CN101434540B - Method for synthesizing alpha-chlorine (2-chlorine) methyl phenyl acetate - Google Patents
Method for synthesizing alpha-chlorine (2-chlorine) methyl phenyl acetate Download PDFInfo
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Abstract
The present invention relates to a synthetic method of Alpha-chloro-(2-chloro) methyl phenyl acetate, pertaining to the field of chemical synthesis. The technical problem to be solved by the invention is that a high-purity synthetic method of the Alpha-chloro-(2-chloro) methyl phenyl acetate with high purity is provided. The technical proposal comprises the steps as follows: pyridine is taken as a solvent, and O-chloro mandelic acid methyl ester reacts with thionyl chloride under the condition of 25 DEG C to 80 DEG C for 0.5h to 5h, and then filtered. Filtrate is extracted by water for impurity removal, and anhydrous sodium sulfate is added for removing water. Filtering is carried out for removing solid sodium sulfate and the filtrate is depressurized for distilling off the solvent to obtain the Alpha-chloro-(2-chloro) methyl phenyl acetate. The reaction formula is shown as the formula as follows.
Description
Technical field
The present invention relates to the synthetic method of α-chlorine (2-chlorine) methyl phenylacetate, belong to the field of chemical synthesis.
Background technology
Bisulfate clopidogrel (Clopidogrel Bisulfate) is a kind of platelet suppressant drug, is researched and developed successfully trade(brand)name Plavix (Bo Liwei) in 1986 by French Sai Nuofei (Sanofi) company.Present data shows that as the adp receptor antagonist of brand-new type, clopidogrel is a kind of safe and effective anticoagulant.It provides omnibearing countermeasure for the prevention of atherosclerosis thrombotic diseases, can reduce the danger of acute coronary syndrome with cox-2 inhibitors such as acetylsalicylic acid coupling, and short-term and secular cardioprotection are provided.This product took the lead in entering multinational markets such as Europe, North America, Australia, Singapore subsequently, and going on the market in China August calendar year 2001 in U.S.'s listing in March, 1998.
α-chlorine (2-chlorine) methyl phenylacetate is the important intermediate of synthesizing clopidogrel hydrogen sulfate, and WO2007126258 discloses the synthetic method of a kind of α-chlorine (2-chlorine) methyl phenylacetate.Specifically be to adopt the 3g amygdalic acid to be dissolved in 40ml methyl alcohol, drip H
2SO
4, be warming up to 80 ℃ of reaction 3h.Add ethyl acetate and water, it is neutral that sodium hydroxide is transferred pH, tells organic layer, and decompression steams solvent, obtains the o-Chloromelic acid methyl esters.Add the 2.1ml SULPHURYL CHLORIDE in the product that obtains, 65 ℃ are stirred 12h, with ethyl acetate, water extraction, obtain α-chlorine (2-chlorine) methyl phenylacetate then.
The contriver is impure according to the product that above-mentioned literature method obtains, and impurity is very many, be difficult for removing, and productive rate is very low.In order to improve conversion of raw material, obtain highly purified α-chlorine (2-chlorine) methyl phenylacetate, patent application of the present invention is proposed.
Summary of the invention
Technical problem to be solved by this invention provides the synthetic method of the high α-chlorine of a kind of purity (2-chlorine) methyl phenylacetate.
Technical scheme of the present invention: with the pyridine is solvent, drips thionyl chloride in the o-Chloromelic acid methyl esters, reaction 0.5-5h.Filter, the filtrate water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, and filtrate decompression steams solvent, promptly gets α-chlorine (2-chlorine) methyl phenylacetate.
Because sulfur oxychloride is a fuming liquid, and the strong and stimulating smell is arranged, meets water or alcohol and resolve into sulfurous gas and hydrogenchloride.And this reaction is thermopositive reaction, and therefore, sulfur oxychloride is preferably under the cold condition and drips, such as adopting ice bath (under 0 ℃ of condition) to drip.Reaction formula is as follows:
Further, in order to improve the productive rate of α-chlorine (2-chlorine) methyl phenylacetate, filter residue after above-mentioned reaction is filtered washs with ethyl acetate, contain a certain amount of α-chlorine (2-chlorine) methyl phenylacetate in the washings, merging filtrate and washings, water abstraction impurity removal, the decompression of dry back steams solvent, and (adding anhydrous sodium sulphate dewaters, solids removed by filtration sodium sulfate slag), filtrate decompression steams solvent, promptly gets α-chlorine (2-chlorine) methyl phenylacetate.
Preferred scheme is:
A, o-Chloromelic acid methyl esters, pyridine are added in the reaction flask, stir dissolving;
B, ice bath are chilled to 0 ℃, slowly drip thionyl chloride, dropwise, and remove ice bath, and reacting liquid temperature slowly rises to 25～80 ℃, continue to stir 0.5-5h;
C, filtration, ethyl acetate filter wash slag;
D, merging filtrate and ethyl acetate washings add the water extracting impurities, remove moisture with anhydrous sodium sulfate drying again, filter, and filtrate decompression steams solvent, promptly.
Wherein, the mol ratio 0.5-10 of o-Chloromelic acid methyl esters and thionyl chloride; Preferred 0.5-5, more preferably 1: 1, optimal reaction temperature was 40 ℃.
The present invention has following advantage compared with the prior art:
Adopt method of the present invention to prepare o-Chloromelic acid methyl esters yield up to 99%, product purity is up to 99.9%, and do not have by product.
Description of drawings
The HPLC figure of Fig. 1 embodiment 2
Fig. 2 comparative example 1 HPLC figure
Embodiment
Below by embodiment the present invention is further described, be limitation of the invention but should not be construed as.Those of ordinary skills can also make modification, replacement, the change of various ways according to technique scheme.All modification, replacement, changes of doing based on above-mentioned technological thought all belong to scope of the present invention.
Below by embodiment the present invention is further described.
The preparation of embodiment 1 o-Chloromelic acid methyl esters
Measure 10L methyl alcohol and join in the 30L reactor, add the 1000g o-Chloromelic acid, be stirred to dissolving fully, slowly the Dropwise 5 00ml vitriol oil dropwises, and is warming up to 80 ℃ of reaction 3h, is cooled to room temperature; It is neutral regulating pH with sodium hydroxide solution.Add 5L water, and add the 8L ethyl acetate extraction, ethyl acetate layer washs with saturated sodium bicarbonate, and drying concentrates, and obtains o-Chloromelic acid methyl esters 920g.
The preparation of embodiment 2 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slow Dropwise 5 0g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 40 ℃.Temperature control continues to stir 1h at 40 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets α-chlorine (2-chlorine) methyl phenylacetate 87g, and HPLC purity is 99.9%, nuclear magnetic resonance data:
1H NMR (CDCl
3): δ (ppm)=3.78 (s, 3H), 5.89 (S, 1H), 7.3-7.6 (m, 4H).The HPLC collection of illustrative plates is seen Fig. 1.
The preparation of embodiment 3 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slowly drip the 25g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 40 ℃.Temperature control continues to stir 1h at 40 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 48%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 80g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 40%.
The preparation of embodiment 4 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slowly drip the 100g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 40 ℃.Temperature control continues to stir 1h at 40 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets α-chlorine (2-chlorine) methyl phenylacetate 83g, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 99.7%.
The preparation of embodiment 5 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slowly drip the 200g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 40 ℃.Temperature control continues to stir 1h at 40 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 75g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 92%.
The preparation of embodiment 6 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slow Dropwise 5 00g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 40 ℃.Temperature control continues to stir 1h at 40 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 62g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 86%.
The preparation of embodiment 7 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slow Dropwise 5 0g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 25 ℃.Temperature control continues to stir 5h at 25 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 90%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 67g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 91%.
The preparation of embodiment 8 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slow Dropwise 5 0g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 60 ℃.Temperature control continues to stir 1h at 60 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 84g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 97%.
The preparation of embodiment 9 α-chlorine (2-chlorine) methyl phenylacetate
80g o-Chloromelic acid methyl esters and 38.4g pyridine are added in the reaction flask, stir, dissolving is cooled to 0 ℃.Slow Dropwise 5 0g thionyl chloride.Dropwise, remove ice bath, reacting liquid temperature slowly rises to 80 ℃.Temperature control continues to stir 1h at 80 ℃, and the HPLC detection reaction finishes, and transformation efficiency is 100%.Filter ethyl acetate washing filter residue.Merging filtrate and washings, the water abstraction impurity removal adds anhydrous sodium sulphate and dewaters, solids removed by filtration sodium sulfate slag, filtrate decompression steams solvent, gets the 82g crude product, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 94%.
The preparation of comparative example 1 α-chlorine (2-chlorine) methyl phenylacetate
The 3g amygdalic acid is dissolved in 40ml methyl alcohol, drips the 88ml vitriol oil, is warming up to 80 ℃ of reaction 3h.Add ethyl acetate and water, it is neutral that sodium hydroxide is transferred pH, tells organic layer, and decompression steams solvent, obtains the o-Chloromelic acid methyl esters.Add the 2.1ml SULPHURYL CHLORIDE in the product that obtains, 65 ℃ are stirred 12h, with ethyl acetate, water extraction, obtain the 2g crude product then, and α-chlorine (2-chlorine) methyl phenylacetate HPLC purity is 40%.The HPLC collection of illustrative plates is seen Fig. 2.
Claims (9)
1. the synthetic method of α-chlorine (2-chlorine) methyl phenylacetate, it is characterized in that: it is to be solvent with the pyridine, under 25～80 ℃ of conditions, o-Chloromelic acid methyl esters and thionyl chloride reaction 0.5-5h, filter, the filtrate water abstraction impurity removal, the decompression of dry back steams solvent, promptly get α-chlorine (2-chlorine) methyl phenylacetate, reaction formula is as follows:
2. the synthetic method of α-chlorine according to claim 1 (2-chlorine) methyl phenylacetate, it is characterized in that: the filter residue after the filtration washs with ethyl acetate, merging filtrate and washings, water abstraction impurity removal, the decompression of dry back steams solvent, promptly gets α-chlorine (2-chlorine) methyl phenylacetate.
3. the synthetic method of α-chlorine according to claim 2 (2-chlorine) methyl phenylacetate, it is characterized in that: it is to be finished by following steps:
A, o-Chloromelic acid methyl esters, pyridine are added in the reaction flask, stir dissolving;
B, ice bath are chilled to 0 ℃, slowly drip thionyl chloride, dropwise, and remove ice bath, and reacting liquid temperature slowly rises to 25～80 ℃, continue to stir 0.5-5h;
C, filtration, ethyl acetate filter wash slag;
D, filtrate and ethyl acetate washing filtrate wash with water, and the decompression of dry back steams solvent promptly.
4. the synthetic method of α-chlorine according to claim 1 (2-chlorine) methyl phenylacetate, it is characterized in that: the mol ratio of o-Chloromelic acid methyl esters and thionyl chloride is 0.5～10.
5. the synthetic method of α-chlorine according to claim 4 (2-chlorine) methyl phenylacetate, it is characterized in that: the mol ratio of o-Chloromelic acid methyl esters and thionyl chloride is 0.5～5.
6. the synthetic method of α-chlorine according to claim 5 (2-chlorine) methyl phenylacetate, it is characterized in that: the mol ratio of o-Chloromelic acid methyl esters and thionyl chloride is 1: 1.
7. the synthetic method of α-chlorine according to claim 1 (2-chlorine) methyl phenylacetate, it is characterized in that: temperature of reaction is 25～80 ℃.
8. the synthetic method of α-chlorine according to claim 1 (2-chlorine) methyl phenylacetate, it is characterized in that: temperature of reaction is 30～50 ℃.
9. the synthetic method of α-chlorine according to claim 8 (2-chlorine) methyl phenylacetate, it is characterized in that: temperature of reaction is 40 ℃.
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| CN101987854A (en) * | 2009-08-04 | 2011-03-23 | 北京万全阳光医学技术有限公司 | Preparation method of clopidogrel and salts thereof |
| CN109867684B (en) * | 2017-12-01 | 2022-06-17 | 武汉武药制药有限公司 | Preparation method of II-type clopidogrel hydrogen sulfate |
| CN109867685B (en) * | 2017-12-01 | 2022-04-08 | 武汉武药制药有限公司 | Preparation method of clopidogrel hydrogen sulfate II type |
| CN114634492B (en) * | 2022-04-14 | 2024-10-22 | 浙江东亚药业股份有限公司 | Preparation method of lanoconazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5204469A (en) * | 1990-07-10 | 1993-04-20 | Sanofi | Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5204469A (en) * | 1990-07-10 | 1993-04-20 | Sanofi | Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Ki-Nam Uhm."Enantioselective resolution of methyl 2-chloromandelate by Candida antarctica lipase A in a solvent-free transesterification reaction ".<Journal of molecular catalysis>.2007,第35页2.3. |
| 周林芳.氯吡格蕾的合成路线研究.《安徽医药》.2006,第10卷(第8期),全文. * |
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Effective date of registration: 20161025 Address after: 401220, No. four, 2 branch, South Road, Chongqing economic and Technological Development Zone, Changshou District Patentee after: Chongqing Laimeilong Yu Pharmaceutical Co. Ltd. Address before: 401336 No. eight, Rose Road, Nan'an District, Chongqing Patentee before: Chongqing Lummy Pharmaceutical Co., Ltd. |