CN107098849B - A kind of preparation method of Levobupivacaine HCL - Google Patents
A kind of preparation method of Levobupivacaine HCL Download PDFInfo
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- CN107098849B CN107098849B CN201710230919.3A CN201710230919A CN107098849B CN 107098849 B CN107098849 B CN 107098849B CN 201710230919 A CN201710230919 A CN 201710230919A CN 107098849 B CN107098849 B CN 107098849B
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- carboxylic acid
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- dimethylaniline
- butyl piperidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention belongs to chemosynthesis technical fields, and in particular to a kind of preparation method of Levobupivacaine HCL.The present invention uses the 2-piperidinecarboxylic acid of racemization or S configuration for starting material, catalytic hydrogenation obtains 1- butyl piperidine -2- carboxylic acid after reacting with n-butanal, Bupivacaine or chirocaine are generated with 2,6- dimethylaniline condensation reaction later, obtains final product Levobupivacaine HCL by subsequent processing.The present invention has many advantages, such as that synthetic route is short, method is simple and convenient to operate, low in cost, the easy to industrialized production and present invention respectively walks more mild reaction condition relative to existing synthetic route, process stabilizing, avoids using strong corrosive chlorinating agent, reduces pollution to environment.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to the preparation method of Levobupivacaine HCL.
Background technique
Chirocaine is the individual isomer of racemization Bupivacaine, and by Chiroscience company, Britain, (existing UCB is public
Department) exploitation, belong to long-acting local anesthetics of amide derivatives, is suitable for peripheral blockade, epidural anesthesia and ubarachnoid block.
Cut-off 2 months 2010, chirocaine is in the national list marketing in the whole world more than 60.
The structural formula of Levobupivacaine HCL is as follows:
The Levobupivacaine HCL principal synthetic routes of existing literature report are as follows:
Synthetic route one (CN 104003930 and Hunan University's Master's thesis " Ropivacaine HCL and hydrochloric acid Bu Bika
The synthesising process research of cause ")
In this reaction route, piperidinecarboxylic acid and hydrochloric acid salt-forming steps need dry water removal, cumbersome;Prepare piperidines acyl chlorides
Strong corrosive thionyl chloride is needed, and the acid chloride intermediate stability generated is poor, to water sensitive, this wants the anhydrous of reaction dissolvent
Ask very high;The yield of the acid chloride intermediate and 2, the reaction of 6- dimethylaniline is low, only 60-65%, butyl reported in the literature
Change reaction yield 70% or so, it is lower (40% or so) to lead to the total recovery of two-step reaction, thus cause cost excessively high, it is unfavorable
In industrialized production.
Synthetic route two (CN 105418489A)
The synthetic route first protects the secondary amine on piperidine ring with benzyloxycarbonyl group (Cbz) using piperidinecarboxylic acid as raw material, then
So that carboxyl and 2,6- dimethylaniline on piperidine ring is carried out acid amide condensation reaction and obtains 2- ((2,6- 3,5-dimethylphenyl) amino)
Piperidines -1- benzyl formate, then so that secondary amine is taken off Cbz protecting group by hydrogenation and obtain 2- ((2,6- 3,5-dimethylphenyl) amino) piperazine
Pyridine intermediate, makes the secondary amine of the intermediate carry out butylation with bromobutane and reacts, and generates bupivacaine HCl at salt by acidification.
In this synthetic route, starting material piperidinecarboxylic acid is protected by upper Cbz, and the later period needs again to take off the protecting group
Fall, preparation process route extends, and increases the production cycle, and three wastes generation increases, and causes industrial production cost substantially to increase, no
Conducive to industrialized production.
In conclusion that there is synthetic routes in Levobupivacaine HCL synthetic route in the prior art is long, it is cumbersome,
Severe reaction conditions, high production cost, the shortcomings that being unfavorable for industrialized production.The preparation technical field of Levobupivacaine HCL,
Need to develop a kind of process route simpler, mature, with cost advantage.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of preparation methods of Levobupivacaine HCL.
The present invention is realized by following technical solutions:
A kind of preparation method of Levobupivacaine HCL, specifically comprises the following steps:
(1) using the 2- pyridine carboxylic acid of racemization or S configuration as starting material, starting material is added to n-butanal organic molten
It is stirred to react in agent about 1 hour, is passed through hydrogen later, catalytic hydrogenation 1~10 hour, obtains the 1- fourth of racemization or S configuration
Phenylpiperidines -2- carboxylic acid;
(2) the 1- butyl piperidine -2- carboxylic acid of racemization described in step (1) or S configuration has been added sequentially to activator
It in solvent, is stirred to react at room temperature 1 hour, 2,6- dimethylaniline is added later and contracts under the conditions of 30~140 DEG C
Close reaction generation racemization in 8~24 hours or chirocaine;
(3) racemization Bupivacaine described in step (2) and D- tartaric acid are split, obtains chirocaine tartaric acid
Levobupivacaine HCL is prepared at salt with hydrochloric acid alcoholic solution then by hydrolysis tartrate in salt;Or it will be in step (2)
The chirocaine, which is directly reacted into hydrochloric acid alcoholic solution, generates Levobupivacaine HCL.
Further,
The molar ratio of n-butanal and starting material is (1~3): 1, preferably (1~1.5): 1 in step (1);
Catalyst is selected from the one or more of nickeliferous, palladium, platinum catalyst, preferably thunder in catalytic hydrogenation in step (1)
The mass ratio of Buddhist nun's nickel, 5% palladium carbon or 10% palladium carbon, catalyst and starting material is (0.05~0.5): 1;It is preferred that (0.05~
0.1): 1;
The hydrogen source of catalytic hydrogenation is hydrogen in step (1), and reaction pressure is 1~20atm, preferably 1~5atm;
In step (1), the organic solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, methylene chloride, three chloromethanes
One of alkane, ethyl acetate, acetonitrile are a variety of.
Further,
Activator is selected from methylchloroformate, ethyl chloroformate, isobutyl chlorocarbonate, carbonyl dimidazoles in step (2), preferably
The molar ratio of carbonyl dimidazoles, the activator and 1- butyl piperidine -2- carboxylic acid is (1~1.5): 1, preferably (1~1.25): 1;
The molar ratio of 2,6- dimethylaniline described in step (2) and 1- butyl piperidine -2- carboxylic acid is (1.5~3): 1;
Organic solvent is selected from tetrahydrofuran, methylene chloride, ethyl acetate, acetonitrile, N, N- dimethyl formyl in step (2)
One of amine, dimethyl sulfoxide, N-Methyl pyrrolidone are a variety of.
Further,
The molar ratio of racemization Bupivacaine described in step (3) and D- tartaric acid is 1:1;
The preferred methanol hydrochloride solution of hydrochloric acid alcoholic solution, ethanol solution hydrochloride, hydrochloric acid isopropanol described in step (3) are molten
Liquid.
The method that racemization Bupivacaine is prepared Levobupivacaine HCL in step (3), optinal plan are, by Bu Bika
Cause, equimolar D- tartaric acid are dissolved with methanol solution, are warming up to reflux, and cool down crystallization, obtain chirocaine D- tartrate.
Chirocaine tartrate is dissolved in methanol, with concentrated ammonia liquor (25wt%) adjusting pH value to 9~10, makes that solid is precipitated, after
It continuous stirring half an hour, filters, filtrate decompression concentration is spin-dried for obtaining chirocaine.Chirocaine is dissolved in ethyl acetate again,
Methanol hydrochloride solution is added dropwise, solid is precipitated, filters, drying obtains Levobupivacaine HCL.
As a preferred solution of the present invention,
The n-butanal of S configuration 2-piperidinecarboxylic acid and 2 times of equivalents has been added in methanol, stir about 1 hour, by palladium carbon plus
Enter into reaction solution, the mass ratio of palladium carbon and S configuration 2-piperidinecarboxylic acid is 1:10, is passed through hydrogen, pressure liter after 3 gas exchanges
To 5atm, pressure is kept to react at room temperature 5~6 hours, terminates reaction after TLC detects fully reacting.Simultaneously by reaction solution filtering
Filtrate is collected, petroleum ether mashing is added after filtrate is spin-dried for, filters and collects filter cake, obtain S configuration 1- butyl piperidine -2- after dry
Carboxylic acid.
The carbonyl dimidazoles of S configuration 1- butyl piperidine -2- carboxylic acid and 1.5 equivalents are added sequentially in dimethyl sulfoxide,
1h is stirred at room temperature, 2 equivalents 2 are then added, 6- dimethylaniline is warming up to 130~140 DEG C and continues to be stirred to react 8h, examines through TLC
Reaction is terminated after surveying fully reacting.Saturated aqueous ammonium chloride is added in reaction solution, and methylene chloride is added and extracts liquid separation, gained is organic
Mutually washed 3 times with saturated common salt, it is dry, it decolourizes, is concentrated under reduced pressure, it is molten that acidic alcohol is added dropwise after being dissolved with ethyl acetate in gained crude product
Solid is precipitated in liquid, is beaten 2h, filters, dries to obtain Levobupivacaine HCL.
The advantages of present invention is relative to existing synthetic route:
1) synthetic route is brief, and method is simple, easy to operate, low in cost, easy to industrialized production;
2) each step reaction condition of the present invention is more mild, and process stabilizing is avoided using strong corrosive chlorinating agent, reduction pair
The pollution of environment.
Reagent, material involved in the present invention are all from commercially available.
Specific embodiment
The present invention is further illustrated below by embodiment, for a person skilled in the art, should not will under
Column embodiment is interpreted as limitation of the present invention, instructs according to prior art, it is modified or improved belong to it is of the invention
In protection scope.
Embodiment 1: preparation S configuration 1- butyl piperidine -2- carboxylic acid
20g (0.155mol) S configuration 2-piperidinecarboxylic acid and 11.17g (0.155mol) n-butanal are added to 200ml methanol
In solvent, stir about 1 hour, the palladium carbon for weighing 1g mass fraction 10% was added in reaction solution, was passed through hydrogen, 3 gas exchanges
Pressure rises to 20atm afterwards, and pressure is kept to react at room temperature 1~2 hour, and reaction is terminated after detecting fully reacting.By reaction solution
Filtrate is filtered and collected, the mashing of 200ml petroleum ether is added after filtrate is spin-dried for, filters and collects filter cake, obtain S configuration 1- after dry
Butyl piperidine -2- carboxylic acid 27.5g.Yield 95.7%.MS:184[M-H]
1H-NMR(400MHz,DMSO-d6),ppm:3.26-3.23(m,1H),3.12-3.08(m,1H),3.0-2.9(m,
2H),1.91-1.87(m,1H),1.63-1.50(m,6H),1.38-1.35(m,1H),1.29-1.23(m,2H),0.89-0.86
(t, J=7.2Hz, 3H)
Embodiment 2: preparation S configuration 1- butyl piperidine -2- carboxylic acid
20g (0.155mol) S configuration 2-piperidinecarboxylic acid and 33.53g (0.465mol) n-butanal are added into 200ml isopropanol
It in solvent, stir about 1 hour, weighs 10g Raney's nickel and adds in reaction solution, be passed through hydrogen, pressure rises to after 3 gas exchanges
5atm keeps pressure to react at room temperature 5~6 hours, and reaction is terminated after detecting fully reacting.Reaction solution is filtered and collects filter
The mashing of 200ml petroleum ether is added in liquid after being spin-dried for filtrate, filter and collect filter cake, obtain S configuration 1- butyl piperidine -2- after dry
Carboxylic acid 27.3g.Yield 95.0%.
Embodiment 3: preparation racemization 1- butyl piperidine -2- carboxylic acid
20g (0.155mol) 2-piperidinecarboxylic acid and 16.8g (0.233mol) n-butanal are added in 200ml alcohol solvent,
It stir about 1 hour, weighs the palladium carbon that 2g mass fraction is 5% and adds in reaction solution, be passed through hydrogen and 3 gas exchanges, later
It is continually fed into hydrogen, at room temperature synthesis under normal pressure 8~10 hours, reaction is terminated after detecting fully reacting.Simultaneously by reaction solution filtering
Filtrate is collected, the mashing of 200ml petroleum ether is added after filtrate is spin-dried for, filters and collects filter cake, obtain 1- butyl piperidine -2- after dry
Carboxylic acid 27.8g.Yield 96.8%.
Embodiment 4: Levobupivacaine HCL is prepared
10g (54mmol) S configuration 1- butyl piperidine -2- carboxylic acid, 10.9g (67.5mmol) carbonyl dimidazoles are added to
In 150ml n,N-Dimethylformamide, 1h is stirred at room temperature, 9.8g (81mmol) 2,6- dimethylaniline is then added, is warming up to
110~120 DEG C are continued to be stirred to react 15h;Reaction solution pours into saturated aqueous ammonium chloride, and the extraction of 200ml methylene chloride is added
Liquid separation, gained organic phase are washed 3 times with saturated common salt, dry, are decolourized, and are concentrated under reduced pressure, after gained crude product is dissolved with ethyl acetate
Ethanol solution hydrochloride is added dropwise, solid is precipitated, is beaten 2h, filters, dries to obtain 13.5g Levobupivacaine HCL, yield 85%.MS:
261[M+H];E.e.%:99.7%.
1H-NMR(400MHz,DMSO-d6),ppm:9.78(s,1H),7.16-7.09(m,3H),4.26-4.21(m,
1H), 3.51-3.50 (d, J=11.2Hz, 1H), 3.15-3.09 (m, 2H), 3.04-2.97 (m, 1H), 2.32-2.29 (d, J=
12Hz,1H),2.16(s,6H),1.86-1.73(m,5H),1.71-1.62(m,1H),1.54-1.52(m.1H),1.35-1.26
(m, 2H), 0.91-0.88 (t, J=7.2Hz, 3H)
Embodiment 5: Levobupivacaine HCL is prepared
10g (54mmol) S configuration 1- butyl piperidine -2- carboxylic acid, 11g (108mmol) triethylamine are added to 150ml dichloro
In methane, it is cooled to 0 DEG C, 7.4g (54mmol) isobutyl chlorocarbonate is added dropwise, finishes, reaction 1h is warmed to room temperature, is then added
13.1g (108mmol) 2,6- dimethylaniline is warming up to 30~40 DEG C of reactions for 24 hours, and reaction solution pours into saturated aqueous ammonium chloride
In, 100mL methylene chloride is added and extracts liquid separation, gained organic phase is washed 3 times with saturated common salt, and it is dry, it decolourizes, is concentrated under reduced pressure,
Gained crude product uses column chromatography purifying purification, which is dissolved in ethyl acetate, and ethanol solution hydrochloride is added, and is precipitated
Solid filters, dries to obtain 11.4g Levobupivacaine HCL, yield 65%.E.e. it is worth: 99.5%.
Embodiment 6: Levobupivacaine HCL is prepared
20g (108mmol) racemization 1- butyl piperidine -2- carboxylic acid, 26g (162mmol) carbonyl dimidazoles are added to 300ml
In dimethyl sulfoxide, 1h is stirred at room temperature, 39.3g (324mmol) 2,6- dimethylaniline is then added, is warming up to 130~140 DEG C
Continue to be stirred to react 8h;Reaction solution pours into saturated aqueous ammonium chloride, and 200ml methylene chloride is added and extracts liquid separation, gained has
Machine is mutually washed 3 times with saturated common salt, dry, is decolourized, and is concentrated under reduced pressure, is obtained racemization Bupivacaine crude product 25g, yield 79.9%.
25g Bupivacaine (86.6mmol), 13g (86.6mmol) D- tartaric acid are added to 300mL ethyl alcohol and 40mL water
In the mixed solvent is warming up to reflux, keeps the temperature 1h, and cool down crystallization, filters, dries to obtain 18.2g chirocaine D- tartrate;It will
Chirocaine D- tartrate is added in 300mL methanol, is added dropwise 12mL ammonium hydroxide (25wt%), and 2h is stirred, and is filtered, filtrate
Reduced pressure is spin-dried for obtaining chirocaine, is dissolved in ethyl acetate, and ethanol solution hydrochloride is added dropwise, and solid is precipitated, and filters, and dries
Do to obtain 14g Levobupivacaine HCL, yield 90%.E.e. it is worth: 99.4%.
Claims (4)
1. a kind of preparation method of Levobupivacaine HCL, route are as follows:
Specifically includes the following steps:
(1) using (S) -2-piperidinecarboxylic acid as starting material, starting material and n-butanal is added in organic solvent, are stirred to react
1 hour, it is passed through hydrogen later, catalytic hydrogenation 1~10 hour, obtains (S) -1- butyl piperidine -2- carboxylic acid;
(2) (S) -1- butyl piperidine -2- carboxylic acid described in step (1) and activator are added sequentially in organic solvent, in room
It is stirred to react under the conditions of temperature 1 hour, 2,6- dimethylaniline is added later, condensation reaction 8~24 is small under the conditions of 30~140 DEG C
When, generate chirocaine;
(3) chirocaine described in step (2) is directly reacted with hydrochloric acid alcoholic solution and generates Levobupivacaine HCL;
Catalyst used in catalytic hydrogenation described in step (1) is selected from Raney's nickel, 5% palladium carbon or 10% palladium carbon, described
The mass ratio of catalyst and starting material is (0.05~0.1): 1;
The reaction pressure of step (1) described catalytic hydrogenation is 1~20atm;
Activator described in step (2) is carbonyl dimidazoles, mole of carbonyl dimidazoles and the 1- butyl piperidine -2- carboxylic acid
Than for (1~1.5): 1, it is added after 2,6- dimethylaniline and is reacted 8~15 hours under the conditions of 110~140 DEG C.
2. preparation method according to claim 1, which is characterized in that n-butanal described in step (1) and starting material
Molar ratio is (1~3): 1.
3. preparation method according to claim 1, which is characterized in that 2,6- dimethylaniline described in step (2) with
The molar ratio of (S) -1- butyl piperidine -2- carboxylic acid is (1.5~3): 1.
4. preparation method according to claim 1, which is characterized in that in step (1) with (S) -2-piperidinecarboxylic acid be starting
The molar ratio of raw material, n-butanal and (S) -2-piperidinecarboxylic acid is (1~1.5): 1, the catalyst of the catalytic hydrogenation is selected from
The mass ratio of Raney's nickel, 5% palladium carbon or 10% palladium carbon, the catalyst and starting material is (0.05~0.1): 1, reaction pressure
For (1~5) atm;Activator is carbonyl dimidazoles, the carbonyl dimidazoles and (S) -1- butyl piperidine -2- carboxylic acid in step (2)
Molar ratio be (1~1.25): 1;The molar ratio of the 2,6- dimethylaniline and (S) -1- butyl piperidine -2- carboxylic acid is 2:1;
2,6- dimethylaniline is added to react 8~15 hours under the conditions of 110~140 DEG C later.
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CN108727214B (en) * | 2018-05-14 | 2021-04-23 | 青岛市妇女儿童医院 | Synthetic method of anesthetic bupivacaine impurity |
CN109734654A (en) * | 2019-02-26 | 2019-05-10 | 南京亿华药业有限公司 | A kind of preparation method of Levobupivacaine HCL |
CN113105385B (en) * | 2020-01-09 | 2023-12-19 | 鲁南制药集团股份有限公司 | Preparation method of levobupivacaine |
CN113087655B (en) * | 2020-01-09 | 2023-12-19 | 鲁南制药集团股份有限公司 | Levobupivacaine intermediate compound |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999043658A1 (en) * | 1998-02-27 | 1999-09-02 | Warner-Lambert Company | Heterocyclic substituted aniline calcium channel blockers |
WO2001076599A1 (en) * | 2000-04-06 | 2001-10-18 | Cristália Produtos Químicos Farmacéuticos Ltda. | Process of making racemic bupivacaine's enantiomers, levobupivacaine's pharmaceutical compositions, levobupivacaine's pharmaceutical compositions formulated on its free base form or its pharmaceutical acceptable salts and use of levobupivacaine's pharmaceutical compositions formulated on its free base form |
CN104961723A (en) * | 2005-04-11 | 2015-10-07 | 艾伯维巴哈马有限公司 | 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors |
-
2017
- 2017-04-11 CN CN201710230919.3A patent/CN107098849B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999043658A1 (en) * | 1998-02-27 | 1999-09-02 | Warner-Lambert Company | Heterocyclic substituted aniline calcium channel blockers |
WO2001076599A1 (en) * | 2000-04-06 | 2001-10-18 | Cristália Produtos Químicos Farmacéuticos Ltda. | Process of making racemic bupivacaine's enantiomers, levobupivacaine's pharmaceutical compositions, levobupivacaine's pharmaceutical compositions formulated on its free base form or its pharmaceutical acceptable salts and use of levobupivacaine's pharmaceutical compositions formulated on its free base form |
CN104961723A (en) * | 2005-04-11 | 2015-10-07 | 艾伯维巴哈马有限公司 | 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors |
Non-Patent Citations (1)
Title |
---|
Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties;Raffael Vorberg et al.,;《ChemMedChem》;20160915;第11卷;第2217页Scheme 1和第2230页左栏1段 * |
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