CN105399745A - Preparation method of pyrazine hydroxyl pyrrolidone compound - Google Patents
Preparation method of pyrazine hydroxyl pyrrolidone compound Download PDFInfo
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- CN105399745A CN105399745A CN201510964385.8A CN201510964385A CN105399745A CN 105399745 A CN105399745 A CN 105399745A CN 201510964385 A CN201510964385 A CN 201510964385A CN 105399745 A CN105399745 A CN 105399745A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention discloses a preparation method of a pyrazine hydroxyl pyrrolidone compound. The preparation method comprises the steps of: (a) adjusting the pH value of water to higher than 7 with inorganic base to obtain an aqueous solution of inorganic base, or adjusting the pH value of a water-containing organic solvent to higher than 7 with inorganic base to obtain an inorganic base water-containing organic solvent solution, and dissolving potassium borohydride or sodium borohydride; and (2) dissolving the raw materials in a solvent in a container to obtain a raw material solution, controlling the reaction temperature at 11-15 DEG C, adding a potassium borohydride solution or a sodium borohydride solution, and reacting to obtain the pyrazine hydroxyl pyrrolidone compound. According to the method, potassium borohydride or sodium borohydride is added in the form of solution into the reaction system, and the control of feed rate by temperature indication avoids instantaneous release of excessive hydrogen. The method solves in the problem of instantaneous release of excessive hydrogen due to difficulty in controlling a single dosage in the traditional methods, and has the characteristics of simpleness, safe and reliable production, high yield and good product quality.
Description
Technical field
The invention belongs to a kind of preparation method of chemical intermediate, be specifically related to the intermediate pyrazine of anti-insomnia medicine Lunesta and hydroxyl pyrrolidine ketone compounds, chemistry 6-(5-chloro-2-pyridyl)-6 by name, 7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] preparation method of pyrazine-5-ketone, belong to field of medicaments.
Background technology
Zopiclone (Zopiclone) chemistry 6-(5-chloropyridine-2-base)-7-[(4-methylpiperazine-1-yl) carbonyl oxygen base]-5 by name, 6-pyrrolin also [3,4-b] pyrazine-5-ketone, be the third generation sedative hypnotic being developed listing by French Rhone-PoulencRorer company in 1987 first, be used for the treatment of sleep disordered.This medicine overcomes the shortcoming of the first-generation (barbiturates) and the s-generation (benzodiazepines) sedative hypnotic, transformation period is only 5 hours in vivo, take before sleeping, secondary morning seldom produces " hangover phenomenon ", do not affect time cerebration in morning and the dexterity of action, and because of using dosage little, reuse unlikely accumulation, security is higher.
Lunesta (Eszopiclone) chemistry (+)-6-(5-chloropyridine-2-base)-7-[(4-methylpiperazine-1-yl) carbonyl oxygen base]-5 by name, 6-pyrrolin also [3,4-b] pyrazine-5-ketone, being the quick fugitive Non-benzodiazepine sedative hypnotic developed by Sepracor company of the U.S., is the dextrorotation individual isomer of Zopiclone.In December, 2004, FDA ratified Lunesta listing.This medicine is first insomnia medicine getting permission life-time service, be first can for a long time for improving initial sleep and maintaining the medicine of sleep quality.
Current most of Lunesta is all obtain by the following method: 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone obtains Zopiclone through condensation reaction, and chiral fractionation obtains Lunesta to the latter is again one of common method preparing Lunesta.
In the Zopiclone synthetic route (US3862149) of Rhone-PoulencRorer company, to 6-(5-chloro-2-pyridyl)-5,7-dioxo-5H-pyrrolo-[3,4-b] add potassium borohydride reduction in solid mode in the water of pyrazine and dioxane mixing solutions and obtain intermediate 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone, yield is 63.7%.Ren Jian etc. [Chinese pharmaceutical chemistry magazine, 20 (4), 259-263] adopt similarity method to prepare 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone, yield 60%.
CN101058582 utilizes acyloxy POTASSIUM BOROHYDRIDE/sodium to 6-(5-chloro-2-pyridyl)-5,7-dioxy-5H-pyrrolo-[3,4-b] pyrazine carries out regioselective reduction and obtains Zopiclone intermediate 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone.In the method, again reaction substrate is reduced after first need obtaining acyloxy POTASSIUM BOROHYDRIDE/sodium by POTASSIUM BOROHYDRIDE/organic acid reaction such as sodium and Glacial acetic acid.And preparing the feed way still adopting portion-wise addition POTASSIUM BOROHYDRIDE/sodium solid in reaction system in acyloxy POTASSIUM BOROHYDRIDE/sodium process.The yield being prepared 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone by the method is 92%.
In the above-mentioned methods, the feed way of portion-wise addition POTASSIUM BOROHYDRIDE/sodium solid in reaction system is all adopted.Because this kind of feed way is difficult to control feed rate and each feeding quantity, therefore very easily due to reinforced too fast or single charge amount is excessive and cause vigorous reaction, instantaneous release goes out a large amount of hydrogen, there is very big potential safety hazard.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of pyrazine and the preparation method of hydroxyl pyrrolidine ketone compounds.
Technical scheme of the present invention is summarized as follows:
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) the pH > 7 of water is regulated to obtain inorganic base aqueous solution with mineral alkali, or regulate the pH > 7 of water-containing organic solvent to obtain mineral alkali water-containing organic solvent solution with mineral alkali, dissolve POTASSIUM BOROHYDRIDE or sodium borohydride, obtain solution of potassium borohydride that concentration is 20-200g/L or concentration is the sodium borohydride solution of 20-200g/L; Described water-containing organic solvent is that the first organic solvents of 1:0.1 ~ 10 and water form by volume ratio;
(2) in a reservoir, raw material (II) is dissolved in solvent and obtains raw material (II) solution, controlling temperature of reaction is 11 DEG C-15 DEG C, add solution of potassium borohydride or sodium borohydride solution, reaction, obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I);
Reaction formula is as follows:
Product (I) chemistry is by name: 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone;
The chemistry of raw material (II) is called: 6-(5-chloro-2-pyridyl)-5,7-dioxy-5H-pyrrolo-[3,4-b] pyrazine.
The pH of step (1) preferably 9 ?13.
Mineral alkali is preferably at least one in potassium hydroxide, sodium hydroxide, saleratus, sodium bicarbonate, salt of wormwood and sodium carbonate.
The first organic solvent is preferably methyl alcohol, ethanol, Virahol, DMF, acetonitrile and acetone at least one.
The second organic solvent of step (2) described solvent to be volume ratio be 2-4:1 and water composition, described the second organic solvent is tetrahydrofuran (THF), methyl alcohol and dioxane at least one.
Advantage of the present invention:
Method of the present invention is by being that the solution form of 20-200g/L joins in reaction system with concentration by POTASSIUM BOROHYDRIDE or sodium borohydride, and by the control of temperature instruction feed rate, the instantaneous release amount avoiding hydrogen is excessive.Solve exist in traditional method to control the problem that single charge amount causes abrupt release amounts of hydrogen excessive then, have easy and simple to handle, production safety is reliable, reaction yield is high, the feature of good product quality.
Embodiment:
The present invention will be further described by the following examples, but be not construed as limiting the invention in any form.
Embodiment 1
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) regulate the pH=13 of water to obtain aqueous sodium hydroxide solution with sodium hydroxide, as solvent, with 14.5g sodium borohydride for solute, compound concentration is the sodium borohydride solution of 50g/L;
(2) in a reservoir, add 2L dioxane and 1L water, add raw material (II) 100g to dissolve, controlling temperature of reaction is 13 DEG C, progressively adds sodium borohydride solution, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 95.7g, content 98.7% (HPLC detection).
Embodiment 2
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) by volume ratio be 1:0.1 first alcohol and water mixing, regulate pH=12 with potassium hydroxide, as solvent, with 14.5g POTASSIUM BOROHYDRIDE for solute, compound concentration is the solution of potassium borohydride of 20g/L;
(2) in a reservoir, add 4L tetrahydrofuran (THF) and 1L water, mixing, adds raw material (II) 100g and dissolves, controlling temperature of reaction is 11 DEG C, progressively add solution of potassium borohydride, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 94.9g, content 98.4% (HPLC detection).
Embodiment 3
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) mix with the second alcohol and water that volume ratio is 1:10, regulate pH=9 with saleratus, as solvent, with 14.5g POTASSIUM BOROHYDRIDE for solute, compound concentration is the solution of potassium borohydride of 200g/L;
(2) in a reservoir, add 3L methyl alcohol and 1L water, mixing, adds raw material (II) 100g and dissolves, controlling temperature of reaction is 15 DEG C, progressively add solution of potassium borohydride, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 95.0g, content 98.1% (HPLC detection).
Embodiment 4
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) mix with the isopropyl alcohol and water that volume ratio is 1:5, regulate pH=10 with sodium bicarbonate, as solvent, with 14.5g sodium borohydride for solute, compound concentration is the sodium borohydride solution of 200g/L;
(2) in a reservoir, add 1L dioxane, 1L methyl alcohol and 1L water, mixing, adds raw material (II) 100g and dissolves, controlling temperature of reaction is 13 DEG C, progressively add sodium borohydride solution, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 95.2g, content 98.0% (HPLC detection).
Embodiment 5
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) be the DMF of 1:1 and water mixing by volume ratio, regulate pH=11 with salt of wormwood, as solvent, with 14.5g POTASSIUM BOROHYDRIDE for solute, compound concentration is the solution of potassium borohydride of 50g/L;
(2) in a reservoir, add 3L dioxane and 1L water, mixing, adds raw material (II) 100g and dissolves, controlling temperature of reaction is 13 DEG C, progressively add solution of potassium borohydride, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 95.5g, content 98.1% (HPLC detection).
Embodiment 6
A kind of pyrazine the preparation method of hydroxyl pyrrolidine ketone compounds (I), comprise the steps:
(1) be the mixing of the acetonitrile of 0.5:0.5:1, acetone and water by volume ratio, regulate pH=11 with sodium carbonate, as solvent, with 14.5g sodium borohydride for solute, compound concentration is the sodium borohydride solution of 20g/L;
(2) in a reservoir, add 3L dioxane and 1L water, mixing, adds raw material (II) 100g and dissolves, controlling temperature of reaction is 13 DEG C, progressively add sodium borohydride solution, reaction, with HPLC monitoring to material content < 0.5%, reacting liquid filtering, filter cake is with water washing, dry that faint yellow solid obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I) 95.4g, content 98.1% (HPLC detection).
Claims (5)
1. pyrazine a preparation method for hydroxyl pyrrolidine ketone compounds (I), is characterized in that comprising the steps:
(1) the pH > 7 of water is regulated to obtain inorganic base aqueous solution with mineral alkali, or regulate the pH > 7 of water-containing organic solvent to obtain mineral alkali water-containing organic solvent solution with mineral alkali, dissolve POTASSIUM BOROHYDRIDE or sodium borohydride, obtain solution of potassium borohydride that concentration is 20-200g/L or concentration is the sodium borohydride solution of 20-200g/L; Described water-containing organic solvent is that the first organic solvents of 1:0.1 ~ 10 and water form by volume ratio;
(2) in a reservoir, raw material (II) is dissolved in solvent and obtains raw material (II) solution, controlling temperature of reaction is 11 DEG C-15 DEG C, add solution of potassium borohydride or sodium borohydride solution, reaction, obtains a kind of pyrazine and hydroxyl pyrrolidine ketone compounds (I);
Reaction formula is as follows:
Product (I) chemistry is by name: 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxyl-5H-pyrrolo-[3,4-b] pyrazine-5-ketone;
The chemistry of raw material (II) is called: 6-(5-chloro-2-pyridyl)-5,7-dioxy-5H-pyrrolo-[3,4-b] pyrazine.
2. method according to claim 1, it is characterized in that described step (1) pH=9 ?13.
3. method according to claim 1, is characterized in that described mineral alkali is at least one in potassium hydroxide, sodium hydroxide, saleratus, sodium bicarbonate, salt of wormwood and sodium carbonate.
4. method according to claim 1, is characterized in that the first organic solvent described is methyl alcohol, ethanol, Virahol, DMF, acetonitrile and acetone at least one.
5. method according to claim 1, it is characterized in that described step (2) described solvent to be volume ratio be the second organic solvent and the water composition of 2-4:1, described the second organic solvent is tetrahydrofuran (THF), methyl alcohol and dioxane at least one.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3862149A (en) * | 1972-01-07 | 1975-01-21 | Rhone Poulenc Sa | Pyrrolo (3,4-b) pyrazine derivatives |
| CN101058582A (en) * | 2006-04-21 | 2007-10-24 | 天津天士力集团有限公司 | Method of preparing esopiclone intermediate 6-(5-chloro-2-pyridyl)-5-hydro-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazine |
| CN101857599A (en) * | 2009-04-09 | 2010-10-13 | 广州斯威森科技有限公司 | Industrial stereospecific synthesis of beta-artemether by using artemisinin as raw material |
| CN103145728A (en) * | 2013-04-12 | 2013-06-12 | 张梅 | Industrialized oriented synthesis method of beta-artemether |
| CN105037370A (en) * | 2015-06-26 | 2015-11-11 | 华中药业股份有限公司 | Preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine |
-
2015
- 2015-12-17 CN CN201510964385.8A patent/CN105399745A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3862149A (en) * | 1972-01-07 | 1975-01-21 | Rhone Poulenc Sa | Pyrrolo (3,4-b) pyrazine derivatives |
| CN101058582A (en) * | 2006-04-21 | 2007-10-24 | 天津天士力集团有限公司 | Method of preparing esopiclone intermediate 6-(5-chloro-2-pyridyl)-5-hydro-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazine |
| CN101857599A (en) * | 2009-04-09 | 2010-10-13 | 广州斯威森科技有限公司 | Industrial stereospecific synthesis of beta-artemether by using artemisinin as raw material |
| CN103145728A (en) * | 2013-04-12 | 2013-06-12 | 张梅 | Industrialized oriented synthesis method of beta-artemether |
| CN105037370A (en) * | 2015-06-26 | 2015-11-11 | 华中药业股份有限公司 | Preparation method of 6-(5-Cl-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4b]pyrazine |
Non-Patent Citations (2)
| Title |
|---|
| 王明慧 等: ""硼氢化钠还原法合成1-(2,4-二氯苯基)-2-氯-乙醇"", 《有机化学》 * |
| 陶松 等: ""硼氢化钠在氢氧化钠溶液中的密度和黏度"", 《无机盐工业》 * |
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Application publication date: 20160316 |