CN105646482B - A kind of preparation method of Ropivacaine HCL impurity F - Google Patents
A kind of preparation method of Ropivacaine HCL impurity F Download PDFInfo
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- CN105646482B CN105646482B CN201511013381.8A CN201511013381A CN105646482B CN 105646482 B CN105646482 B CN 105646482B CN 201511013381 A CN201511013381 A CN 201511013381A CN 105646482 B CN105646482 B CN 105646482B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to chemosynthesis technical field, and in particular to a kind of Ropivacaine HCL impurity F（8aS）‑2‑（2,6 3,5-dimethylphenyls）3,3 dimethyl-imidazos [1,5 a] pyridine 1（5H）The preparation method of ketone.The method is with (S) N (2', 6' xylyls) 2 piperidine formamides and acetone is raw material, there is condensation reaction in acid condition and slough a molecular water, solvent is evaporated off and is adjusted to basic treatment as impurity F crude product, then carry out being refining to obtain the Ropivacaine HCL impurity F of high-purity.The present invention has that synthetic route is short, simple to operate, product purity is high, can provide qualified impurity reference substance for the quality control of Ropivacaine HCL.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to a kind of Ropivacaine HCL impurity F（8aS）-2-（2,6-
3,5-dimethylphenyl）- 3,3- dimethyl-imidazols simultaneously [1,5-a] pyridine -1（5H）The preparation method of -one.
Background technology
Ropivacaine HCL is a kind of New-type long-acting amide-type local anesthetic, is listed in 1996, by Sweden A Site
Pain management center is drawn to develop.Chemical name is (-)-(2S)-N- (2,6- 3,5-dimethylphenyls) -1- n-propyl piperidines -2-
Carboxamide hydrochloride, trade name Naropin.Ropivacaine HCL is long-acting, the safe local anesthetic of a new generation；For outer
Section's surgery anesthesia, midwifery process, part or regional anesthesia, and Acute Pain or postoperative pain treatment.
The impurity of hydrochloric acid sieve piperazine card is mainly its catabolite, has certain toxicity, therefore should strictly control its content.EP
There are 8 impurity in 8.0 editions Ropivacaine HCL quality standards, wherein impurity F chemistry is entitled（8aS）-2-（2,6- dimethyl benzenes
Base）- 3,3- dimethyl-imidazols simultaneously [1,5-a] pyridine -1（5H）-one, chemical formula C17H24N2O, structural formula is as follows：
。
Hydrochloric acid sieve piperazine card impurity F in the market is not sold, and the synthetic method of impurity F was also reported without open source information.But
It is that correlative study of the impurity F to Ropivacaine HCL impurity is extremely important, it can be used for impurity in Ropivacaine HCL production
Qualitative and quantitative analysis, such that it is able to improve the quality standard of Ropivacaine HCL, for safe medication provide important guiding meaning
Justice.Accordingly, it would be desirable to study the synthetic method of impurity F.
The content of the invention
It is the matter of Ropivacaine HCL it is an object of the invention to provide a kind of preparation method of Ropivacaine HCL impurity F
Amount control provides qualified reference substance.
The present invention is achieved by the following technical solutions：
A kind of preparation method of Ropivacaine HCL impurity F, comprises the following steps：
(S)-N- (2', 6'- xylyl) -2- piperidine formamides are added in acetone, are heated to reflux after adding acid, instead
Solvent is evaporated off after should finishing；Deionized water is added, solution is adjusted to alkalescence, filters, is dried to obtain impurity F crude product, obtained after refining
Impurity F fine work, the impurity F is（8aS）-2-（2,6- 3,5-dimethylphenyls）- 3,3- dimethyl-imidazols simultaneously [1,5-a] pyridine -1
（5H）-one.
The preparation method reaction equation is as follows：
In the preparation method of above-mentioned Ropivacaine HCL impurity F, (S)-N- (2', 6'- the xylyl) -2- piperidines
Formamide is 1 with the mass ratio of acetone:3~8.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the acid is in hydrochloric acid, sulfuric acid, formic acid, acetic acid
Kind.(S)-N- (2', 6'- the xylyl) -2- piperidine formamides are 1 with the mass ratio of acid:0.1~0.7.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the heating reflux reaction time is 5~10 hours.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the impurity F crude product refining method：It is that impurity F is thick
Product are added in organic solvent, after being heated to reflux 30 minutes, are cooled to room temperature, filtered, be dried to obtain impurity F fine work.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the organic solvent is methyl alcohol, ethanol, acetonitrile, methyl
One kind in isobutyl ketone, the mass ratio of the organic solvent is 1:2~8.
Preferably, in the preparation method of above-mentioned Ropivacaine HCL impurity F, the organic solvent is methyl-isobutyl first
Ketone.
The present invention with (S)-N- (2', 6'- xylyl) -2- piperidine formamides and acetone for raw material, in acid condition
A molecular water is sloughed in generation condensation reaction, solvent is evaporated off and is adjusted to basic treatment as impurity F crude product, is then refining to obtain
The Ropivacaine HCL impurity F of high-purity.The present invention has that synthetic route is short, simple to operate, product purity is high, can be hydrochloric acid sieve
The quality control of piperazine cacaine provides qualified impurity reference substance.Solve the difficulty of Ropivacaine HCL impurity reference substance quality control
Topic.
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate skill of the invention
Art scheme, and non-limiting essence of the invention.
Concentrated hydrochloric acid used is that mass percent concentration is 37% in the present invention.
Embodiment 1
Will be equipped with adding in mechanical agitation 250ml cleaning there-necked flasks acetone 100g and (S)-N- (2', 6'- xylyl)-
2- piperidine formamide 20g, agitating heating makes solid all dissolve.Acetic acid 5g is subsequently adding, backflow is continuously heating to, reaction 5 is small
Shi Hou, thin layer detection raw material fundamental reaction is complete（TLC condition dichloromethane：Methyl alcohol=10:1）.Start slow normal pressure and solvent be evaporated off,
Solvent distillation is finished to 50 DEG C of deionized water 300g are added in residue, slowly separates out solid, then adjust pH with sodium hydroxide solution
Be worth is 9.Filtering, filter cake is washed with deionized, and dry 19g crude products, liquid phase purity is more than 97%.19g crude products are added
To in 76g ethanol, it is heated to reflux making solid dissolving in 30 minutes；Room temperature, filtering are cooled to, filtration cakes torrefaction obtains impurity F sterling
15.3g；Liquid phase purity is more than 99%, and two-step reaction molar yield is 65.2%.
Embodiment 2：
Will be equipped with adding in mechanical agitation 500ml cleaning there-necked flasks acetone 200g and (S)-N- (2', 6'- xylyl)-
2- piperidine formamide 25g, agitating heating makes solid all dissolve.Concentrated hydrochloric acid 15g is subsequently adding, backflow, reaction is continuously heating to
After 10 hours, thin layer detection raw material fundamental reaction is complete（TLC condition dichloromethane：Methyl alcohol=10:1）.Start slow normal pressure to be evaporated off
Solvent, solvent distillation is finished to 50 DEG C of deionized water 375g are added in residue, slowly separates out solid, then use sodium hydroxide solution
It is 9 to adjust pH values.Filtering, filter cake is washed with deionized, and dry 24g crude products, liquid phase purity is more than 96%.24g is slightly produced
Thing is added in 168g hexones, is heated to reflux making solid dissolving in 30 minutes；Room temperature, filtering are cooled to, filter cake is done
It is dry, obtain impurity F sterling 19.8g；Liquid phase purity is more than 99%, and two-step reaction molar yield is 67.5%.
Embodiment 3：
Will be equipped with adding in mechanical agitation 250ml cleaning there-necked flasks acetone 75g and (S)-N- (2', 6'- xylyl)-
2- piperidine formamide 25g, agitating heating makes solid all dissolve.Sulfuric acid 2.5g is subsequently adding, backflow, reaction 8 is continuously heating to
After hour, thin layer detection raw material fundamental reaction is complete（TLC condition dichloromethane：Methyl alcohol=10:1）.Start slow normal pressure be evaporated off it is molten
Agent, solvent distillation is finished to 50 DEG C of deionized water 375g are added in residue, slowly separates out solid, then adjusted with sodium hydroxide solution
PH values are 9.Filtering, filter cake is washed with deionized, and dry 25g crude products, liquid phase purity is more than 96%.By 25g crude products
It is added in 50g acetonitriles, is heated to reflux making solid dissolving in 30 minutes；Room temperature, filtering are cooled to, filtration cakes torrefaction obtains impurity F pure
Product 19.4g；Liquid phase purity is more than 99%, and two-step reaction molar yield is 66.2%.
Claims (6)
1. a kind of preparation method of Ropivacaine HCL impurity F, comprises the following steps：
(S)-N- (2', 6'- xylyl) -2- piperidine formamides are added in acetone, are heated to reflux after adding acid, reacted
Solvent is evaporated off after finishing；Deionized water is added, solution is adjusted to alkalescence, filters, is dried to obtain impurity F crude product, impurity F is obtained after refining
Fine work, the impurity F is（8aS）-2-（2,6- 3,5-dimethylphenyls）- 3,3- dimethyl-imidazols simultaneously [1,5-a] pyridine -1（5H）-
Ketone；
The impurity F crude product refining method：It is that impurity F crude product is added in organic solvent, after being heated to reflux 30 minutes, cooling
To room temperature, filter, be dried to obtain impurity F fine work.
2. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that (the S)-N-
(2', 6'- xylyl) -2- piperidine formamides are 1 with the mass ratio of acetone:3~8.
3. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that the acid is hydrochloric acid,
One kind in sulfuric acid, formic acid, acetic acid.
4. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that (the S)-N-
(2', 6'- xylyl) -2- piperidine formamides are 1 with the mass ratio of acid:0.1~0.7.
5. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that described to be heated to reflux
Reaction time is 5~10 hours.
6. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that the organic solvent
It is hexone.
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