CN114763342A - Synthesis method of high-purity 4-methylpiperazine-1-formic ether - Google Patents
Synthesis method of high-purity 4-methylpiperazine-1-formic ether Download PDFInfo
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- CN114763342A CN114763342A CN202110026638.2A CN202110026638A CN114763342A CN 114763342 A CN114763342 A CN 114763342A CN 202110026638 A CN202110026638 A CN 202110026638A CN 114763342 A CN114763342 A CN 114763342A
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- 238000001308 synthesis method Methods 0.000 title abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012074 organic phase Substances 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 8
- 239000012071 phase Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 5
- KNWWGBNAUNTSRV-UHFFFAOYSA-N 4-methylpiperazine-1-carboxylic acid Chemical compound CN1CCN(C(O)=O)CC1 KNWWGBNAUNTSRV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 2
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 14
- 229960000820 zopiclone Drugs 0.000 description 13
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 10
- 239000012535 impurity Substances 0.000 description 9
- USYYUUDWGLOMDJ-UHFFFAOYSA-N ethyl 4-methylpiperazine-1-carboxylate Chemical compound CCOC(=O)N1CCN(C)CC1 USYYUUDWGLOMDJ-UHFFFAOYSA-N 0.000 description 7
- PWPJWHXPIKDVAY-UHFFFAOYSA-N methyl 4-methylpiperazine-1-carboxylate Chemical compound COC(=O)N1CCN(C)CC1 PWPJWHXPIKDVAY-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- RAHXETRASSRFBX-UHFFFAOYSA-N propan-2-yl 4-methylpiperazine-1-carboxylate Chemical compound CC(C)OC(=O)N1CCN(C)CC1 RAHXETRASSRFBX-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 description 3
- 229960001578 eszopiclone Drugs 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- OCMLGXQLXQVDSJ-UHFFFAOYSA-N C(=O)OC.CN1CCNCC1 Chemical compound C(=O)OC.CN1CCNCC1 OCMLGXQLXQVDSJ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004799 sedative–hypnotic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- -1 4-methylpiperazine-1-isopropyl formate Chemical compound 0.000 description 1
- FUUXOEKDNNWZTR-UHFFFAOYSA-N 6-(5-chloropyridin-2-yl)-7-hydroxy-7h-pyrrolo[3,4-b]pyrazin-5-one Chemical compound O=C1C2=NC=CN=C2C(O)N1C1=CC=C(Cl)C=N1 FUUXOEKDNNWZTR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- RBLBYTZYRCQBOP-UHFFFAOYSA-N ethyl formate 1-methylpiperazine Chemical compound C(=O)OCC.CN1CCNCC1 RBLBYTZYRCQBOP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- WICNYNXYKZNNSN-UHFFFAOYSA-N hydron;4-methylpiperazine-1-carbonyl chloride;chloride Chemical compound Cl.CN1CCN(C(Cl)=O)CC1 WICNYNXYKZNNSN-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthesis method of high-purity 4-methylpiperazine-1-formic ether, the method comprises the following steps, 1) 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane are mixed, then fatty alcohol is added, the temperature is reduced, sodium cyanide is added in batches, and the room temperature is recovered after the addition, and the stirring is carried out; 2) adding water, adjusting pH to 6-7, stirring at room temperature, separating, and keeping water phase; 3) adjusting pH of the water phase to 8-10 with sodium carbonate aqueous solution, extracting with dichloromethane for 2-3 times, mixing the organic phases, drying, and vacuum spin-drying the organic phase to obtain light yellow transparent oily 4-methylpiperazine-1-formate; the reaction formula of the method is as follows:
Description
Technical Field
The invention relates to the field of chemical drug synthesis, in particular to a method for preparing 4-methylpiperazine-1-formic ether.
Technical Field
Zopiclone is a third generation sedative hypnotic developed by Rhono-Poulene Rorer, rona, france for the treatment of sleep disorders. Eszopiclone (Eszopiclone) is a fast acting non-benzodiazepine sedative hypnotic developed by Seprator corporation, USA, marketed in the United states at 4 months 2005. The racemate zopiclone is marketed in nearly hundreds of countries and regions, and the eszopiclone is the first medicine which can be used for treating difficulty in falling asleep and maintaining quality for a long time.
Zopiclone structure is as follows:
the synthesis method usually uses 6- (5-chloro-2-pyridyl) -5-hydroxy-7-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyrazine as a raw material to be condensed with 4-methylpiperazine-1-formyl chloride hydrochloride to obtain zopiclone. Wherein, the structure of the 4-methylpiperazine-1-formyl chloride hydrochloride (A) is as follows:
from this, it is known that 4-methylpiperazine-1-carbonyl chloride hydrochloride is a key raw material for synthesizing zopiclone.
The starting material is generally purchased from the market, and has the problems of low purity and impurities, which may be brought in during the synthesis of zopiclone, and the related impurities are researched to comprise 4-methylpiperazine-1-formate (referred to as compound C in the present invention),
in the formula: r is CH3，CH3CH2，(CH3)2CH。
When R is CH3When the compound is 4-methylpiperazine-1-carboxylic acid methyl ester (CAS number 7560-85-2), it is CH2CH3When the compound is 4-methyl-1-piperazinecarboxylic acid ethyl ester (CAS number 59325-11-0), is (C)H3)2CH, the compound is 4-methyl-1 piperazine carboxylic acid isopropyl ester.
The compound C is a genotoxic impurity in the quality research of the zopiclone, so that a simple and low-cost method for preparing the compound C is urgently needed to be provided, and a high-purity impurity reference substance is provided for the quality control of the zopiclone.
The preparation of 4-methylpiperazine-1-carboxylate in the known compound C is as follows: and (3) reacting the 4-methylpiperazine with methyl chloroformate or ethyl chloroformate to obtain 4-methylpiperazine-1-carboxylic acid methyl ester or 4-methyl-1-piperazinecarboxylic acid ethyl ester.
In the preparation method, the raw materials of methyl chloroformate and ethyl chloroformate are toxic and harmful to operators, strong alkali and sodium cyanide are needed to participate in the reaction condition, the reaction is violent, the reaction is not easy to control, and a plurality of byproducts are generated. TLC shows that the Rf value of the by-product is relatively close to that of the main product, and the by-product is difficult to separate by chromatographic column chromatography.
In the post-treatment process, the inventors have found that by-products of the reaction can be effectively removed by adjusting the pH of the system, thereby obtaining the high-purity compound C, in combination with the structural characteristics of the compounds.
Disclosure of Invention
The invention provides a synthesis method of a high-purity zopiclone impurity compound C, which is simple to operate, easy to separate and purify and high in purity of an obtained product.
The invention provides a synthesis method of a high-purity zopiclone impurity compound C, which has the following reaction formula:
in the formula: r is CH3，CH3CH2，(CH3)2CH。
The specific operation method is as follows,
1) mixing 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane, adding fatty alcohol, cooling, adding sodium cyanide in batches, and recovering to room temperature after adding, and stirring;
2) adding water, adjusting pH to 6-7, stirring at room temperature, separating, and keeping water phase;
3) adjusting pH of the water phase to 8-10 with sodium carbonate aqueous solution, extracting with dichloromethane for 2-3 times, mixing the organic phases, drying, and vacuum drying to obtain compound C as light yellow transparent oil.
The method comprises the following steps:
in step 1):
the ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride to the dichloromethane to the fatty alcohol to the sodium cyanide is 5-15 g: 40-60 ml: 3-6 ml: 1-3g, preferably 10 g: 50 ml: 5 ml: 2g (including but not limited to g, kg and ml, L);
the fatty alcohol is selected from: methanol, ethanol or isopropanol.
In step 2):
the amount of water added is equal to the volume of dichloromethane added in step 1).
Purpose of water addition: firstly, water is needed for layered extraction and secondly, the pH value is adjusted.
The pH value is 6 to 6.6, preferably 6.4 to 6.6.
The pH adjusting solvent was 4M dilute hydrochloric acid.
In step 3):
the pH is 8.5-9.1.
The solvent used for the pH adjustment was an aqueous solution of sodium carbonate (25% strength).
The invention also provides application of the compound C, namely, a reference substance is provided for the research on the quality of the zopiclone and the raw materials thereof.
In the content detection method, the impurity compound C synthesized by the method of the present invention can be used as a standard reference substance for detecting the impurity content in zopiclone and its raw materials and preparations thereof, so as to perform qualitative and quantitative analysis on zopiclone and its raw materials.
The method provided by the invention has the following advantages:
1. the method is the same as the traditional method:
the traditional method uses toxic raw materials, strong alkali and strong acid are used for reaction, the reaction is violent and is not easy to control, the yield is about 59 percent, a large amount of byproducts are generated, and column chromatography purification is adopted. The method has the advantages of non-toxic reactants and mild reaction conditions.
2. The method provided by the invention has the advantages that the yield is more than 65%, and the purity is more than 98.3%, so that the method has higher economy.
3. The method provided by the invention has the characteristics of simple operation, short reaction time, high yield and the like, and provides a foundation for the research of zopiclone genotoxic impurities.
Drawings
FIG. 1: a mass spectrum of 4-methylpiperazine-1-carboxylic acid methyl ester;
FIG. 2 is a schematic diagram: 4-methylpiperazine-1-carboxylic acid methyl ester nuclear magnetic resonance image;
FIG. 3: 4-methylpiperazine-1-carboxylic acid ethyl ester mass spectrum;
FIG. 4: 4-methylpiperazine-1-carboxylic acid ethyl ester nuclear magnetic resonance map;
FIG. 5: 4-methylpiperazine-1-formic acid isopropyl ester mass spectrum;
FIG. 6: nuclear magnetic resonance image of 4-methylpiperazine-1-carboxylic acid isopropyl ester.
Detailed description of the preferred embodiments
The following examples are intended to further illustrate the invention and are not to be construed as limiting the invention in any way.
Example 1: preparation method of 4-methylpiperazine-1-methyl formate
1. Adding 10g of-1-formyl chloride hydrochloride and 50ml of dichloromethane into a reaction bottle, adding 5ml of methanol, cooling to 0-5 ℃, adding 2g of sodium cyanide in batches, recovering the room temperature after the addition, and stirring for 2 hours.
2. After water (50ml) was added to the system, the pH was adjusted to 6.4 with 4M diluted hydrochloric acid, and the mixture was stirred at room temperature, separated, and the aqueous phase was retained.
3. The aqueous phase was again adjusted to pH 9 with aqueous sodium carbonate, extracted 2 times with 50ml dichloromethane, the organic phases were combined and dried and the organic phase was dried under vacuum at 40 ℃ to give 6.6g of methyl 4-methylpiperazine-1-carboxylate as a pale yellow transparent oil. The yield was 82.5% and the purity 98.3%.
1HNMR(400MHz，CDCl3)δ3.70-3.69(m,3H)，δ3.49(s,4H)，δ2.36(s,4H)，δ2.31-2.29(m,3H)。
The mass spectrum and nuclear magnetic resonance image of 4-methylpiperazine-1-methyl formate are shown in FIGS. 1 and 2.
Example 2: preparation method of 4-methylpiperazine-1-ethyl formate
1. Adding 10g of 4-methylpiperazine-1-formyl chloride hydrochloride and 50ml of dichloromethane into a reaction bottle, adding 5ml of ethanol, cooling to 0-5 ℃, adding 2g of sodium cyanide in batches, recovering the room temperature after the addition, and stirring for 2 hours.
2. 50ml of water was added to the system, and then pH was adjusted to 6.4 with 4M diluted hydrochloric acid, followed by stirring at room temperature, liquid separation and retention of the aqueous phase.
3. The aqueous phase is again adjusted to pH 9 with aqueous sodium carbonate solution, extracted 2 times with 50ml dichloromethane, the organic phases are combined and dried and the organic phase is dried in vacuo at 40 ℃ to give 5.7g of ethyl 4-methylpiperazine-1-carboxylate as a pale yellow transparent oil. The yield is 65.5 percent, and the purity is 98.8 percent.
1HNMR(400MHz，CDCl3)δ4.16-4.10(m,2H),δ3.50-3.49(d,4H)，δ2.37-2.36(d,4H)，δ2.31-2.29(d,3H)，δ1.28-1.23(m,3H)。
The mass spectrum and nuclear magnetic resonance image of 4-methylpiperazine-1-carboxylic acid ethyl ester are shown in figures 3 and 4 respectively.
Example 3: preparation method of 4-methylpiperazine-1-isopropyl formate
1. 10g of 4-methylpiperazine-1-formyl chloride hydrochloride and 50ml of dichloromethane are added into a reaction bottle, 5ml of isopropanol is added, 2g of sodium cyanide is added in batches at room temperature, and the mixture is stirred for 2 hours at 40 ℃.
2. After adding 50ml of water, the pH value of the system is adjusted to 6.6 by using 4M dilute hydrochloric acid, and the system is stirred and separated at room temperature, and the water phase is reserved.
3. The aqueous phase is then adjusted to pH 9 with aqueous sodium carbonate, extracted 2 times with 50ml dichloromethane, the organic phases are combined and dried and the organic phase is dried in vacuo at 40 ℃ to give 6.1g of methyl 4-methylpiperazine-1-carboxylate as a pale yellow transparent oil. The yield was 64.9% and the purity 98.6%.
1HNMR(400MHz，CDCl3)δ4.90-4.84(m,1H),δ3.43-3.42(d,4H)，δ2.31(s,4H)，δ2.25(d,3H)，δ1.21-1.19(m,6H)。
The mass spectrum and nuclear magnetic resonance image of 4-methylpiperazine-1-formic acid isopropyl ester are shown in figures 5 and 6 respectively.
Claims (8)
1. A preparation method of high-purity 4-methylpiperazine-1-formic ether comprises the following reaction formula:
in the formula: 4-methylpiperazine-1-carboxylic acid ester, i.e. formula C, R is CH3，CH3CH2，(CH3)2CH。
2. The method for preparing the compound of claim 1, comprising the following steps,
1) mixing 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane, adding fatty alcohol, cooling, adding sodium cyanide in batches, and recovering to room temperature after adding, and stirring; the fatty alcohol is selected from: methanol, ethanol or isopropanol;
2) adding water, adjusting pH to 6-7, stirring at room temperature, separating, and keeping water phase;
3) adjusting pH of the water phase to 8-10 with sodium carbonate aqueous solution, extracting with dichloromethane for 2-3 times, mixing the organic phases, drying, and vacuum drying to obtain light yellow transparent oil.
3. The method according to claim 1, wherein in step 1): the ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride to the dichloromethane to the fatty alcohol to the sodium cyanide is 5-15 g: 40-60 ml: 3-6 ml: 1-3 g.
4. The method according to claim 1, wherein in step 2): the addition amount of the water is equal to the volume of the dichloromethane added in the step 1), and the pH value is 6-6.6.
5. The method according to claim 1, wherein in step 3): the pH is 8.5-9.1.
6. The method according to claim 1, wherein in step 1): the ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride to the dichloromethane to the fatty alcohol to the sodium cyanide is 10 g: 50 ml: 5 ml: 2g of the total weight of the composition.
7. The method according to claim 1, wherein in step 2): the pH value is 6.4-6.6; the pH adjusting solvent was 4M dilute hydrochloric acid.
8. The method according to claim 1, wherein in step 3): the solvent used for adjusting the pH value is a 25% sodium carbonate aqueous solution.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195624A (en) * | 2007-12-19 | 2008-06-11 | 齐鲁天和惠世制药有限公司 | Method for preparing zopiclone |
| CN101272685A (en) * | 2005-09-27 | 2008-09-24 | Irm责任有限公司 | Diarylamine-containing compounds and compositions, and their use as modulators of C-KIT receptors |
| CN114685401A (en) * | 2020-12-28 | 2022-07-01 | 江苏天士力帝益药业有限公司 | Synthesis method of di (4-methylpiperazine-1-yl) ketone |
| CN114685448A (en) * | 2020-12-25 | 2022-07-01 | 江苏天士力帝益药业有限公司 | Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl) -amide |
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- 2021-01-09 CN CN202110026638.2A patent/CN114763342A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101272685A (en) * | 2005-09-27 | 2008-09-24 | Irm责任有限公司 | Diarylamine-containing compounds and compositions, and their use as modulators of C-KIT receptors |
| CN101195624A (en) * | 2007-12-19 | 2008-06-11 | 齐鲁天和惠世制药有限公司 | Method for preparing zopiclone |
| CN114685448A (en) * | 2020-12-25 | 2022-07-01 | 江苏天士力帝益药业有限公司 | Synthesis method of zopiclone impurity pyrazine-2-carboxylic acid (5-chloro-pyridin-2-yl) -amide |
| CN114685401A (en) * | 2020-12-28 | 2022-07-01 | 江苏天士力帝益药业有限公司 | Synthesis method of di (4-methylpiperazine-1-yl) ketone |
Non-Patent Citations (1)
| Title |
|---|
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