation of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b] -pyrazine of formula (VI) from by reacting pyrazine-2,3 dicarboxylic acid with acetic anhydride and then followed by addition of 2-amino-5-chloropyridine (IV). The obtained product was further reduced to 6-(5-Chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) using biphasic solvent system such as methylene chloride and water. IN 2777/DEL/2007 A disclosed a process for the preparation of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI) from by reacting pyrazine-2,3-dicarboxylic acid anhydride of formula (III) with 2-amino-5-chloropyridine of formula (IV) in presence of acetic anhydride. These two patents involve the isolation of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI) which leads the loss in the yield.

The process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) reported in prior arts have several disadvantages like use of hazardous reagents like thionyl chloride and flammable solvents like diethyl ether & chloroform and also isolation of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI). All the reported processes involve the isolation of at least one of the intermediates namely (V) or (VI) which affect the over all yield and increasing the cost. Hence there is a strong need to develop simple, convenient, efficient and inexpensive process for the commercial scale preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II). Our inventors have carried out several experiments and surprisingly found that an one pot process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) from pyrazine-2,3-dicarboxylic acid anhydride without isolating of intermediate of 3-([(5-chloropyridin-2 yl)amino]carbonyl) pyrazine-2-carboxylic acid (V) and 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine (VI) provides good yield and high purity, so far none of the prior arts teaches or motivates the same.

Objective of the invention

The main objective of the present invention is to provide an one-pot process for the preparation 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) in higher yield and greater chemical purity. Another objective of the present invention is to provide an improved process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II), which would be more simple, economical and easy to implement on commercial scale. One more objective of the present invention is to provide an improved process for the preparation of zopiclone or its isomers via preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) by one pot process which avoids the isolation of unstable compounds, hazardous reagents and interconvertion of compounds formed during the reaction without isolating, the process which it reduces the operation cycle time.

Summary of the invention

Accordingly, the present invention provides an improved process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo [3,4-b]pyrazine-5-one of formula (II) comprising the steps of:

Detailed Description of the Invention

In one embodiment of the present invention, the reaction of pyrazine-2,3-dicarboxylic acid anhydride of formula (III) or its carboxylic acid with 2-amino-5-chloropyridine of formula (IV) of step-i) is carried out in presence of C1-C7 anhydride which is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride, hexanoic anhydride, heptanoic anhydride etc, preferably acetic anhydride. In another embodiment of the present invention, the reaction of pyrazine-2,3-dicarboxylic acid anhydride of formula (III) or its carboxylic acid with 2-amino-5-chloropyridine of formula (IV) is carried out at a temperature in the range of 25 °C to reflux temperature of solvent used for the reaction.

In another embodiment of the present invention the reduction of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI) is carried out in presence of sodium borohydride, potassium borohydride, sodium triacetoxy borohydride, sodium cyano borohydride, lithium aluminum hydride, lithium borohydride, lithium-tri-ethyl borohydride or lithium-tri-sec-butyl borohydride, preferably sodium borohydride. In still another embodiment of the invention, the solvent like acetonitrile, propionitrile, dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, tetrahydrofuran (THF), 2-methyl THF, and dioxane, water or mixtures thereof can be added to step (ii) reaction mass before the addition of reducing agent. Accordingly the present invention provides a simple and robust process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) without isolating the intermediates formed during the reaction such as compound of formula (V) and (VI), which makes the process more convenient, reduces the workup process and operation cycle time.

The 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazine-5-one of formula (II) obtained according to the present invention is optionally re-crystallized with solvents such as methanol, ethanol, isopropanol, propanol, butanol, isobutanol, dimethyl formamide, dimethyl acetamide, dichloromethane, water or mixtures thereof prererably methanol or dimethyl formamide and water. In still another embodiment of the present invention, reaction is carried out in a one-pot in which neither intermediates compound of formula (V) nor compound of formula (VI) is isolated. In the context of the present invention, the term one-pot is intended to mean that the steps referred to are carried out in a single reaction vessel. The starting materials of pyrazine-2,3-dicarboxylic acid anhydride and 2-amino-5-chloropyridine used in the present process can be prepared by conventional methods or process known in the prior arts. Further the 2-amino-5-chloropyridine material can be optionally purified (recrystallized) by using solvents selected from group consisting of methanol, ethanol, isopropanol and n-propanol to obtain a good purity of compound.

The 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazine-5-one of formula (II) prepared according to the present invention is used to prepare the Zopiclone and its isomers, particularly Eszopiclone by any conventional methods. The final compound of zopiclone or its isomers, particularly eszopiclone obtained by the known process from compound of formula (II) of the present invention having pharmaceutical acceptable level of impurities such as ethyl zopiclone, zopiclone-N-oxide, desmethyl-zopiclone, and dehydroxy-imino alcohol. Ethyl zopiclone zopiclone-N-oxide desmethyl-zopiclone dehydroxy-imino alcohol The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example 1:

Preparation of 6-(5-chIoro-2-pyridinyI)-7-hydroxy-6,7-dihydro-5H-pyrroIo [3,4-b]pyrazine-5-one of compound of formula (II). To a mixture of 2, 3-pyrazinedicarboxylic acid anhydride (10 g) and acetic anhydride solvent, 2-amino-5-chloro pyridine (8.5 g) was added and gradually heated to 110-140 °C under stirring. The stirring was continued till completion of reaction and then gradually cooled to 15-20 °C. To the reaction mass, acetonitrile was added at 15-20 °C, and then sodium borohydride solution (3.5 g in 35 mL of water and 35 mg of sodium hydroxide) was added under stirring and maintained till reaction completion. After completion of the reaction, the reaction mixture was poured in to water at 0-15 °C under stirring and the obtained solid was filtered, washed with water and suck dried. The resultant solid was recrystallized using methanol to get pure compound (12 gm). The above table clearly indicates the advantages of the present invention over the prior art process.

We Claim:

1. An improved process for the preparation of 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) OH Formula (II) comprising the steps of:

(i) reacting pyrazine-2,3-dicarboxylic acid anhydride of formula (III) or its carboxylic acid o Formula (III) with 2-amino-5-chloropyridine of formula (IV)
£f
H2N N
Formula (IV) in presence of solvent to obtain 3-([(5-chloropyridin-2-yl)amino]carbonyl) pyrazine-2-carboxylic acid of formula (V);
N COOH Formula (V)

(ii) cyclizing 3-([(5-chloropyridin-2-yl)amino]carbonyl) pyrazine-2- carboxylic acid of formula (V) at a temperature in the range of 25° C to reflux temperature to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI); and o Formula (VI)

(iii) reducing 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine of formula (VI) to obtain 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one of formula (II) using a • reducing agent and optionally in the presence of solvent; wherein neither one of the products steps (i) or (ii) is isolated, the process step i), ii) and iii) are carried out conveniently in an one pot without changing the reaction vessel.

2. The process according to the claim 1, wherein the solvent used in the reaction of step (i) is C1-C7 anhydride which is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride, hexanoic anhydride and heptanoic anhydride, preferably acetic anhydride.

3. The process according to the claim 1, wherein reaction of step (i) & (ii) is carried out at a temperature from 25 °C to reflux temperature of solvent used for the reaction.

4. The process according to the claim 1, wherein the reducing agent used in step (iii) is selected from group consisting of sodium borohydride, potassium borohydride, sodium triacetoxy borohydride, sodium cyano borohydride, lithium aluminum hydride, lithium borohydride, lithium-tri- ethyl borohydride and lithium-tri-sec-butyl borohydride, preferably sodium borohydride.

5. The process according to the claim 1, wherein the solvent used in step (iii) is selected from group consisting of acetonitrile, propionitrile, dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, tetrahydrofuran (THF), 2-methyl THF, and dioxane, water or mixtures thereof.

6. The process according to claim 1, wherein neither one of the products of steps (i) or (ii) is isolated.

7. The process according to claim 1, wherein steps (i),(ii) and (iii) are carried out in a single reaction vessel.

8. A process for preparation of zopiclone or its isomers which comprises preparing 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo [3,4-b]pyrazine-5-one of formula (II) according to claim 1, and converting into zopiclone or its isomers.