WO2009079939A1 - A method for preparing zopiclone - Google Patents

Abstract

A method for preparing zopiclone comprises the reaction of raw materials 6-(5-chloro-2-pyridyl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine and 1-chloroformyl-4-methylpiperazine hydrochloride, in an anhydrous organic solvent and alkaline condition in the presence of 4-substituted pyridine as a catalyst. Using organic solvent with low toxicity and not easy to deflagrate, and with a specific catalyst, the method of the present invention is carried completely, obtains the product with high purity and ideal yield.

Description

 Preparation method of zopiclone

 The invention relates to a method for synthesizing a compound, in particular to a method for preparing zopiclone.

Background technique

 Zopick, chemical name (5 S) (5 - gas - 2 - Pft pyridine) 7 oxo - 6, 7... two 5 Η · · · pyrrolo [3, 4-b] Pftazine 5 Base 4 methylpyrazine I carboxylate, is a research institute of Rhone-PouIent Rorer, France. It is a compound of the genus, which is a new type of non-benzene used in trampolines. Diazo sedative hypnotics for the treatment of insomnia, especially for patients who cannot tolerate the residual effects of the morning.

 As the third-generation non-benzene-based gas-promoting K drug can selectively act on the Β2Ϊ receptor, the retention effect is relatively small, and the phenomenon of “sleeping” rarely occurs in the morning, which does not affect the mental activity of the morning. And the sensitivity of the action, and the amount of reversal is small, and the repeated application also reduces accumulation, so it is safer.

 In 1975, US Patent (US 3,862,149) reported: using M, N-dimethylformamide as a solvent, as a catalyst for 6-(δ-chloro-2-pyridyl)-5-hydroxy-7-oxo ~ 5,6-Dihydropyrrolo[3,4-b-pyrazine and 1 gas-methyl-indolyl-4-methylpyrazine were used as starting materials to prepare zopiclone. The method has three problems; L flammable articles, safety in large-scale production is difficult to guarantee: 2 <lower yield, crude product yield 76%; 3> using a chromatography column during refining, which is not conducive to large-scale production.

 In 1993, Chen Chang et al. [Journal of Zhengzhou University (Natural Science Edition), 1993, 25, ?3 ?6] reported: using dichloromethane as solvent, 6-(δ-Μ~2-««) -5-light The benzyl- 7-oxo-5,6-dihydro 3-pyrolo[3,4- fa] 3⁄4-azine and the i-carbamoyl 4-methylpyridazine hydrochloride were used to prepare zopiclone. The main problem with this method is that the reaction is not thorough, resulting in low purity of the finished product and high impurity content.

In 1994, Zhang Yafang et al. (Chinese Journal of Medicinal Chemistry, 1994, 4 (1), 62-64) reported 遒; anhydrous pyridine as M' 6- (5-Μ~ ~ Φ ^: ) - 5 - - 7 - oxygen Generation - 5, 6-II. Gaso[3,4-b] 嗉-3⁄4 1 -chloromethyl--methyl piperazine hydrochloride was used as a starting material to prepare zopiclone. The method has two!' motifs: 1-1 ratio of crude product yield; 2. The reaction solution is poured into ice water during crystallization, which makes the pyridine difficult to collect, if the mother liquor (* ingot mixed with water) Liquid> Abandoned, not only increases the cost but also is not conducive to environmental protection. The radiance is out of the bottom, and the requirements of the European Pharmacopoeia are not met.

S content

 SUMMARY OF THE INVENTION The object of the present invention is to overcome the deficiencies of the prior art and to provide a novel method for synthesizing zopiclone which is characterized by safety and reliability, short reaction time > high reaction yield and good product quality.

 The technical scheme of the present invention is as follows;

A preparation method of zopiclone, e~(5- ''3⁄4 ingot) - 5 -diaperyl-7-oxy-5, 6 - 2 «desine 3⁄4 4 - b]fft嚷 and 1 - armor The hydrazide-4-propenylpiperazine acid salt is used as a raw material, and is obtained by reacting a 4-substituted pyridine as a catalyst under an alkaline condition in an anhydrous organic solvent. The reaction formula is as follows;

 Wherein R is a tertiary amino group, a C! C8 linear or branched alkane, a C?~C« aryl alkane, a C3~C8 cycloalkane, an aromatic group.

 Wherein, the anhydrous organic solvent is one or more of gas-married, acetonitrile, tetrachlorofuran, dioxane, acetone, ethyl acetate, '-dimethylformamide, preferably di-methane.

 The anhydrous organic solvent is 6 to 50 times by weight of 6 (:5 chloro-2-pyridyl) 5 3⁄4 yl-oxo-oxo, 6·di-[3,4- 3 pyridinium; The amount of anhydrous organic solvent is 6-(5-weityl)-·δ-trans-yl-7-oxo-δ, 6-dioxazide and [3, 4 b]azine in the amount of 25~35S

 The alkaline condition is an organic base, and particularly preferably from methylamine, diethylamine, triethylamine, dipropylamine, diisopropylamine, cyclic diamine, cycloethylamine, aniline, methylamine, N, One or a combination of dimethylaniline or pyridine. The amount of organic base added is 1.1.

 The catalyst 4-substituted pyridine selected from the group consisting of 4-dimethylaminopyrazole, -ylpyridine, 4-P-glycolyl 3⁄4 pyridine, 4-piperidinyl*pyridine., - (4 methyl-1 Shouting pyridine) 3⁄4 pyridine or 4 - one of the Marinji clocks,

 In the above preparation method, pyridine is added as a co-solvent, and the amount thereof is 6-(δ-gas-2-nyl) 5 hydroxy 7 oxo-5,6-diaminopyrrolo[3,4-azine 1 to 2 times (by weight).

 Preferably, the molar ratio of the catalyst to the starting material 6-(δ-Gas-2-pyridyl)-5-yl-7-oxo-5,6-dichloropyrrolo[4b]pyrazine is (0. H~0,5): 1.

 Preferably, the starting material 6·- (5 «-2 P pyridine) 5-hydroxy? The molar ratio of oxo-5,6-.dioxapyrrolo[3,4-b]pyridinium to i-3⁄4formyl-4-methylpyrazine salt is i: (1-1,7) ),

 Preferably, the reaction temperature is from iO to the boiling point of the solvent system.

 Preferably, the reaction time is i~4, 5 hours. More preferably, the reaction time is preferably 1.5 to 3.5 hours. After the completion of the above reaction, the following post treatment is carried out - a water layer is added to the reaction system, the water layer is discarded, and the dinitrogen is vacuum concentrated. Add ethyl acetate liter & M 78V, addictive anthrax, filter, cool down and crystallize, filter, dry, and obtain a 3⁄4 pressure liquid phase (HPLC) spectrum of the product obtained from the white-like solid zopiclone (Figure 1 It is well known that the separation of the liquid phase (HPLC) of the zopiclone standard is consistent.

 The preparation method of the zopiclone of the invention adopts an organic solvent which is relatively less toxic and is not flammable, and the reaction is thorough, the purity of the finished product is high, and an ideal yield is obtained. The technical feature of the preparation method of zopiclone of the present invention is also:

1. Selection of Catalysts The present invention has found, in addition to a large number of experiments, that 4-substituted pyridine can accelerate the reaction rate of zopiclone preparation and reduce side reactions, thereby extracting product yield and yield.

2. The catalyst 4-reactive radical "pyridine" of the invention is reacted with the reactant S-(5 chloro-2-pyridyl) 5-hydroxy-?-oxo 6-dioxapyrido[3,4-b]pyrazine The ratio is particularly preferably 0.0i~0.5: Ϊ, I have found through experiments that I can't clearly lift the reaction rate when the molar ratio is less than 0.01:1, if it is from 0.5: Ϊ and 糜尔比在ί).01: 1 With 5: 1 There is no significant difference in the improvement of the reaction rate, which increases the amount of catalytic tilt, which increases the production cost.

3. The reaction temperature of the present invention is preferably -10 Torr to the boiling point of the solvent system. If it is lower than ΪΟΌ, the reaction will be delayed, and the reaction will be prolonged, and the labor cost will be increased.

 The reaction time of the present invention is preferably ϊ4 hours. It has been verified by experiments that we found that the reaction time is less than Ϊhour, which makes the reaction incomplete. The reaction time is higher than 4.5 hours, which not only does not increase the yield of the product, but instead The color of the product is deepened.

 In addition to the above characteristics, the preparation method of the zopiclone of the invention has the characteristics of safety and reliability, short reaction time, high reaction yield and good product quality.

 m

 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a high 'pressure liquid (H:) spectrum of the product of the present invention, abscissa time, in minutes.

detailed description

 The present invention will be further described below in conjunction with the implementation, but is not limited thereto.

 Implementation tree I t

 Into a 500 reaction flask, 250 g of dichloromethane, 10. Og 6 - ( 5 -钺 - 2 - 3⁄4-pyridyl) - 5 -hydroxy-? -oxo-S,6 di- succinyl [3,4-b]pyrazine, 10, Og 1 -carbamoyl-4-methylpyrazine hydrochloride, I 1M pyridine, ethylamine and i. 4-dimethylaminopyridine, the temperature was raised to reflux, and the reaction was kept for 1.5 hours. Then, iOOai purified water was added, the layers were separated, and the aqueous layer was discarded. The methylene chloride was concentrated. 8t:, add g activated carbon, stir for 30 minutes, filter, cool down and crystallize, filter, and obtain a white solid of zopicl, 13. 73⁄4 yield 92.9%, content 98, 5% (HPLC).

 Example 2:

 Into the 5Wnd counter-injection bottle, 35i) g of di-methane, 10. 3⁄4 6-(5-chloro-2-pyridyl) 5-based oxo-oxo, 6-dichloropyrrolo[3, 4 -1x1 pyrazine , iO. Og 1-carboyl- 4 -methylpiperazine bath salt, Ilmi pyridine, 15 diamine and 2. Og 4 dimethylamine bisphenol, heated to the chamber flow, and the reaction was kept for 1 hour; Add iOOmi purified water, layer, discard the water layer, dilute the methane methane in vacuo, add ΐ 503⁄4ι ethyl acetate to raise the temperature to c, add lg activated carbon, stir for a while, filter, cool and crystallize, filter, dry, get the Pico it white solid 14.00 g, yield 94. 59%, content ^. 3% (HPLC).

 Example 3;

 Into a 5-bed reaction flask, 253⁄4 Ν, Ν-dimethylformamide, 1.0. Og 6 (5 gas 2 pyridyl) 5 thiol 7 oxo 5> 6-di 3⁄4 pyrrole [3, 4 - bmm O. 1 Og 1 甲甲基基·4-methylpiperazine hydrochloride, 3⁄4 pyridine, diisopropylamine and 1. Og 4 -dimethylaminopyridine, incubated at 25 ° C 3. 0 hours Then, 103⁄41 purified water was added, the layers were separated, and the aqueous layer was discarded. After concentrating the N,N-di-ytylformamide in vacuo, the mixture was heated to 78 ° C by adding acetonitrile, stirred for 30 minutes, and filtered. The temperature is crystallization, filtration, and drying, to obtain a white solid of zopiclone 13.6 g, grazing rate 91.89%, content 98. 03⁄4 CHPLC),

 Example 4:

Into a 500 ml reaction flask, 350 g of N, ^ dimethylformamide, 10. 0 g of 6-(5-chloro-' 2-pyridyl)-5 hydroxy-7-oxo 5, δ-dichloropyrrolo[3] were sequentially introduced. , 4 - b] pyrazine, 10. 0g i chloromethylmethylmethyl sulfazine hydrochloride, 2 (1⁄2ϊ pyridine {3⁄41 triethylamine and i. Og 4-piperidylpyridine, warmed to reflux, protected Reaction i, 5 hours; then, add ICKimi purified water, layer, the water layer is discarded * Concentrate N, N-dimethylformamide in vacuo, add 150 B Ethyl acetate was heated to 78 Ό, lg activated carbon was added, mixed for 30 minutes, filtered, cooled and crystallized and filtered, dried to obtain 3,.32 g of zopiclone white solid, yield 90,03⁄4, content 99, « <HFlC ) _e

Claims

i, a preparation method of zopiclone, 6 - (5 - - 2 - oxaridinyl) ~ 5 - 3⁄43⁄4 - 7 - oxo - 5, 6 - dichloropyrrolo[3⁄4 4 - b] H» It is prepared by reacting 1 - gas flat mouse - 4 methyl sulfonate hydrochloride in an anhydrous organic solvent under alkaline conditions with 4 -substituted pyridine as a catalyst;

 Wherein R is a tertiary amine group, a C~CS linear or branched hydrocarbon, a C7~C!5 aralkyl, a C3~C8 cycloalkane, a fragrance  The anhydrous organic solvent is one or more of gas, acetonitrile, tetrachlorofuran, dioxane, succinyl, ethyl ethyl ethoxide, and N-dimethylformamide, and is used for anhydrous organic dissolution. The amount is 6 (5 gas 2-pyridyl) 5 hydroxy-7-oxo 6-dihydropyridin [3, 4 b] « 10 to 50 weight times of hydrazine; preferably 25 to 35 weight times.  The method for producing zopiclone according to claim 1, wherein the anhydrous organic solvent is dichloromethane. 3. A method for preparing a clone of Zuo 2, such as Quan Li, which is characterized in that methylamine, diethylamine, triethylamine, dipropylamine, diisopropylamine, cyclopropylamine, and a ring are used in an alkaline condition. One or a combination of ethylamine, aniline, methylaniline, dimethylaniline or pyridine, the amount of the organic base is preferably pH-8 U.  4. Process for the preparation of zopiclone according to claim 1 characterized in that the catalyst 4 -substituted pyridine is derived from 4 dimethylaminopyridine, 4-benzyl 3⁄4 pyridine, 4 - pyrrolidinyl group Pyridine, 4-piperidinyl! «Acridine, - (4 methyl i piperidyl) β ingot or one of 4-morpholinylpyridine  The method for preparing zopiclone according to claim 1, wherein a pyridin is added as a co-solvent in an amount of 6-(5 gas-·2-pyridyl) 5 hydroxy oxime 5, 6 Dioxapyrrole! :3, 4 b〗 Sftazine 1~2 weight times ·  The method for preparing zopiclone according to claim 1, characterized in that the catalyst and the mash (S~~2~pyridyl)-5-hydroxy-7-oxo-δ, δ-dichloropyrrole The molar ratio of [3, 4-b]pyrazine is 3⁄4 01~ 5) : ί.  ? The preparation method of zopiclone according to claim 1, characterized in that 6-( 5-chloro-2- ft pyridine)-S hydroxy oxo 5, 6 bis 3⁄4 pyrrole [3, The molar ratio of 4 to b]pyrazine to 1 chloroformyl-4-methylpiperazine hydrochloride is 1: <1 to L 7).  The method for producing zopiclone according to claim 1, wherein the reaction temperature is from 10 Torr to the boiling point of the solvent system.  9. A method of producing zopiclone according to claim 1, wherein the reaction time is I 4. S hours. Ϊ0. The preparation method of the 2S clone according to the claim, characterized in that after the reaction is finished, the following post-treatment is carried out; the purified water is added to the reaction system, and the water is discarded, and the two-gas methane is concentrated in vacuo, and then added. ^Is the acid vinegar warmed up to? 8υ, add activated carbon ochre, filter, and reduce temperature, filter, dry, get white-like solid zopiclone.