CN112390767A - Preparation method of eperisone hydrochloride impurity F - Google Patents
Preparation method of eperisone hydrochloride impurity F Download PDFInfo
- Publication number
- CN112390767A CN112390767A CN202110065521.5A CN202110065521A CN112390767A CN 112390767 A CN112390767 A CN 112390767A CN 202110065521 A CN202110065521 A CN 202110065521A CN 112390767 A CN112390767 A CN 112390767A
- Authority
- CN
- China
- Prior art keywords
- reaction
- eperisone hydrochloride
- hydrochloride impurity
- impurity
- eperisone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
Abstract
The invention provides a preparation method of eperisone hydrochloride impurity F, which is characterized in that 2-bromoethylbenzene is used as a raw material, 1- (2-ethylphenyl) propanol is obtained through Grignard reaction, 2-ethyl propiophenone is obtained through oxidation reaction, and finally the eperisone hydrochloride impurity F is obtained through Mannich reaction of the 2-ethyl propiophenone, paraformaldehyde and piperidine hydrochloride by a one-pot method, wherein the structure of the eperisone hydrochloride impurity F is shown as a formula (I).
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of an eperisone hydrochloride impurity F.
Background
Eperisone hydrochloride, also known as miazina, espiramate, is a β -aminoketone central muscle relaxant, chemically known as 4' -ethyl-2-methyl-3- (1-piperidinyl) propiophenone hydrochloride, first marketed in japan in 1983 under the trade name Myonal. Mainly acts on the central nervous system and vascular smooth muscle, can inhibit animal experimental rigidity, dilate blood vessel, improve blood circulation, resist vertigo and relieve pain, and can ensure that patients with cerebrovascular accident can smoothly exercise at will. The traditional Chinese medicine composition is mainly used for improving muscle tension caused by neck-shoulder-arm syndrome, scapulohumeral periarthritis, lumbago and the like and improving spastic paralysis caused by diseases such as cerebrovascular disorder, spastic spinal cord paralysis, cervical spondylosis, operation sequelae, amyotrophic lateral sclerosis, infantile cerebral palsy, spinocerebellar degeneration, spinal vascular disorder, subacute neuromuscular neuromyelitis and other cerebrospinal diseases. In order to ensure the safety of the medicine and achieve the aim of effectively controlling the quality of the medicine, the research on impurities in the medicine is particularly important, and the current international method is to analyze and verify the impurities by using an impurity reference substance, so that the development of the synthetic research on the impurities in the eperisone hydrochloride has important significance.
In the prior art, the synthesis of eperisone hydrochloride is reported in the family of Prunaceae, journal of Chinese medicine industry 1994.25(9):392-393, and the process route is as follows:
the first step adopts Friedel-crafts acylation reaction, and the eperisone hydrochloride impurity F can be generated in the process according to theoretical inference, but the impurity is generated in the form of impurity, and the practicability is poor. Patent CN103232415B discloses a method for producing eperisone hydrochloride, which specifically includes preparation of piperidine hydrochloride, synthesis of mannich base, salification and refining of eperisone, and the method does not mention the synthesis method related to impurity F of eperisone hydrochloride. Patent CN111393272A discloses a method for synthesizing 3 ' -methyl phenylpropanone, which uses m-methyl benzaldehyde as raw material, and reacts with ethyl format reagent to obtain 3 ' -methyl phenylpropanol, and then uses oxygen as oxidant, and uses a composite catalyst composed of nitroxide free radical, inorganic bromide and nitrite to catalytically oxidize 3 ' -methyl phenylpropanol to generate 3 ' -methyl phenylpropanone, according to the preparation method provided by the patent, a person skilled in the art can deduce a method for synthesizing 2 ' -methyl phenylpropanone, thereby synthesizing eperisone hydrochloride impurity F.
In summary, the prior art has many synthetic routes for eperisone hydrochloride, but there is no method for synthesizing eperisone hydrochloride impurity F, and it is inferred from the prior art that it is difficult to obtain eperisone hydrochloride impurity F by a simple reaction.
Disclosure of Invention
The invention aims to provide a method for synthesizing eperisone hydrochloride impurity F, which has the advantages of short synthetic route, simple synthetic process and high product purity and can be used as a reference substance for quality research.
In order to achieve the purpose, the invention adopts the technical scheme that:
an eperisone hydrochloride impurity F, the structural formula of the eperisone hydrochloride impurity F is shown as the formula (I):
a preparation method of an eperisone hydrochloride impurity F comprises the steps of taking 2-bromoethylbenzene as a raw material, obtaining 1- (2-ethylphenyl) propanol through a Grignard reaction, obtaining 2-ethyl propiophenone through an oxidation reaction, and finally obtaining the eperisone hydrochloride impurity F through a Mannich reaction of the 2-ethyl propiophenone, paraformaldehyde and piperidine hydrochloride.
Preferably, the preparation method of the eperisone hydrochloride impurity F specifically comprises the following steps:
(1) adding 2-bromoethylbenzene into an organic solvent for full dissolution, adding metal magnesium into a reaction solution, then adding an iodine simple substance for initiating a reaction, and obtaining a Grignard reagent 2-ethylbenzene magnesium bromide after the reaction is finished;
(2) dropwise adding n-propionaldehyde into the Grignard reagent in the step (1), and reacting at room temperature until the reaction is complete;
(3) adding the reaction solution obtained in the step (2) into ice water, adding an extraction solvent to obtain an organic phase and a water phase, removing the solvent from the organic phase under reduced pressure to obtain 1- (2-ethylphenyl) propanol, and dissolving the 1- (2-ethylphenyl) propanol in a dichloromethane solution for later use;
(4) adding an oxidant into a reaction bottle, cooling, dropwise adding the dichloromethane solution of the 1- (2-ethylphenyl) propanol obtained in the step (3), and stirring until the reaction is complete;
(5) dropwise adding triethylamine into the reaction liquid obtained in the step (4), then pouring the reaction liquid into water, adding an extraction solvent to obtain an organic phase and a water phase, washing the organic phase with water to be neutral, and then concentrating under reduced pressure to obtain 2-ethyl propiophenone;
(6) adding the 2-ethyl propiophenone, piperidine hydrochloride, paraformaldehyde and isopropanol obtained in the step (5) into a reaction bottle, and reacting at 90-100 ℃ until the reaction is complete;
(7) cooling the reaction system in the step (6) to normal temperature, adding an extraction solvent, adding alkaline water to adjust the pH to be alkaline, extracting and separating liquid to obtain an organic phase, washing the organic phase with water, adding equivalent hydrochloric acid, and concentrating under reduced pressure to obtain an eperisone hydrochloride impurity F crude product;
(8) and (3) adding the crude eperisone hydrochloride impurity F product obtained in the step (7) and isopropanol into a reaction bottle, heating to dissolve and clarify, adding acetone, cooling to grow crystals, and filtering to obtain eperisone hydrochloride impurity F.
Preferably, the organic solvent in the step (1) is any one of tetrahydrofuran, diethyl ether and isopropyl ether, and the metal magnesium is any one of magnesium powder, magnesium strips and magnesium chips; in the step (1), iodine is used as an initiator.
Preferably, the temperature for initiating the reaction in the step (1) is-5 to 5 ℃.
Preferably, the temperature for dropping the n-propionaldehyde in the step (2) is-5 to 5 ℃.
Preferably, the oxidizing agent in the step (4) is any one of a combination of dimethyl sulfoxide and oxalyl chloride, a combination of dimethyl sulfoxide and trifluoroacetic anhydride, a combination of pyridine and chromium trioxide, a combination of sulfuric acid and chromium trioxide, a dess-martin reagent and a solvent composition.
Preferably, the reaction temperature in the step (6) is 90-100 ℃.
Preferably, in the cooling and crystal growing process in the step (8), the mass ratio of the solvent is isopropanol: acetone =1:2-1: 5.
Preferably, the extraction solvent is any one of ethyl acetate, dichloromethane, chloroform and toluene.
As a further preferable mode of the above scheme, the preparation method of the eperisone hydrochloride impurity F is to use 2-bromoethylbenzene as a raw material, obtain 1- (2-ethylphenyl) propanol through grignard reaction, obtain 2-ethylphenylketone through oxidation reaction, and finally obtain the eperisone hydrochloride impurity F through mannich reaction of 2-ethylphenylketone, paraformaldehyde and piperidine hydrochloride by a one-pot method, and the synthetic route is as follows:
the invention also provides application of the eperisone hydrochloride impurity F as a reference substance in the aspect of quality research.
The technical scheme of the invention has the following beneficial effects: the preparation method of the eperisone hydrochloride impurity F is short in route, raw materials and experimental equipment are simple and easy to obtain, the intermediate is purified only through extraction and liquid separation, the final product can be obtained through crystallization, and the purification method is simple and suitable for industrial production. The purity of the eperisone hydrochloride impurity F obtained by the technical scheme can reach more than 99 percent, and the eperisone hydrochloride impurity F can be used as a reference substance for quality research.
Drawings
FIG. 1 shows the impurity F of eperisone hydrochloride according to the present invention1HNMR nuclear magnetic spectrum;
FIG. 2 shows the impurity F of eperisone hydrochloride according to the present invention13CNMR nuclear magnetic spectrum;
FIG. 3 is a liquid chromatogram of eperisone hydrochloride impurity F according to the present invention;
FIG. 4 is a UV spectrum of eperisone hydrochloride impurity F according to the present invention.
Detailed Description
In order to better understand the technical solutions and advantages of the present invention, the present invention is further described below by way of specific embodiments.
Example 1
Adding 13g of 2-bromoethylbenzene into a 250ml three-neck flask, adding 52g of tetrahydrofuran for dissolving, cooling to-5 ℃, adding magnesium chips, adding 0.5g of elemental iodine, and initiating reaction for 2 hours at the temperature of-5 ℃. Controlling the temperature at-5 ℃, dropwise adding 5.3g of n-propionaldehyde, heating to room temperature for reaction after the dropwise adding is finished, and monitoring by HPLC (high performance liquid chromatography) until the reaction is complete to obtain the Grignard reagent 2-ethylbenzene magnesium bromide. The reaction solution was added dropwise to 100g of ice water, extraction solvent was added, the organic layer was washed with water 2 times, and then, after standing and separating, the organic layer was concentrated under reduced pressure to obtain 1- (2-ethylphenyl) propanol with a purity of 98.0%, a weight of 11g, and a yield of 95%.
Taking a 250ml three-necked bottle, adding 23g of dimethyl sulfoxide, cooling to below-30 ℃, dropwise adding 27g of trifluoroacetic anhydride, stirring for 15 minutes after dropwise adding, dropwise adding a mixed solution of 6g of 1- (2-ethylphenyl) propanol and 30g of dichloromethane, stirring for 3 hours at below-30 ℃, and spotting until the reaction is complete. Adding 20g of triethylamine into the reaction solution, pouring the reaction solution into 200g of water, adding an extraction solvent for extraction, washing an organic layer to be neutral by using water, standing for liquid separation, and concentrating the organic layer under reduced pressure to obtain 2-ethyl propiophenone with the purity of 95.0%, wherein the weight is 5g, and the yield is 83%.
Taking a 50ml single-mouth bottle, adding 4.5g of 2-ethyl propiophenone, 3g of piperidine hydrochloride, 1.1g of paraformaldehyde and 3g of isopropanol, heating to 90-100 ℃, reacting for 5 hours, and dotting the bottle until the reaction is complete. Cooling to normal temperature, adding 50g of extraction solvent into the reaction, adding 50g of alkaline water, adjusting the pH to be alkaline, extracting and separating liquid, washing an organic layer for 3 times by using water, standing and separating liquid, adding equivalent hydrochloric acid into the organic phase, and then concentrating under reduced pressure to obtain an eperisone hydrochloride impurity F crude product. Dissolving the crude eperisone hydrochloride impurity F in 2g of isopropanol, heating to 80 ℃, dissolving and clarifying, adding 6g of acetone, cooling to 40 ℃ for crystallization, and cooling to 0-10 ℃ for crystallization for 1h when a large amount of crystals are separated out. Filtering, drying the filter cake at 65 ℃ by using an air-blast drying oven to obtain eperisone hydrochloride impurity F with the weight of 5.5g, the purity of more than 99 percent, the yield of 67 percent, MS: 260.0 (M + H).
Example 2
Adding 13g of 2-bromoethylbenzene into a 250ml three-neck flask, adding 52g of tetrahydrofuran for dissolving, cooling to-5 ℃, adding magnesium chips, adding 0.5g of elemental iodine, and initiating reaction for 2 hours at the temperature of-5 ℃. Controlling the temperature at-5 ℃, dropwise adding 5.3g of n-propionaldehyde, heating to room temperature for reaction after the dropwise adding is finished, and monitoring by HPLC (high performance liquid chromatography) until the reaction is complete to obtain the Grignard reagent 2-ethylbenzene magnesium bromide. The reaction solution was added dropwise to 100g of ice water, extraction solvent was added, the organic layer was washed with water 2 times, and then, after standing and separating, the organic layer was concentrated under reduced pressure to obtain 1- (2-ethylphenyl) propanol with a purity of 98.0%, a weight of 11g, and a yield of 95%.
Adding 23g of dimethyl sulfoxide into a 250ml three-neck flask, cooling to below-70 ℃, dropwise adding 16g of oxalyl chloride, stirring for 15 minutes after dropwise adding, dropwise adding a mixed solution of 6g of 1- (2-ethylphenyl) propanol and 30g of dichloromethane, stirring for 3 hours at below-70 ℃, and spotting until the reaction is complete. Adding 20g of triethylamine into the reaction solution, pouring the reaction solution into 200g of water, adding an extraction solvent for extraction, washing an organic layer to be neutral by water, standing for liquid separation, and concentrating the organic layer under reduced pressure to obtain 2-ethyl propiophenone with the purity of 90.0%, wherein the weight is 4.5g, and the yield is 75%.
Taking a 50ml single-mouth bottle, adding 4.5g of 2-ethyl propiophenone, 3g of piperidine hydrochloride, 1.1g of paraformaldehyde and 3g of isopropanol, heating to 90-100 ℃, reacting for 5 hours, and dotting the bottle until the reaction is complete. Cooling to normal temperature, adding 50g of extraction solvent into the reaction, adding 50g of alkaline water, adjusting the pH to be alkaline, extracting and separating liquid, washing an organic layer for 3 times by using water, standing and separating liquid, adding equivalent hydrochloric acid into the organic phase, and then concentrating under reduced pressure to obtain an eperisone hydrochloride impurity F crude product. Dissolving the crude eperisone hydrochloride impurity F in 2g of isopropanol, heating to 80 ℃, dissolving and clarifying, adding 6g of acetone, cooling to 40 ℃ for crystallization, and cooling to 0-10 ℃ for crystallization for 1h when a large amount of crystals are separated out. Filtering, drying the filter cake at 65 ℃ by using an air-blast drying oven to obtain eperisone hydrochloride impurity F with the weight of 5.5g, the purity of more than 99 percent, the yield of 67 percent, MS: 260.0 (M + H).
Example 3
Adding 13g of 2-bromoethylbenzene into a 250ml three-neck flask, adding 52g of tetrahydrofuran for dissolving, cooling to-5 ℃, adding magnesium chips, adding 0.5g of elemental iodine, and initiating reaction for 2 hours at the temperature of-5 ℃. Controlling the temperature at-5 ℃, dropwise adding 5.3g of n-propionaldehyde, heating to room temperature for reaction after the dropwise adding is finished, and monitoring by HPLC (high performance liquid chromatography) until the reaction is complete to obtain the Grignard reagent 2-ethylbenzene magnesium bromide. The reaction solution was added dropwise to 100g of ice water, extraction solvent was added, the organic layer was washed with water 2 times, and then, after standing and separating, the organic layer was concentrated under reduced pressure to obtain 1- (2-ethylphenyl) propanol with a purity of 98.0%, a weight of 11g, and a yield of 95%.
And (3) adding 6g of 1- (2-ethylphenyl) propanol, 30g of dichloromethane and 9g of diatomite into a 250ml three-necked bottle, cooling to-5 ℃, dropwise adding a mixed solution of 9g of PCC oxidant and 50g of dichloromethane, stirring for 15 minutes after dropwise adding is finished, then stirring for 3 hours at room temperature, and dotting the plate until the reaction is complete. Filtering, pouring the filtrate into 200g of water, adding an extraction solvent for extraction, washing an organic layer to be neutral by using water, standing, separating liquid, and concentrating the organic layer under reduced pressure to obtain 2-ethyl propiophenone with the purity of 95.0%, wherein the weight is 5g, and the yield is 83%.
Taking a 50ml single-mouth bottle, adding 4.5g of 2-ethyl propiophenone, 3g of piperidine hydrochloride, 1.1g of paraformaldehyde and 3g of isopropanol, heating to 90-100 ℃, reacting for 5 hours, and dotting the bottle until the reaction is complete. Cooling to normal temperature, adding 50g of extraction solvent into the reaction, adding 50g of alkaline water, adjusting the pH to be alkaline, extracting and separating liquid, washing an organic layer for 3 times by using water, standing and separating liquid, adding equivalent hydrochloric acid into the organic phase, and then concentrating under reduced pressure to obtain an eperisone hydrochloride impurity F crude product. Dissolving the crude eperisone hydrochloride impurity F in 2g of isopropanol, heating to 80 ℃, dissolving and clarifying, adding 6g of acetone, cooling to 40 ℃ for crystallization, and cooling to 0-10 ℃ for crystallization for 1h when a large amount of crystals are separated out. Filtering, drying the filter cake at 65 ℃ by using an air-blast drying oven to obtain eperisone hydrochloride impurity F with the weight of 5.5g, the purity of more than 99 percent, the yield of 67 percent, MS: 260.0 (M + H).
It should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. The preparation method of the eperisone hydrochloride impurity F is characterized in that 2-bromoethylbenzene is used as a raw material, 1- (2-ethylphenyl) propanol is obtained through a Grignard reaction, 2-ethyl propiophenone is obtained through an oxidation reaction, and the eperisone hydrochloride impurity F is obtained through a Mannich reaction of the 2-ethyl propiophenone, paraformaldehyde and piperidine hydrochloride.
2. The method of preparing eperisone hydrochloride impurity F according to claim 1, characterized in that the method of preparation specifically comprises the steps of:
(1) adding 2-bromoethylbenzene into an organic solvent for full dissolution, adding metal magnesium into a reaction solution, then adding an iodine simple substance for initiating a reaction, and obtaining a Grignard reagent 2-ethylbenzene magnesium bromide after the reaction is finished;
(2) dropwise adding n-propionaldehyde into the Grignard reagent in the step (1), and reacting at room temperature until the reaction is complete;
(3) adding the reaction solution obtained in the step (2) into ice water, adding an extraction solvent to obtain an organic phase and a water phase, removing the solvent from the organic phase under reduced pressure to obtain 1- (2-ethylphenyl) propanol, and dissolving the 1- (2-ethylphenyl) propanol in a dichloromethane solution for later use;
(4) adding an oxidant into a reaction bottle, cooling, dropwise adding the dichloromethane solution of the 1- (2-ethylphenyl) propanol obtained in the step (3), and stirring until the reaction is complete;
(5) dropwise adding triethylamine into the reaction liquid obtained in the step (4), then pouring the reaction liquid into water, adding an extraction solvent to obtain an organic phase and a water phase, washing the organic phase with water to be neutral, and then concentrating under reduced pressure to obtain 2-ethyl propiophenone;
(6) adding the 2-ethyl propiophenone, piperidine hydrochloride, paraformaldehyde and isopropanol obtained in the step (5) into a reaction bottle, and reacting at 90-100 ℃ until the reaction is complete;
(7) cooling the reaction system in the step (6) to normal temperature, adding an extraction solvent, adding alkaline water to adjust the pH to be alkaline, extracting and separating liquid to obtain an organic phase, washing the organic phase with water, adding equivalent hydrochloric acid, and concentrating under reduced pressure to obtain an eperisone hydrochloride impurity F crude product;
(8) and (3) adding the crude eperisone hydrochloride impurity F product obtained in the step (7) and isopropanol into a reaction bottle, heating to dissolve and clarify, adding acetone, cooling to grow crystals, and filtering to obtain eperisone hydrochloride impurity F.
3. The method for preparing eperisone hydrochloride impurity F according to claim 2, wherein the organic solvent in the step (1) is any one of tetrahydrofuran, diethyl ether and isopropyl ether, and the metal magnesium is any one of magnesium powder, magnesium strips and magnesium chips; and (2) adding iodine simple substance to initiate reaction in the step (1).
4. The method for preparing eperisone hydrochloride impurity F according to claim 2, wherein the temperature of the reaction initiated in the step (1) is-5 to 5 ℃.
5. The method for preparing eperisone hydrochloride impurity F according to claim 2, wherein the temperature of the n-propylaldehyde added in step (2) is-5 to 5 ℃.
6. The method for preparing eperisone hydrochloride impurity F according to claim 2, wherein the oxidizing agent in the step (4) is any one of a composition of dimethyl sulfoxide and oxalyl chloride, a composition of dimethyl sulfoxide and trifluoroacetic anhydride, a composition of pyridine and chromium trioxide, and a composition of sulfuric acid and chromium trioxide.
7. The method for preparing eperisone hydrochloride impurity F according to claim 2, wherein the reaction temperature in the step (6) is 90 to 100 ℃; in the cooling and crystal growing process in the step (8), the mass ratio of the solvents is isopropanol: acetone =1:2-1: 5.
8. The method for preparing eperisone hydrochloride impurity F according to claim 2, characterized in that the synthetic route is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110065521.5A CN112390767A (en) | 2021-01-19 | 2021-01-19 | Preparation method of eperisone hydrochloride impurity F |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110065521.5A CN112390767A (en) | 2021-01-19 | 2021-01-19 | Preparation method of eperisone hydrochloride impurity F |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112390767A true CN112390767A (en) | 2021-02-23 |
Family
ID=74625387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110065521.5A Pending CN112390767A (en) | 2021-01-19 | 2021-01-19 | Preparation method of eperisone hydrochloride impurity F |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112390767A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3431291A (en) * | 1965-12-27 | 1969-03-04 | Merck & Co Inc | (2-alkylidenealkanoyl)phenoxy derivatives of acetonitrile |
| US20030077227A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
| CN102060679A (en) * | 2009-11-18 | 2011-05-18 | 中国中化股份有限公司 | Method for preparing aryl propanal derivatives |
| CN102643273A (en) * | 2011-02-18 | 2012-08-22 | 浙江九洲药业股份有限公司 | Preparation method of iloperidone |
| CN103232415A (en) * | 2013-05-07 | 2013-08-07 | 湖南亚大制药有限公司 | Eperisone hydrochloride production method |
| CN103508920A (en) * | 2012-06-21 | 2014-01-15 | 贵州百灵企业集团制药股份有限公司 | Preparation method for optical isomers of phenylalaninol compound and application thereof |
| CN109369353A (en) * | 2018-11-28 | 2019-02-22 | 嘉实（湖南）医药科技有限公司 | A kind of preparation method of metoprolol intermediate |
| CN110845443A (en) * | 2019-12-11 | 2020-02-28 | 嘉实（湖南）医药科技有限公司 | Method for preparing high-purity tolperisone hydrochloride |
-
2021
- 2021-01-19 CN CN202110065521.5A patent/CN112390767A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3431291A (en) * | 1965-12-27 | 1969-03-04 | Merck & Co Inc | (2-alkylidenealkanoyl)phenoxy derivatives of acetonitrile |
| US20030077227A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
| CN102060679A (en) * | 2009-11-18 | 2011-05-18 | 中国中化股份有限公司 | Method for preparing aryl propanal derivatives |
| CN102643273A (en) * | 2011-02-18 | 2012-08-22 | 浙江九洲药业股份有限公司 | Preparation method of iloperidone |
| CN103508920A (en) * | 2012-06-21 | 2014-01-15 | 贵州百灵企业集团制药股份有限公司 | Preparation method for optical isomers of phenylalaninol compound and application thereof |
| CN103232415A (en) * | 2013-05-07 | 2013-08-07 | 湖南亚大制药有限公司 | Eperisone hydrochloride production method |
| CN109369353A (en) * | 2018-11-28 | 2019-02-22 | 嘉实（湖南）医药科技有限公司 | A kind of preparation method of metoprolol intermediate |
| CN110845443A (en) * | 2019-12-11 | 2020-02-28 | 嘉实（湖南）医药科技有限公司 | Method for preparing high-purity tolperisone hydrochloride |
Non-Patent Citations (6)
| Title |
|---|
| A SHIOZAWA, K NARITA等，: ""Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants"", 《EUR J MED CHEM》 * |
| JEANETTE SEE LENG YAP等，: ""Mechanistic Insights into the PdII-Catalyzed Chemoselective N-Demethylation vs. Cyclometalation Reactivity Pathways in 1-Aryl-N,N-dimethylethanamines"及其Supporting Information", 《EUR. J. INORG. CHEM》 * |
| TOVE SLAGBRAND等，: ""Bimetallic Catalysis: Asymmetric Transfer Hydrogenation of Sterically Hindered Ketones Catalyzed by Ruthenium and Potassium"及其Supporting Information", 《CHEMCATCHEM》 * |
| 刘庆俭: "《有机化学 上册》", 30 November 2018, 同济大学出版社 * |
| 朱红军主编，: "《有机化学 中文版》", 30 April 2008, 化学工业出版社 * |
| 龙慧玲等，: ""高效液相色谱法测定盐酸乙哌立松中的有机杂质"", 《中南药学》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101104583B (en) | Technique for preparing diacerein by two-step oxidation process | |
| CN113121416A (en) | Preparation method of lefenacin | |
| CN107879962B (en) | Preparation method of glycopyrronium bromide | |
| CN116514704B (en) | Rafenacin intermediate and preparation method thereof | |
| CN112390767A (en) | Preparation method of eperisone hydrochloride impurity F | |
| CN105175317B (en) | A kind of method for preparing picosulfate sodium | |
| CN112142604A (en) | Preparation method of bromhexine hydrochloride and intermediate thereof | |
| CN110845562B (en) | Method for recycling betamethasone or dexamethasone synthetic mother liquor material | |
| WO2022078312A1 (en) | Method for purifying paroxetine hydrochloride | |
| CN111100062A (en) | Synthesis method of donepezil hydrochloride | |
| CN113461567A (en) | Preparation method of 2-bromo-4-cyanobenzaldehyde | |
| CN114516827A (en) | Method for reducing content of indobufen genotoxic impurities | |
| CN113754715B (en) | Optical selective process synthesis method of (5R) -5-hydroxyl triptolide | |
| CN114014825B (en) | Synthesis method of histamine H3 receptor antagonist telithromycin | |
| CN112142595B (en) | Preparation method and purification method of ethyl 2,4, 5-trifluoro-benzoylacetate | |
| CN113788872B (en) | Preparation method of androstane-2-alkene-17-ketone | |
| CN113773223B (en) | Method for purifying 2-amino-4-acetamino anisole by precipitation method | |
| CN111825688B (en) | Preparation method of 6-tert-butyl-3 ', 3', 3-trimethylpyrano [3,2-a ] carbazole | |
| CN111072543B (en) | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound | |
| CN115850115B (en) | Ruxolitinib intermediate and preparation method thereof | |
| CN112125844B (en) | Synthetic method of 3, 7-dichloro-8-quinolinecarbonyl chloride | |
| CN112430222B (en) | Amino intermediate refining method | |
| WO2016090707A1 (en) | Synthesis of m-hydroxyacetophenone by one-pot method | |
| DE3914227A1 (en) | METHOD FOR PRODUCING 2,7-DIFLUOR-9-FLUORENONE AND NEW INTERMEDIATE PRODUCTS | |
| CN107382684A (en) | A kind of synthetic method of the pyrene formaldehyde of high-purity 1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210223 |
|
| WD01 | Invention patent application deemed withdrawn after publication |