CN108727214B - Synthetic method of anesthetic bupivacaine impurity - Google Patents
Synthetic method of anesthetic bupivacaine impurity Download PDFInfo
- Publication number
- CN108727214B CN108727214B CN201810453820.4A CN201810453820A CN108727214B CN 108727214 B CN108727214 B CN 108727214B CN 201810453820 A CN201810453820 A CN 201810453820A CN 108727214 B CN108727214 B CN 108727214B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- dichloromethane
- impurity
- crude product
- 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.)
- Expired - Fee Related
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a method for synthesizing an anesthetic bupivacaine impurity, which comprises the following steps: (a) adding 6-bromohexanoic acid, dichloromethane and N, N-dimethylformamide into a reaction container, dropwise adding oxalyl chloride under the protection of ice salt bath and nitrogen, and reacting at 0-25 ℃; after the reaction is finished, concentrating, adding toluene and concentrating again to obtain a crude product of 6-bromohexanoyl chloride; dissolving the 6-bromohexanoyl chloride crude product in dichloromethane, dropwise adding a dichloromethane solution of dimethylaniline under the conditions of a cold salt bath and nitrogen protection, and reacting at 5-10 ℃; after the reaction is finished, directly carrying out suction filtration, washing and drying to obtain a compound ii; (b) adding the compound ii, n-butylamine, potassium carbonate and acetonitrile into another reaction vessel, and reacting at 30-50 ℃; and (5) purifying after the reaction is finished. 6-bromohexanoic acid and oxalyl chloride are used as raw materials to prepare the bupivacaine impurity which is determined as the quality standard by European pharmacopoeia, and the method has simple process and convenient reaction steps.
Description
Technical Field
The invention belongs to the field of fine chemical intermediates, relates to a medicine synthesis impurity, and particularly relates to a synthesis method of an anesthetic bupivacaine impurity.
Background
Bupivacaine and analogues thereof are useful as local analgesics or anesthetics. US-A-4180712 describes the use of natural (R, R) -tartaric acid as A resolving agent for the separation of levobupivacaine and its enantiomers. The use of two molar equivalents of base per molar equivalent of acidic resolving agent is not suitable for the preparation of levobupivacaine at an industrial level, and therefore processes for the chemical synthesis of bupivacaine have been developed. Corresponding key impurities can be generated in the process of preparing the bupivacaine; because the chemical formula and nuclear magnetic spectrum of all impurities need to be determined in the preparation process of the medicine, the high-purity anesthetic bupivacaine impurity needs to be synthesized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for synthesizing an impurity of an anesthetic bupivacaine.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing an anesthetic bupivacaine impurity comprises the following steps:
(a) adding 6-bromohexanoic acid, dichloromethane and N, N-dimethylformamide into a reaction container, dropwise adding oxalyl chloride under the protection of ice salt bath and nitrogen, and reacting at 0-25 ℃; after the reaction is finished, concentrating, adding toluene and concentrating again to obtain a crude product of 6-bromohexanoyl chloride; dissolving the 6-bromohexanoyl chloride crude product in dichloromethane, dropwise adding a dichloromethane solution of dimethylaniline under the conditions of a cold salt bath and nitrogen protection, and reacting at 5-10 ℃; after the reaction is finished, directly carrying out suction filtration, washing and drying to obtain a compound ii;
(b) adding the compound ii, n-butylamine, potassium carbonate and acetonitrile into another reaction vessel, and reacting at 30-50 ℃; and (5) purifying after the reaction is finished.
Preferably, in the step (b), after the reaction is finished, concentrating to remove n-butylamine, dissolving the crude product with ethyl acetate and water, stirring, standing for layering, extracting the water phase with ethyl acetate at least once, combining the organic phases, washing with water at least once, drying with anhydrous sodium sulfate, performing suction filtration, concentrating, and purifying by a chromatographic column.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the synthetic method of the anesthetic bupivacaine impurity adopts 6-bromohexanoic acid and oxalyl chloride as raw materials to prepare the bupivacaine impurity which is used as the quality standard of medicines by European pharmacopoeia, and the method has simple process and convenient reaction steps.
Drawings
FIG. 1 is a flow chart of a method for synthesizing an anesthetic, bupivacaine impurity, in accordance with the present invention;
FIG. 2 is a nuclear magnetic spectrum of bupivacaine impurity as an anesthetic.
Detailed Description
The following detailed description of preferred embodiments of the invention is provided:
example 1
This example provides a method for synthesizing an anesthetic, bupivacaine impurity, as shown in fig. 1, which includes the following steps:
(a) adding 6-bromohexanoic acid (30 g), dichloromethane (150 mL) and DMF (1.5 mL) into a 500mL three-necked flask, and cooling to about-5 ℃ by using an ice salt bath under the protection of nitrogen; 22g of oxalyl chloride is dripped (the temperature in the three-mouth bottle is controlled to be less than 0 ℃), and then the temperature is raised to room temperature for reaction for 2 hours after the addition; after concentration, 100ml of toluene is added for secondary concentration to obtain a crude product of 6-bromohexanoyl chloride; adding 6-bromohexanoyl chloride crude product and 1.5L dichloro into 3L three-necked bottleCooling the methane to-5-0 ℃ under the protection of nitrogen; dropping dimethylaniline diluted by dichloromethane (30 mL of dimethylaniline), controlling the temperature at about 0 ℃, heating to about 10 ℃ after adding, reacting for 3 hours, separating out a large amount of solids in the system, directly performing suction filtration, washing a filter cake twice by water and washing a filter cake twice by ethyl acetate to obtain a white solid wet product, and drying by blowing at 50 ℃ to obtain 40g of a compound ii with nuclear magnetism:1H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.16-7.06 (m, 3H), 3.44 (t, J = 8.0 Hz, 2H)，2.43 (t, J = 8.0 Hz, 2H), 2.23(s, 6H), 1.95-1.91 (m, 2H), 1.82-1.78 (m, 2H), 1.63-1.54 (m, 2H)。ESI-MS m/z calcd: C14H20BrNO([M+H]+); 298.07, found: 298.1；
(b) adding 12g of compound ii, 29.5g of n-butylamine, 11.1g of potassium carbonate and 120mL of acetonitrile into a 500mL three-necked flask, heating to about 45 ℃, reacting for 3-4 h (at the moment, the product is completely reacted), concentrating to remove the n-butylamine, dissolving a crude product with ethyl acetate and water, stirring for 10min, standing for layering, extracting a separated water phase once with ethyl acetate, combining organic phases, washing once with water, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, and purifying by a chromatographic column to obtain 20g of compound i (the purity is 99.9%) with nuclear magnetism:1H NMR (400 MHz, CDCl3) δ (ppm): 7.11-7.03 (m, 3H), 6.95 (br, 1H), 2.64-2.52 (m, 4H), 2.48(t, J = 8.0 Hz, 2H)，2.26 (s, 6H), 1.92-1.73 (m, 4H), 1.58-1.523 (m, 2H), 1.49-1.41 (m, 3H), 1.34-1.28 (m, 2H), 0.89 (t, J = 8.0 Hz, 2H). ESI-MS m/z calcd: C18H30N2O([M+H]+) 291.24, found 291.2, as shown in FIG. 2.
Example 2
This example provides a method for the synthesis of an anesthetic, bupivacaine impurity, which is substantially the same as that of example 1, except that: in step (b), the crude product was directly purified by column chromatography to give 18.5g (99.5% purity) of compound i.
Example 3
This example provides a method for the synthesis of an anesthetic, bupivacaine impurity, which is substantially the same as that of example 1, except that: in step (a), the filter cake is washed with water only twice; final purification on a column yields 19.5g (99.9% purity) of compound i.
Comparative example 1
This example provides a method for the synthesis of an anesthetic, bupivacaine impurity, which is substantially the same as that of example 1, except that: in the step (a), 30mL of dimethylaniline is directly dripped, and 35g of compound ii is obtained after forced air drying; the final purification on a column yielded 19.0g of Compound i (purity 99.0%).
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (1)
1. A method for synthesizing an anesthetic bupivacaine impurity is characterized by comprising the following steps:
(a) adding 30g of 6-bromohexanoic acid, 150mL of dichloromethane and 1.5mL of DMF into a 500mL three-necked bottle, and cooling to about-5 ℃ by using an ice salt bath under the protection of nitrogen; controlling the temperature in the three-mouth bottle to be less than 0 ℃, dropwise adding 22g of oxalyl chloride, and heating to room temperature for reaction for 2 hours after the addition is finished; after concentration, 100ml of toluene is added for secondary concentration to obtain a crude product of 6-bromohexanoyl chloride; adding 6-bromohexanoyl chloride crude product and 1.5L dichloromethane into a 3L three-necked bottle, and cooling to-5-0 ℃ under the protection of nitrogen; dripping 30mL of dimethylaniline diluted by dichloromethane, controlling the temperature to be about 0 ℃, heating to 10 ℃ after the addition, reacting for 3 hours, separating out a large amount of solid in the system, directly performing suction filtration, washing a filter cake twice by water and washing the filter cake twice by ethyl acetate to obtain a white solid wet product, and performing forced air drying at 50 ℃ to obtain 40g of a compound ii; the chemical formula of the compound ii is
(b) To 500mL threeAdding 12g of compound ii, 29.5g of n-butylamine, 11.1g of potassium carbonate and 120mL of acetonitrile into a bottle, heating to 45 ℃ for reaction for 3-4 h, concentrating to remove the n-butylamine, dissolving a crude product with ethyl acetate and water, stirring for 10min, standing for layering, extracting a separated water phase once with ethyl acetate, combining organic phases, washing once with water, drying the organic phases with anhydrous sodium sulfate, performing suction filtration, concentrating, and purifying by a chromatographic column to obtain 20g of compound i; the chemical formula of the compound i is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810453820.4A CN108727214B (en) | 2018-05-14 | 2018-05-14 | Synthetic method of anesthetic bupivacaine impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810453820.4A CN108727214B (en) | 2018-05-14 | 2018-05-14 | Synthetic method of anesthetic bupivacaine impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108727214A CN108727214A (en) | 2018-11-02 |
| CN108727214B true CN108727214B (en) | 2021-04-23 |
Family
ID=63937384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810453820.4A Expired - Fee Related CN108727214B (en) | 2018-05-14 | 2018-05-14 | Synthetic method of anesthetic bupivacaine impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108727214B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548303A (en) * | 2020-06-28 | 2020-08-18 | 山东美泰医药有限公司 | Levobupivacaine hydrochloride impurity and preparation and analysis method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098849B (en) * | 2017-04-11 | 2019-09-20 | 山东百诺医药股份有限公司 | A kind of preparation method of Levobupivacaine HCL |
| CN107501167A (en) * | 2017-07-24 | 2017-12-22 | 江西永通科技股份有限公司 | A kind of preparation method of bupivacaine HCl |
-
2018
- 2018-05-14 CN CN201810453820.4A patent/CN108727214B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN108727214A (en) | 2018-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EA018227B1 (en) | A method for the preparation of dabigatran and its intermediates | |
| CN111170892B (en) | Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CN108727214B (en) | Synthetic method of anesthetic bupivacaine impurity | |
| CN114213327A (en) | Synthesis method of (-) -huperzine A | |
| CN108640884B (en) | 2-morpholinone salt, preparation method thereof and preparation method of 2-morpholinone | |
| CN103342707B (en) | For the preparation of the preparation method of A Sainaping intermediate | |
| CN116143599A (en) | Preparation method of high-purity pentoxifylline intermediate | |
| KR100990046B1 (en) | New 4-halobenzylamine salts of montelukast and process for preparing montelukast sodium by using them | |
| CN107513048B (en) | Synthesis method of deuterated vortioxetine hydrobromide | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| JPWO2014051077A1 (en) | Method for producing high purity nitrogen-containing heterocyclic compound | |
| CN106008323B (en) | A method of preparing half tartrate crystal form C of piperazine Ma Selin | |
| CN105693596A (en) | Preparation method of 1-benzyl-4-piperidine formaldehyde | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN101525310B (en) | The synthetic method of 1- benzoyl -3- (2- hydroxyl -1,1- dimethyl ethyl) thiocarbamide | |
| CN109574860A (en) | A method of preparing Vilantro | |
| CN109574991B (en) | Preparation process of polyfluoro substituted aromatic-linked heterocyclic compound | |
| CN110407715A (en) | A kind of synthetic method of pregabalin intermediate | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| CN110551064A (en) | Preparation method of isavuconazole sulfate and intermediate thereof | |
| CN108203435B (en) | Preparation method of entecavir by using Boc protecting group | |
| CN115322194B (en) | Method for resolving carboxylic acid of non-neridone intermediate | |
| CN111138333B (en) | Preparation method of (R) -2- (2, 5-difluorophenyl) -pyrrolidine | |
| CN102898397B (en) | Synthesis method of (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-ol substance and hydrochloride thereof |
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 | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Meng Zhiyan Inventor after: Liu Ke Inventor before: Liu Ke |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210402 Address after: 266000 Tongfu Road, city, Qingdao City, Shandong Province, No. 6 Applicant after: QINGDAO WOMEN AND CHILDREN'S Hospital Address before: 215123 Room 301, building B07, 199 Renai Road, Suzhou Industrial Park, Jiangsu Province Applicant before: SUZHOU YANSHENG BIOTECHNOLOGY Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210423 |