CN108727214A - A kind of synthetic method of anesthetic bupivacaine impurity - Google Patents
A kind of synthetic method of anesthetic bupivacaine impurity Download PDFInfo
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- CN108727214A CN108727214A CN201810453820.4A CN201810453820A CN108727214A CN 108727214 A CN108727214 A CN 108727214A CN 201810453820 A CN201810453820 A CN 201810453820A CN 108727214 A CN108727214 A CN 108727214A
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- 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
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- 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
Abstract
The present invention relates to a kind of synthetic methods of anesthetic bupivacaine impurity, it includes the following steps：（a）6- bromocaproic acids, dichloromethane and n,N-Dimethylformamide are added into reaction vessel, oxalyl chloride is added dropwise under conditions of ice salt bath, nitrogen protection, is reacted at 0 ~ 25 DEG C after finishing；It is concentrated after reaction, toluene is then added and is concentrated to give 6- bromine caproyl chloride crude products again；The 6- bromines caproyl chloride crude product is dissolved in dichloromethane, the dichloromethane solution of dimethylaniline is added dropwise under conditions of ice salt bath, nitrogen protection, is reacted at 5 ~ 10 DEG C after finishing；Directly filter after reaction, washing, dry compound ii；（b）The compound ii, n-butylamine, potassium carbonate and acetonitrile are added into another reaction vessel, is reacted at 30 ~ 50 DEG C；It purifies after reaction.The fourth for being incorporated into drug standard by European Pharmacopoeia by using 6- bromocaproic acids and oxalyl chloride for raw material preparation sends cacaine impurity, and this method is simple for process, reaction step is convenient.
Description
Technical field
The invention belongs to fine-chemical intermediate fields, are related to a kind of medicine synthesis impurity, and in particular to a kind of anesthetic
The synthetic method of bupivacaine impurity.
Background technology
Bupivacaine and the like can be used as topical pain relief agent or anesthetic.US-A-4180712 describe it is natural (R,
R)-tartaric acid is used to detach the purposes of levobupivacaine and its enantiomer as resolution reagent.Acidity per molar equivalent is torn open
It is divided to the reagent alkali of two molar equivalents, this method not to be suitable for preparing levobupivacaine on industrial level, therefore fourth piperazine card
The chemical synthesis process of cause is developed.It will produce corresponding critical impurities during preparing bupivacaine；Due to
Drug is in preparation process it needs to be determined that the chemical formula and nuclear magnetic spectrogram of all impurity, it is therefore desirable to synthesize the anesthetic of high-purity
Bupivacaine impurity.
Invention content
A kind of synthesis of anesthetic bupivacaine impurity is provided the invention aims to overcome the deficiencies in the prior art
Method.
In order to achieve the above objectives, the technical solution adopted by the present invention is：A kind of synthesis side of anesthetic bupivacaine impurity
Method, it includes the following steps：
（a）6- bromocaproic acids, dichloromethane and n,N-Dimethylformamide are added into reaction vessel, in ice salt bath, nitrogen protection
Under conditions of oxalyl chloride is added dropwise, reacted at 0 ~ 25 DEG C after finishing；It is concentrated after reaction, toluene then is added again
It is concentrated to give 6- bromine caproyl chloride crude products；The 6- bromines caproyl chloride crude product is dissolved in dichloromethane, in ice salt bath, the condition of nitrogen protection
The lower dichloromethane solution that dimethylaniline is added dropwise, is reacted after finishing at 5 ~ 10 DEG C；Directly filter, wash after reaction,
Dry compound ii；
（b）The compound ii, n-butylamine, potassium carbonate and acetonitrile are added into another reaction vessel, is carried out at 30 ~ 50 DEG C anti-
It answers；It purifies after reaction.
Optimally, step（b）In, reaction terminates to be concentrated to remove n-butylamine, crude product ethyl acetate and water dissolution,
Stratification after stirring, water phase are extracted with ethyl acetate at least once, merge organic phase and at least primary, subsequent use is washed with water
Anhydrous sodium sulfate is dried, and is filtered, and column chromatography is crossed in concentration.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：Anesthetic fourth of the present invention
The synthetic method of piperazine cacaine impurity is that raw material preparation is incorporated into drug quality by European Pharmacopoeia by using 6- bromocaproic acids and oxalyl chloride
The fourth of standard sends cacaine impurity, and this method is simple for process, reaction step is convenient.
Description of the drawings
Attached drawing 1 is the preparation method flow chart of the synthetic method of anesthetic bupivacaine impurity of the present invention；
Attached drawing 2 is the nuclear magnetic spectrogram of anesthetic bupivacaine impurity of the present invention.
Specific implementation mode
It is described in detail below in conjunction with to the preferred embodiment of the invention：
Embodiment 1
The present embodiment provides a kind of preparation methods of the synthetic method of anesthetic bupivacaine impurity, as shown in Figure 1, it include with
Lower step：
（a）6- bromocaproic acids are added into 500 mL there-necked flasks（30g）, dichloromethane（150 mL）And DMF（1.5 mL）, in nitrogen
Under protection -5 DEG C or so are cooled to ice salt bath；22g oxalyl chlorides are added dropwise（The temperature controlled in there-necked flask is less than 0 DEG C）, after finishing
It is warming up to room temperature reaction 2h；100ml toluene is added after concentration to concentrate again, obtains 6- bromine caproyl chloride crude products；Into 3L there-necked flasks
6- bromine caproyl chloride crude products and 1.5L dichloromethane is added, -5 DEG C ~ 0 DEG C is cooled under nitrogen protection；Instillation is diluted with dichloromethane
Dimethylaniline afterwards（Dimethylaniline is 30 mL）, temperature is controlled at 0 DEG C or so, and 10 DEG C or so reaction 3h, body are warming up to after finishing
There are a large amount of solids to be precipitated in system, directly filters, filter cake is washed twice with water, ethyl acetate washes twice, and it is wet to obtain white solid
Product, obtain 40g compound ii after 50 DEG C of forced air dryings, nuclear-magnetism is：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）12g compounds ii, 29.5g n-butylamine, 11.1g potassium carbonate and 120 mL acetonitriles are added into 500 mL there-necked flasks, add
Heat is warming up to 45 DEG C or so 3 ~ 4h of reaction（The reaction was complete for product at this time）, concentrate and remove n-butylamine, crude product ethyl acetate and water
Stratification after 10min is stirred in dissolving, and the water phase separated is extracted with ethyl acetate once, merges organic phase and is washed with water once,
Organic phase anhydrous sodium sulfate is dried, and is filtered, concentration, is crossed column chromatography and is obtained compound i 20g（Purity is 99.9%）, core
Magnetic is：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 Figure 2.
Embodiment 2
The present embodiment provides a kind of preparation method of the synthetic method of anesthetic bupivacaine impurity, it and the base in embodiment 1
This is consistent, unlike：Step（b）In, the direct column chromatography of crossing of crude product obtains compound i 18.5g（Purity is 99.5%）.
Embodiment 3
The present embodiment provides a kind of preparation method of the synthetic method of anesthetic bupivacaine impurity, it and the base in embodiment 1
This is consistent, unlike：Step（a）In, filter cake is only washed twice with water；Final column chromatography of crossing obtains compound i
19.5g（Purity is 99.9%）.
Comparative example 1
This example provides a kind of preparation method of the synthetic method of anesthetic bupivacaine impurity, it with embodiment 1 in basic one
It causes, unlike：Step（a）In, 30 mL dimethylanilines are directly added dropwise, 35g compounds ii is obtained after forced air drying；Final mistake
Column chromatography obtains compound i 19.0g（Purity is 99.0%）.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (2)
1. a kind of synthetic method of anesthetic bupivacaine impurity, which is characterized in that it includes the following steps：
（a）6- bromocaproic acids, dichloromethane and n,N-Dimethylformamide are added into reaction vessel, in ice salt bath, nitrogen protection
Under conditions of oxalyl chloride is added dropwise, reacted at 0 ~ 25 DEG C after finishing；It is concentrated after reaction, toluene then is added again
It is concentrated to give 6- bromine caproyl chloride crude products；The 6- bromines caproyl chloride crude product is dissolved in dichloromethane, in ice salt bath, the condition of nitrogen protection
The lower dichloromethane solution that dimethylaniline is added dropwise, is reacted after finishing at 5 ~ 10 DEG C；Directly filter, wash after reaction,
Dry compound ii；
（b）The compound ii, n-butylamine, potassium carbonate and acetonitrile are added into another reaction vessel, is carried out at 30 ~ 50 DEG C anti-
It answers；It purifies after reaction.
2. the synthetic method of anesthetic bupivacaine impurity according to claim 1, it is characterised in that：Step（b）In, instead
It should terminate to be concentrated to remove n-butylamine, crude product ethyl acetate and water dissolution, stratification after stirring, water phase acetic acid second
Ester extracts at least once, merges organic phase and is washed with water at least once, then dried with anhydrous sodium sulfate, is filtered, concentration, mistake
Column chromatography.
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Cited By (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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098849A (en) * | 2017-04-11 | 2017-08-29 | 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 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098849A (en) * | 2017-04-11 | 2017-08-29 | 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 |
Non-Patent Citations (1)
| Title |
|---|
| TENTHOREY ET. AL.: "New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (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 |
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