CN105037370A - Preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine - Google Patents

Preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine Download PDF

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Publication number
CN105037370A
CN105037370A CN201510360595.6A CN201510360595A CN105037370A CN 105037370 A CN105037370 A CN 105037370A CN 201510360595 A CN201510360595 A CN 201510360595A CN 105037370 A CN105037370 A CN 105037370A
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Prior art keywords
pyrrolo
pyridyl
dihydro
chloro
pyrazine
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廖俊
付林
曾建华
冯旋
赵成安
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HUAZHONG PHARMACEUTICAL CO Ltd
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HUAZHONG PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The invention provides a preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine. 6-(5-Cl-2-pyridyl)-5,7-bioxo-6,7-dihydro-5H-pyrrolo-[3,4-b]pyrazine is taken as a main raw material, the main raw material is treated in advance, a surfactant is added into a reduction reaction system for reduction reaction in a manner of using water to replace organic solvents such as dioxane or tetrahydrofuran as a reduction reaction solvent. The preparation method overcomes the technical prejudice that an intermediate needs to be prepared in an organic solvent-dissolved homogeneous reaction system, generation of massive organic waste is avoided, environment of a production field is improved, and material-carrying loss of organic sewage is avoided. The process has the advantages of low production cost, favorability for environment protection and suitability for industrialized large scale production.

Description

A kind of 6-(5-chloro-2-pyridyl) preparation method of-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine
Technical field
The present invention relates to a kind of preparation method of medical compounds intermediate, specifically a kind of intermediate 6-(5-chloro-2-pyridyl of anti-insomnia medicine Lunesta) preparation method of-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine.
Background technology
Lunesta (Eszopiclone) is the sedative hypnotic of the latest generation of Sepracor company of U.S. exploitation.This product, as the individual isomer of Zopiclone (Zopiclone), is first insomnia medicine getting permission life-time service, can for a long time for improving initial sleep (having difficulty in going to sleep) and maintaining sleep quality (night awakens or awakens too early between morning).6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine is the intermediate preparing Lunesta, its existing synthesis technique is normally in the dioxane or Tetrahydrofuran System of POTASSIUM BOROHYDRIDE, sodium borohydride; 6-(5-chloro-2-pyridyl is reduced in borine-Tetrahydrofuran System) the 5-position ketone group of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-(3,4-b) pyrazines obtains.Needing in preparation technology to use a large amount of organic solvent---substrate first dissolves by tetrahydrofuran (THF) or dioxane, then in homogeneous system, carries out regioselective reduction reaction; At last handling process, adopt elutriation discharge method to avoid distilling the generation that high temperature causes by product.Document " synthesis of New Chemical Class of Sedative-hypnotic Zopiclone Analogues " (Chinese pharmaceutical chemistry magazine, 1996,6,1, report 26-30) and comprise intermediate 6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6, the synthesis process of 7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine and Zopiclone analogue, after document adopts dioxane to dissolve substrate, add POTASSIUM BOROHYDRIDE to react, the elutriation that reacts completely obtains crude product, then obtains reduzate through refining, and total recovery is 64.1%; Chinese patent CN101058582A improves reducing process, and synthesis yield reaches 80%-92%.Patent technique needs to use a large amount of organic solvent and goes to dissolve substrate, and one of its embodiment needs the dioxane using substrate quality 30 times of volumes, needs equally to use the organic solvents such as a large amount of tetrahydrofuran (THF), acetonitrile in other scheme.Conventional fabrication techniques organic solvent consumption is large, the present situation of the direct elutriation discharging of aftertreatment, not only bring the drawback that production cost raises, also cause three wastes discharge amount large and the band material loss being difficult to process and cannot avoid the organic waste water occurred because the organic solvent in elutriation waste water cannot recycle.
Summary of the invention
Object of the present invention is exactly the defect for prior art, a kind of new 6-(5-chloro-2-pyridyl is provided)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] method of reducing of pyrazine, have that reduction reaction does not need with an organic solvent, do not produce organic waste water, production cost is low, yield is high, the feature of good product quality.
The present invention is with 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-(3,4-b) pyrazine is raw material, be reductive agent with metal borohydride in water, regioselective reduction 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-es [ 3,4-b ] the 5-position ketone group of pyrazine, prepare 6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine.Its synthetic route is as follows:
The invention provides a kind of new 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] method of reducing of pyrazine, it is characterized in that: by advance to main raw material---6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine carries out processing, in reduction reaction system, adding tensio-active agent, realize substituting the organic solvent such as dioxane or tetrahydrofuran (THF) using water and carry out reduction reaction as the mode of reduction reaction solvent, specifically comprise the steps:
In the solvent including tensio-active agent, add treated 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines; After stirring, then add metal borohydride and carry out reduction reaction; After reacting completely, freezing, filter, drying obtains 6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine.
Tensio-active agent used is Tween-60 or tween-80.
The volume of tensio-active agent used is 6-(5-chloro-2-pyridyl) 0.005 ~ 0.01 times of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine quality.
Solvent used is water, and the volume of water is 6-(5-chloro-2-pyridyl) 15 ~ 20 times of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine quality.
Before carrying out reduction reaction, 6-(5-chloro-2-pyridyl used)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines were through pulverizing 40 eye mesh screen process.
Metal borohydride used is sodium borohydride or POTASSIUM BOROHYDRIDE.
Metal borohydride used and 6-(5-chloro-2-pyridyl) mass ratio of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines is 0.070 ~ 0.075:1.
The temperature of reduction reaction is 0 DEG C ~ 10 DEG C, preferably 0 DEG C ~ 5 DEG C.
When metal borohydride is added reaction system, adopt gradation feed postition, control feed time 20 minutes ~ 30 minutes.
The invention has the beneficial effects as follows: in the reduction reaction of Lunesta synthesis process, carry out in the two-phase system of reaction solvent substituting the organic solvent such as dioxane or tetrahydrofuran (THF) using water, overcome prior art and generally believe that this Lunesta intermediate needs the technology prejudice prepared in the homogeneous reaction system of organic solvent dissolution.Adopt present invention process to avoid producing a large amount of organic waste water, improving production on-site environment, avoid the band material loss having organic waste water.Present invention process has the advantage that production cost is low, be conducive to environment protection, be suitable for industrialized production.
Embodiment
Illustrate the present invention with example below, these examples are intended to help to understand technique means of the present invention.But should be understood that these embodiments are exemplary, the present invention is not limited thereto.
Embodiment one
Add in reaction flask 1000ml water, 0.5ml tween-80, through pulverizing the 6-(5-chloro-2-pyridyl of 50g of 40 eye mesh screen process)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine, stir, be cooled to less than 5 DEG C, start from 0 DEG C ~ 5 DEG C gradation and add 3.5g POTASSIUM BOROHYDRIDE, adding the POTASSIUM BOROHYDRIDE time is 20 minutes ~ 30 minutes.Finish, continue at 0 DEG C ~ 5 DEG C stirring reactions 8 hours.React complete, filter, water 100ml × 3 washing leaching cake of 0 DEG C ~ 5 DEG C, dry, obtain the 6-(5-chloro-2-pyridyl of 47.1g) and-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine, HPLC purity 98.4%.
Embodiment two
Add in reaction flask 900ml water, 0.3ml tween-80, through pulverizing the 6-(5-chloro-2-pyridyl of 60g of 40 eye mesh screen process)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine, stir, be cooled to less than 5 DEG C, start from 0 DEG C ~ 5 DEG C gradation and add 4.5g sodium borohydride, adding the sodium borohydride time is 20 minutes ~ 30 minutes.Finish, continue at 2 DEG C ~ 5 DEG C stirring reactions 9 hours.React complete, filter, water 120ml × 3 washing leaching cake of 0 DEG C ~ 5 DEG C, dry, obtain the 6-(5-chloro-2-pyridyl of 56.2g) and-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine, HPLC purity 98.6%.
Embodiment three
Add in reaction flask 1000ml water, 0.4ml Tween-60, through pulverizing the 6-(5-chloro-2-pyridyl of 50g of 40 eye mesh screen process)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine, stir, be cooled to less than 5 DEG C, start from 0 DEG C ~ 5 DEG C gradation and add 3.7g sodium borohydride, adding the sodium borohydride time is 20 minutes ~ 30 minutes.Finish, continue at 1 DEG C ~ 5 DEG C stirring reactions 9 hours.React complete, filter, water 100ml × 3 washing leaching cake of 0 DEG C ~ 5 DEG C, dry, obtain the 6-(5-chloro-2-pyridyl of 47.0g) and-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine, HPLC purity 98.5%.
Embodiment four
Add in reaction flask 900ml water, 0.3ml Tween-60, through pulverizing the 6-(5-chloro-2-pyridyl of 60g of 40 eye mesh screen process)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine, stir, be cooled to less than 5 DEG C, start from 0 DEG C ~ 5 DEG C gradation and add 4.2g POTASSIUM BOROHYDRIDE, adding the POTASSIUM BOROHYDRIDE time is 20 minutes ~ 30 minutes.Finish, continue at 2 DEG C ~ 5 DEG C stirring reactions 9 hours.React complete, filter, water 120ml × 3 washing leaching cake of 0 DEG C ~ 5 DEG C, dry, obtain the 6-(5-chloro-2-pyridyl of 56.1g) and-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine, HPLC purity 98.1%.

Claims (9)

1. a 6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] preparation method of pyrazine, it is characterized in that: by advance to main raw material---6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine carries out processing, in reduction reaction system, adding tensio-active agent, realize substituting the organic solvent such as dioxane or tetrahydrofuran (THF) using water and carry out reduction reaction as the mode of reduction reaction solvent, specifically comprise the steps:
In the solvent including tensio-active agent, add treated 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines; After stirring, then add metal borohydride and carry out reduction reaction; After reacting completely, freezing, filter, drying obtains 6-(5-chloro-2-pyridyl)-5-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrolo-[ 3,4b ] pyrazine.
2. preparation method as claimed in claim 1, is characterized in that: described tensio-active agent is Tween-60 or tween-80.
3. preparation method as claimed in claim 1 or 2, is characterized in that: the volume of described tensio-active agent is 6-(5-chloro-2-pyridyl) 0.005 ~ 0.01 times of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine quality.
4. preparation method as claimed in claim 1, it is characterized in that: described solvent is water, the volume of water is 6-(5-chloro-2-pyridyl) 15 ~ 20 times of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazine quality.
5. preparation method as claimed in claim 1, is characterized in that: before carrying out reduction reaction, 6-(5-chloro-2-pyridyl used)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines were through pulverizing 40 eye mesh screen process.
6. preparation method as claimed in claim 1, is characterized in that: described metal borohydride is sodium borohydride or POTASSIUM BOROHYDRIDE.
7. the preparation method as described in claim 1 or 6, is characterized in that: described metal borohydride and 6-(5-chloro-2-pyridyl) mass ratio of-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[ 3,4-b ] pyrazines is 0.070 ~ 0.075:1.
8. the preparation method as described in claim 1 or 6 or 7, is characterized in that: when metal borohydride is added reaction system, adopts gradation feed postition, controls feed time 20 minutes ~ 30 minutes.
9. preparation method as claimed in claim 1, is characterized in that: the temperature of reduction reaction is 0 DEG C ~ 10 DEG C, preferably 0 DEG C ~ 5 DEG C.
CN201510360595.6A 2015-06-26 2015-06-26 Preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine Pending CN105037370A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105399745A (en) * 2015-12-17 2016-03-16 天津华津制药有限公司 Preparation method of pyrazine hydroxyl pyrrolidone compound

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2008126105A2 (en) * 2007-04-12 2008-10-23 Matrix Laboratories Ltd Improved process for the preparation of zopiclone and it's enantiomerically enriched isomer

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WO2008126105A2 (en) * 2007-04-12 2008-10-23 Matrix Laboratories Ltd Improved process for the preparation of zopiclone and it's enantiomerically enriched isomer

Non-Patent Citations (2)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105399745A (en) * 2015-12-17 2016-03-16 天津华津制药有限公司 Preparation method of pyrazine hydroxyl pyrrolidone compound

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