CN101657437B - New procedure for preparation of levocetirizine and its intermediates - Google Patents
New procedure for preparation of levocetirizine and its intermediates Download PDFInfo
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- CN101657437B CN101657437B CN200880008231.XA CN200880008231A CN101657437B CN 101657437 B CN101657437 B CN 101657437B CN 200880008231 A CN200880008231 A CN 200880008231A CN 101657437 B CN101657437 B CN 101657437B
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- 0 Clc1ccc(*c2ccccc2)cc1 Chemical compound Clc1ccc(*c2ccccc2)cc1 0.000 description 4
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Abstract
The present invention describes a novel process for the preparation of levocetirizine and pharmaceutically acceptable acid addition salts thereof using diglycolic acid or derivatives thereof and new intermediates used in that process.
Description
Technical field
The present invention relates to a kind of preparation levocetirizine and intermediate thereof, with and the novel method of pharmacy acceptable salt and ester.
Background technology
Known left-handed [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group] levocetirizine general by name (levocetirizine) of acetic acid, it is proved to be able to as the pharmacological agent anaphylactic disease.
Levocetirizine and comprise that the salt of its dihydrochloride is known, and in the treatment of anaphylactic disease effectively.Anaphylactic disease includes but not limited to, chronic and acute allergic rhinitis, anaphylaxis conjunctivitis, pruritus, urticaria and similar disease.Levocetirizine belongs to the H1 Histamine Receptors antagonist of the s-generation, and it is considered to can show significant advantage with respect to first-generation compound.Studies show that levocetirizine can alleviate periodically irritated symptom safely and effectively.Levocetirizine also is used for the treatment of the chronic idiopathic urticaria.
GB 2,225, described a kind of method for preparing left-handed type cetirizine, dextrorotatory form cetirizine or its mixture in 321, and it comprises hydrolysis optically pure [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group] acetonitrile.Under the initiation of acid or alkali, hydrolysis takes place in water, ethanol or water-ethanol medium, and thus obtained acid is converted into its dihydrochloride.Obtain starting raw material 1-[(4-chloro-phenyl-with opticity by splitting corresponding racemic compound) phenmethyl] piperazine, preferably be converted into the salt of its diastereomer with tartrate.The productive rate that splits is quite low, namely has only 12.7%.The opticity intermediate that obtains further transforms with the chloroethoxy acetonitrile, and productive rate is 69%.
The shortcoming of open reaction is: it need be to N, and N-two (2-haloethyl) amine is protected, and therefore need carry out deprotection to the medium that obtains.
The preparation of left-handed type cetirizine is with optically pure 1-[(4-chloro-phenyl-) phenmethyl] piperazine undertakies by known synthetic method.Therefore, the enantiomer that has the optical purity of improvement and a good yield for preparation provides new route to look like to be worth very much.
Polymorphic I and the noncrystalline form thereof of the left-handed dihydro villaumite crystal of cetirizine all have been disclosed in WO2004/050647 and WO 2004/065360.Crystalline form is from containing ketone solvent, as preparing by crystallization in acetone, butanone, dimethyl ketone, 2 pentanone and composition thereof.Noncrystalline form prepares by solvent evaporation.
Therefore just need a kind of high-efficiency synthesis method of levocetirizine to reach the new intermediate that uses in the method, to be suitable for mass preparation.
Summary of the invention
The invention provides the new high-efficiency synthesis method of a kind of levocetirizine and pharmacy acceptable salt thereof, and the new intermediate that uses in the method.
According to first aspect, the present invention relates to a kind of method for preparing levocetirizine, comprise the steps:
I) make the intermediate of formula II
With structural formula be
Diglycollic acid derivative or X-CO-CH
2-O-CH
2-R reacts, and wherein X is OH or halogen group, and R is the group that COOH maybe can be converted into COOH, and preferred R is selected from: COOH; COX, X wherein is halogen; COOM, M wherein are basic metal or alkaline-earth metal or N (R
1)
4CONH
2CONR
1R
2, COOR
1, CN, CHO, CH
2OH or CH (OR
1)
2, R wherein
1And R
2Be independently selected from H, low alkyl group, aryl, thereby the intermediate of the formula of acquisition IV
R wherein is same as described above;
If ii) obtained R wherein and be the intermediate in the formula (IV) of COOH, it can be converted into the compound that R wherein is the formula (IV) that can be converted into the group of COOH arbitrarily;
Iii) use the intermediate in the selective reduction agent reduction-type (IV), obtain the product in the formula V.
R wherein is with above-mentioned identical;
If iv) R is not COOH, (V) is converted into levocetirizine with intermediate; And V) randomly levocetirizine is converted into its pharmacy acceptable salt.
The diglycollic acid derivative can be the glycol ether acid anhydride of following formula,
Or general formula is X-CO-CH
2-O-CH
2The derivative of-R, wherein X is OH or halogen, and R is the group that COOH maybe can be converted into COOH.Preferably, R is selected from: COOH; COX, wherein X is halogen; COOM, wherein M is basic metal or alkaline-earth metal or N (R
1)
4CONH
2CONR
1R
2, COOR
1, CN, CHO, CH
2OH or CH (OR
1)
2, R wherein
1Or R
2Be independently selected from H, low alkyl group and aryl.Term lower alkyl refers to have the saturated fatty hydrocarbyl group of the straight or branched of 1 to 6 carbon atom, as methyl, ethyl, sec.-propyl, the tertiary butyl etc.; Perhaps refer to the aryl substituted alkyl (akyl) of straight or branched, as phenmethyl or trityl.Term aryl refers to replace or unsubstituted aromatic yl group.
For the compound of preparation formula (IV), use diglycollic acid derivative excessive or equimolar amount basically, the preferred use surpasses 1.5 moles, most preferably uses above 1.1 moles.Reaction can be carried out in organic solvent, water or its mixture.If water is as solvent, this method can be carried out in the presence of phase-transfer catalyst.Suitable organic solvent comprises that polarity or nonpolar organic solvent are as dimethyl formamide, methyl-sulphoxide, acetonitrile; Halocarbon such as chloroform, methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether such as diethyl ether, dioxan, tetrahydrofuran (THF), 1,3-glycol dimethyl ether etc.; Aromatic hydrocarbons such as benzene,toluene,xylene.This reaction also can be carried out under the condition of solvent not having.
Reaction also can be carried out under the situation that following material exists: TBAC tetrabutylammonium chloride, the cyaniding tetrabutylammonium, tetrabutylammonium fluoride, tetrabutylammonium iodide, TBAH, chlorination tetrabutyl phosphine, tricaprylylmethylammchloride chloride, tetraethylammonium chloride, tetramethylammonium bromide, the trioctylethylphosphobromide bromide phosphine, tricaprylylmethylammchloride chloride, chlorination trioctylphosphine propyl ammonium, the bromination tetrapropyl ammonium, tetraphenylarsonium chloride base arsenic, bromide four diphenylphosphino, tetraphenylarsonium chloride base phosphine, benzyltrimethylammonium hydroxide, hexaoxacyclooctadecane-6-6 (18-crown-6), dibenzo-18-crown-6 (DB18C6) (dibenzo-18-crown-6), dicyclohexyl-18-crown-6 (DC18C6) (dicyclohexyl-18-crown-6) or their mixture.The preferred positive fourth ammonium of bromination or the positive fourth ammonium of iodate of using.
The temperature of reaction can be the boiling point of spending to reaction mixture from about 0, and preferred range is from about 60 ℃ of boiling points to reaction mixture.Reaction times should enough make to react completely carries out, normally from 1h to 24h.
Reactant is fully mixed, to be dissolved in when stirring preferably that diglycollic acid in the solvent or diglycollic acid derivative solution join in batches also is in the amine aqueous solution among the formula II that is dissolved in the solvent, under the condition that heats or do not heat, continue to stir time enough, so that reaction carries out forming fully the desired product in the formula (IV) in reaction mixture.Product can reclaim or with the ordinary method purifying, for example extraction method, chromatography or with traditional method evaporate all or part of solvent and reclaim separate or as residue remaining solid or oil.
Obtain product in the formula V with the compound in the further reduction-type of selective reduction agent (IV).The selective reduction agent can be selected from: choosing wantonly is having under the situation of carboxylic acid or NaBH under the situation of sulfonic acid is being arranged
4, carboxylic acid such as acetic acid, trifluoroacetic acid formic acid; Choose wantonly at the NaBH that has under the situation of carboxylic acid
3CN, carboxylic acid such as acetic acid, propionic acid, trifluoroacetic acid; NaBH
3OCOR
3Or NaBH (COOR
3)
3, R wherein
3Be methyl, trifluoromethyl etc.; Borine such as borine-solvent mixture, solvent wherein is selected from tetrahydrofuran (THF) (H
3B-THF), dimethyl thioether (H
3B-SMe
2, BMS), diethyl ether (H
3B-diethylether); (R
4)
3OBF
4/ NaBH
4, R wherein
4Be methyl, ethyl, propyl group etc.
The solvent that is suitable for using in reduction mutually is inert organic solvents, and it can be selected from: ether such as dioxan (dioxane), tetrahydrofuran (THF), t-butyl methyl ether, diethyl ether, diisopropyl ether, 2-methyltetrahydrofuran; Carboxylic acid such as acetic acid; Halohydrocarbon; Aromatic hydrocarbons.Preferred solvent is THF and dioxan.
Because the relative reactivity of diborane is similar with acid amides to carboxylic acid, preferably protects carboxyl with ester group or acid halo group.Therefore, if borine is used as the selective reduction agent, the R in the compound of preferred formula (IV) is the group except COOH.
Usually, the ratio of reductive agent and formula (IV) compound is from 6: 1 to 1: 1, preferred 3: 1 to 1: 1, and more preferably 1.75: 1 to 1: 1, most preferably 1.2: 1 to 1: 1.
Reaction is generally carried out in the following manner, and the solution of acid amides in solvent with formula (IV) joins in the borine solution under the temperature of room temperature at 0 ℃.The mixture heating up that obtains to the temperature from room temperature to the reaction mixture boiling point, and is kept 0.5h to several hrs so that reaction is finished substantially.
After reaction is finished, adopt ordinary method to separate and purified product, for example extraction and crystallization.Purifying by extraction preferably includes several steps.In the first step extraction, preferably when pH9-12, carry out alkaline extraction., reaction mixture is mixed with water for this reason, use water immiscible solvent halogenation or non-halogenated then, as ethyl acetate, methylene dichloride or toluene extraction.In the extraction of second step, pH preferably is adjusted to pH4-5, is more preferably 4.2-4.8.This step can by use with the first step in identical solvent systems carry out, water immiscible solvent water/halogenation or non-halogenated for example is as ethyl acetate, methylene dichloride or toluene.
If the R group in the formula V product is not OH, just by methods known in the art intermediate (V) is changed into levocetirizine.
According to the present invention, can be according to disclosed method among the present invention or any other currently known methods as formula (II) compound of initial compounds, as 2,225,321, EP 0 617 028, disclosed method prepares among the IN501/MUM/04.
Another aspect of the present invention relates to a kind of new formula (IV) compound,
R wherein is as defined above.The intermediate of formula (IV) can be as the intermediate of preparation preparation levocetirizine.
(2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid is characterized in that its X-ray powder diffraction figure the peak occurs at following place particularly preferably to be R-2-.
Initial compounds (II), (-)-1-[(4-chloro-phenyl-) phenmethyl] piperazine can effective means by the hydrochloride prepared in reaction with R-(-)-4-chlorodiphenyl methylamine (chlorobenzhydryamine) and two (2-haloethyl) amine.Find in this reaction, do not have racemize to take place surprisingly.
Reaction and display is in following reaction formula 1.
Reaction formula 1:
Can use two (2-haloethyl) amine hydrochlorate, X wherein is chlorine, bromine or iodine atom.
Reaction generally is to carry out under the situation that organic bases exists, and organic bases is simultaneously as solvent and hydrogen chloride scavenger.Organic bases can be selected from: primary alkylamine, secondary alkylamine, uncle's alkanamine, and as the n-ethyl diisopropyl amine, triethylamine, diethylamine, the butyl hexahydroaniline, Diisopropylamine, dibutylamine, or heterocyclic amine, as tetramethyleneimine, piperidines, or its alkyl-substituted derivative or their mixture.The mixture of various alkali can mix with arbitrary proportion, preferably uses the mixture of n-ethyl diisopropyl amine and diethylamine, and its volume ratio is 1: 1 to 1: 0.01, most preferably 1: 0.08.
Reaction is carried out to the temperature of the backflow point of reaction mixture at 50 ℃ usually, preferably 80 ℃ of backflow points to reaction mixture.Reaction can continue 2 hours to 24 hours, preferred 6 to 8 hours.
Two kinds of reactants, namely-(-)-molar ratio of 4-chloro benzhydrylamine (cholobenzhydryamine) and two (2-haloethyl) amine hydrochlorate can be a variation in 1: 1 to 1: 2, and preferred 1: 1.4 to 1: 1.7.It is found that, use excessive two (2-haloethyl) amine hydrochlorate can improve productive rate.
Usually, after reaction is finished, reaction mixture is concentrated.In residue, add water and ethyl acetate.Adjust the pH value to alkalescence with sodium hydroxide solution, use the chromatographic column purifying then.The pH value of the reaction mixture before the purifying should be greater than 9, preferably between 10 to 11.
Preferably; reaction is under the situation that has diethylamine to exist; by general-(-)-4-chlorodiphenyl methylamine and two (2-haloethyl) amine hydrochlorate in the n-ethyl diisopropyl amine; the back flow reaction several hrs carries out, can be by containing water and organic solvent, as ethyl acetate; extract in the solvent systems of chloroform, methylene dichloride and separate, so that thick (-)-1-[(4-chloro-phenyl-to be provided) phenmethyl]-the 4-[(4-tolyl) alkylsulfonyl] piperazine.The product that obtains can be further purified by the separation method that uses silica gel chromatography, and final from hexane crystallization obtain HPLC purity and be higher than 98% product.
The intermediate of the formula II that obtains by the method among the present invention can by any currently known methods change into levocetirizine with and pharmacy acceptable salt randomly.
According to another aspect, the present invention relates to the pure levocetirizine of a kind of preparation or its pharmacy acceptable salt method, it comprises the steps:
A) in protophobic solvent with the intermediate of formula II
With intermediate or its reactant salt of formula III,
X wherein is defined as :-C (=O)-CH
2-O-CH
2-R, wherein R is the group that COOH maybe can be converted into COOH, or-CH
2CH
2-O-CH
2-CN,
B) intermediate III or its salt are converted into thick levocetirizine or its pharmacy acceptable salt,
C) thick levocetirizine or its pharmacy acceptable salt purifying are obtained pure levocetirizine or its pharmacy acceptable salt, randomly, by forming solvate.
Preferably, radicals R is that top those define in a first aspect of the present invention.
Preferably, pure levocetirizine or its pharmacy acceptable salt contain the intermediate that is less than 0.2% formula II.
Just now the X group in the method for describing hereinbefore be-C (=O)-CH
2-O-CH
2-R, step (b) generally comprises with aforesaid selective reduction agent and reduces described group.
Levocetirizine, randomly with pharmacy acceptable salt, as the form of dihydrochloride, also can be by with reaction shown in the reaction formula 2 being the method preparation of feature.
Reaction formula 2:
At acid scavenging agent, under the condition that exists as alkaline carbonate, randomly, under the condition that has the small amount of alkali metal iodide, make (-)-1-[(4-chloro-phenyl-of formula II) phenmethyl]-4-piperazine and 2-(2-chloroethoxy) acetonitrile reaction be with the raising speed of response.This reaction can be carried out in inert solvent, as alcohol, and as ethanol, propyl carbinol, aromatic hydrocarbons, as toluene, dimethylbenzene, halohydrocarbon, as methylene dichloride, nitrile is as acetonitrile.Preferred especially protophobic solvent.Most preferred solvent is acetonitrile.By the present invention, we find can be by with the product of the isolated in form formula III a of its hydrochloride [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group]-acetonitrile and improve the productive rate of this reaction greatly.The dihydrochloride form preferably makes in the following manner: introduce the HCl of gaseous state in the reaction mixture, or add the gaseous state HCl solution that is dissolved in reaction solvent in this mixture, reach 3 to 0.5 up to the pH value, preferably be lower than 1, most preferably 1.The productive rate that this reaction of carrying out according to the present invention obtains surpasses 90%, preferred 95%.
This reaction can't cause racemization, if therefore use optically pure initial compounds, its optical purity will remain unchanged.Just in this point, find that protophobic solvent has significant advantage.
Further aim of the present invention is prepared in accordance with the method for the present invention [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group]-polymorphic forms of the dihydrochloride of acetonitrile, and it is characterized in that: X-ray powder diffraction figure the peak occurs at following place.
It is found that [the 2-[4-[(4-chloro-phenyl-) phenmethyl] of formula III a-1-piperazinyl] oxyethyl group]-purity of acetonitrile can be improved by flooding in alcohol or ketone to the boiling temperature at 0 ℃.The alcohol that is used for dipping can be C
1-C
5Alcohol, particular methanol and ethanol.The ketone that is used for dipping can be acetone, methyl ethyl ketone (MEK) or mibk.Generally speaking, finish the product chromatographic purity of dipping acquisition afterwards greater than 98%, single foreign matter content of planting is lower than 0.2%.
If use 2-(2-chloroethoxy) acetonitrile that surpasses molar weight, this reaction has better productive rate.Optimum molar ratio between the intermediate of formula II and 2-(2-chloroethoxy) acetonitrile can be a variation in 1: 1.1 to 1: 4, preferably from 1: 1.5 to 1: 3, most preferably from 1: 1.5 to 1: 2.
This reaction is under the temperature between 60 to 200 ℃, preferably under the temperature between 80 to 120 ℃, carries out as shown in the reaction formula 2 about 7 to 24 hours.
2-(2-chloroethoxy) acetonitrile can make with any known mode in this area, as Suomen Kemistilehti (1944), and 17B, 17-19, Croatica Chemica Acta (1986), 59 (19), 307-11.The HPLC purity that participates in 2-(2-chloroethoxy) acetonitrile of reaction should be 95% at least.
The nitrile intermediate of formula III a is by alkali or acid hydrolysis, or passes through enzymatic hydrolysis.
When alkaline hydrolysis, being selected from water or alcohol, as methyl alcohol, ethanol, propyl alcohol has mineral alkali in the solvent of 2-propyl alcohol or its mixture, under the situation about existing as alkali metal hydroxide the nitrile intermediate of formula III a is heated to 20 ℃ to 110 ℃ temperature, preferably is heated to 60 to 90 ℃.The preferred use as alkali-metal oxyhydroxide such as KOH or NaOH with as the methyl alcohol of solvent or the mixture of ethanol.Most preferably, in methanol/water mixture, use KOH.
We find that at work excessive alkali metal hydroxide can cause racemization.Therefore, the optimum weight ratio of the intermediate of alkali metal hydroxide and formula III a is from 1: 1 to 4: 1, preferred 1.5: 1 to 3: 1.
The levocetirizine that forms is present in the reaction mixture with the form of an alkali metal salt,, by mineral acid, preferred hydrochloric acid acidifying mixture makes acid therefrom dissociate out.Then, use organic solvent, as methylene dichloride, toluene, ethyl acetate, preferred methylene dichloride extracts levocetirizine acid.We find that the pH value of aqueous solution before extracting can influence extraction yield.So it should remain between 4 and 5, preferably between 4.2 and 4.8.
After extraction is finished, can levocetirizine be converted into the dihydrochloride of levocetirizine by HCl gas is introduced dichloromethane extract.In order to obtain better productive rate and better product quality, can evaporate methylene dichloride, and residue is dissolved in the another kind of solvent, as alcohol, aromatic hydrocarbons, ester or ketone.Preferred solvent is toluene, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate and acetone.Most preferred solvent is acetone.In order to make its precipitation, introduce this solution with hydrochloric acid gas or with the saturated acetone of hydrochloric acid gas.
Usually, the method for disclosed basic hydrolysis can obtain to be higher than 90% productive rate, and HPLC (area) purity that obtains product is higher than 98% or even be higher than 99%.
When acidic hydrolysis, under the condition that has the mineral acid example hydrochloric acid, preferably in aqueous medium, the intermediate of formula III a is heated to 60 ℃ between the reflux temperature of reaction mixture.Use organic solvent then, as methylene dichloride, toluene, ethyl acetate is preferably used methylene dichloride, and levocetirizine acid is extracted from reaction mixture.
Then by free levocetirizine acid is dissolved in the ketone solvent, and the HCl that introduces gaseous state forms reaction mixture and/or by introduce the HCl gas solution in reaction solvent, reach 0.5 to 3 up to the pH value, preferred 0.5 to 1, free levocetirizine acid is converted into dihydrochloride.Ketone solvent can be selected from acetone, butanone, valerone, diisopropyl ketone, preferred acetone.
The salt that obtains can exist with disclosed polycrystalline form among WO2004/050647 or the IPCOM 000146553D.
The dihydrochloride of levocetirizine can form solvent/anti-solvent mixture by recrystallization.Can use carboxylic acid or water as solvent with as ketone, ester or ether are as anti-solvent.Preferred solvent is acetic acid or water, and preferred anti-solvent is acetone, ethyl acetate, isopropyl acetate or butylacetate.Most preferably, use acetic acid as solvent, use acetone as anti-solvent.The degree of purity of production that obtains is higher than 99.5%.The X-ray powder diffraction pattern of the acetic acid solvent thing of thus obtained levocetirizine dihydrochloride the peak occurs at following place:
The size of control levocetirizine dihydrochloride particle is very important in its preparation process.The mean particle size that makes particle is 5 to 200 μ m, preferred 20 to 150 μ m.If without stirring, the crystallization in the organic solvent also may produce bigger particle, and for example, mean diameter surpasses 200 μ m, its in being applied to pharmaceutical cpd before, need to handle through the method for grinding or any other can reduce granularity.By grinding, can produce mean diameter less than the particle of 3 μ m.Based on this purpose, the air spray runner milling, ball mill or hammer runner milling all are normally used grinding equipments, still, the mean particle size of only controlling particle is not enough, also needs to control size-grade distribution.
Mean particle size and size-grade distribution are very important for guaranteeing that processing method is suitable for industrial preparation, that is, if it is without compressing tablet/compression after the preparation press sheet mixture, can not cause the composition of press sheet mixture to occur separating.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of acetic acid solvent thing of the dihydrochloride of levocetirizine;
Fig. 2 is the FT-IR spectrogram of acetic acid solvent thing of the dihydrochloride of levocetirizine;
Fig. 3 is the DSC Thermogram of acetic acid solvent thing of the dihydrochloride of levocetirizine.
Fig. 4 is [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group]-the X-ray powder diffraction figure of the dihydrochloride of acetonitrile;
Fig. 5 is [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group]-the FT-IR spectrogram of the dihydrochloride of acetonitrile;
Fig. 6 is [2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl] oxyethyl group]-the DSC Thermogram of the dihydrochloride of acetonitrile;
Fig. 7 is R-2-(2-(the X-ray powder diffraction figure of 4-((4-chloro-phenyl-) (phenmethyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid;
Fig. 8 is R-2-(2-(the FT-IR spectrogram of 4-((4-chloro-phenyl-) (phenmethyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid;
Fig. 9 is R-2-(2-(the DSC Thermogram of 4-((4-chloro-phenyl-) (phenmethyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid.
Embodiment
Now by the following embodiment that does not play the restriction effect the present invention is described.
(-)-1-[(4-chloro-phenyl-) phenmethyl]-the 4-piperazine
Get the N-ethyl diisopropyl amine of 300mL, 30g-(-)-4-chloro benzhydrylamine (chlorobenzhydryamine) (Clemo, J.Chem.Soc. (1939) 1958-1969; Ingold, J.Chem.Soc. (1933) 1493-1505) and the hydrochloride of two (2-chloroethyl) amine of 42g drop into reaction vessel, stirring heating also refluxed 3 hours.Be cooled to 60 ℃, add the diethylamine of 24mL, and then mixture heating up is continued 5 hours to reflux temperature.After reaction was finished, vacuum evaporating solvent added water the mixture (1: 1) with ethyl acetate, and the sodium hydroxide solution with 30% is regulated the pH value of water to 10-11.Separate organic phase and aqueous phase extracted with ethyl acetate.Organic phase with the pure water washing merges makes the organic phase decolouring with gac, and vacuum-evaporation filtrate.Use silica gel chromatography, by coming separating impurity with ethyl acetate/ethanol (7: 1) and/or ethyl acetate/ethanol afterwards/ammoniacal liquor (7: 1: 0.25) wash-out.Collect elutriant and vacuum evaporating solvent, and obtain the oiliness residue, it further is dissolved in the hexane, use activated carbon treatment, heating is also filtered.Filtrate is cooled to 10 ℃ kept 1 hour, collecting precipitation and at 40-45 ℃ of following vacuum-drying 5-8 hour, to obtain product.HPLC (area) is 98-99%.
Embodiment 2
A) [the 2-[4-[(4-chloro-phenyl-) phenmethyl]-the 1-piperazinyl] oxyethyl group]-the acetonitrile dihydrochloride
The acetonitrile of getting 2400mL drops into reaction vessel, under agitation condition, adds (-)-1-[(4-chloro-phenyl-of 400g successively) phenmethyl]-the 4-piperazine, the Na of 300g
2CO
3, the KI of 20g and the 2-of 300g (2-chloroethoxy) acetonitrile.
Stir also and be warming up to 110-115 ℃ gradually.Kept temperature 20 hours, and after reaction is finished, mixture was cooled to 80-90 ℃, and add the gac of 25g, stirred 20 minutes.Elimination carbon is also with an amount of acetonitrile washing leaching cake.Introduce dry HCl gas to pH value in the filtrate that merges and reach 0.5-1.Continue to stir slurries filtered in 20 minutes then.Use the adequate amount of ethanol washing leaching cake, and descended dry 10 hours at 50-55 ℃, obtain the title product of 520g.
Productive rate is that 95%, HPLC (area) is 95%.[the 2-[4-[(4-chloro-phenyl-) phenmethyl] that obtains-1-piperazinyl] oxyethyl group]-the acetonitrile dihydrochloride in the X-ray powder diffraction pattern under 28.7 ± 0.2 ° of 2 θ about 8.5; 18.5; 19.1; 22.7; 24.9; 25.7; 25.9 located the peak.
B) slightly [the 2-[4-[(4-chloro-phenyl-) phenmethyl]-the 1-piperazinyl] oxyethyl group]-the acetonitrile dihydrochloride
Dipping
[2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazinyl with 10g] oxyethyl group]-the acetonitrile dihydrochloride is suspended in the methyl alcohol of 30mL.Suspension is heated to boiling temperature, and under this temperature, stirred at least 20 minutes.Afterwards, suspension is cooled to 0 ℃ and under this temperature, stirred 1 hour.Leach precipitation, with cold methanol wash and dry.HPLC (area) is 98%.
Embodiment 3
Levocetirizine
[2-[4-[(4-chloro-phenyl-) phenmethyl]-1-piperazine with the methyl alcohol of 3000mL and 300g] oxyethyl group]-the acetonitrile dihydrochloride joins in the reaction vessel, stir the KOH solution that keeps temperature of reaction to be lower than under 40 ℃ the condition making to the pure water of the KOH that wherein adds 600g and 600mL and.Temperature is increased to 70-76 ℃ gradually, and kept 24 hours.After reaction is finished, reaction mixture is cooled to 40-45 ℃, and under reduced pressure methyl alcohol is removed in distillation.Then, add the pure water of 1000mL and the CH of 3000mL
2Cl
2, and temperature is reduced to 20-30 ℃.HCl with 37% regulates the pH value to 4.2-4.8.Separate organic layer, with the CH of 2000mL
2Cl
2Extract water layer twice.
Merge organic phase and use the anhydrous sodium sulfate drying of 200g also to filter in 1 hour.Concentrate organic phase, until obtaining the oiliness residue, it is dissolved in the acetone of 3L.Introduce dry HCl gas in the acetone soln, until the pH value less than 1.Reaction mixture is heated to 60 ℃, and refluxed 20 minutes.It is cooled to 30-35 ℃, filters then, and with the washing with acetone filter cake of 1L.Afterwards, again it was reduced pressure down at 50-55 ℃ (0.08～-0.1MPa) dry 8 hours.Obtain the levocetirizine dihydrochloride of 280g.
Embodiment 4
R-2-(2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid
A selects
2g R-1-((4-chloro-phenyl-) (phenyl) methyl) piperazine and 0.88g anhydride diethylene glycol are dissolved in the 107mL acetonitrile.With reaction mixture refluxed 12h.After reaction is finished, solvent is steamed, and the residue that obtains is dissolved into added 2mL, in the water of the NaOH of 1M, add the methylene dichloride of 10mL again.Stirred suspension 20 minutes is also isolated organic phase.Add the methylene dichloride of the 10mL of another part to aqueous phase, regulate the pH to 4.5 of suspension to 5.With twice of the dichloromethane extraction water of 2x10mL.Collect organic phase, use anhydrous sodium sulfate drying, filter and evaporation concentration.The crude product that obtains can use in next step and need not be further purified.
B selects
R-1-((4-chloro-phenyl-) (phenyl) methyl) piperazine of 2g and the anhydride diethylene glycol of 0.88g are dissolved in the methyl-sulphoxide of 10ml.The Tetrabutyl amonium bromide that adds 20ml in the solution.With solution restir 10 hours, finish until reaction.With the water diluting soln of 67ml, and the isopropyl acetate of adding 15ml.Make to be separated, water layer extracts with isopropyl acetate again.Organic layer mixes with demineralised water (40ml), and with the NaOH of the 2M pH regulator to 10 with suspension.Layer is separated, and add the isopropyl acetate of 40ml to aqueous phase.Regulate the pH to 3.5 of suspension.Layer is separated, and water is extracted twice with isopropyl acetate again.The flushing of organic phase water also is evaporated to drying.2.5g product (HPLC (area) is 98.5%) crystallize out, at 50 ℃ of these products of following vacuum-drying.
Levocetirizine dihydrochloride
Oily product in the preceding step is dissolved in the dioxan of 20mL, adds the NaBH of 1.3g in the solution
4Suspension is cooled to 10 ℃, and adds the acetic acid that 2.1g is dissolved in the 7mL dioxan simultaneously intensively stirred.With reaction mixture refluxed 2 hours, and cool to room temperature, after leaching solid matter.Evaporated filtrate adds the water of 20mL and regulates pH to 5 in residue.With the dichloromethane extraction water of 10mL three times.Merge organic extraction and use anhydrous sodium sulfate drying, and solvent is removed in decompression.The thick levocetirizine that obtains is dissolved in the acetone of 10mL, and adds 2mL, 36% HCl stirred 1 hour.Leach product and dry.
Embodiment 6
(2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-base-2-oxo oxyethyl group) acetic acid product is dissolved in the tetrahydrofuran (THF) of 10ml under 0 ℃ with 1g R-2-.The oxalyl chloride that dropwise adds 0.23ml in the intensively stirred while.After half an hour, when acid was finished to the conversion of chloride of acid, (10M was with BH to add 0.8ml dimethylsulphide borane complexes in three batches
3Calculate).After reaction is finished, reaction mixture is poured in the water (250ml) into restir half an hour.Add the ethyl acetate of 100ml in the suspension, regulate pH to 10, and be separated.Add the methyl chloride of 100ml to aqueous phase, transfer pH to 4.2 with concentrating hydrochloric acid, and be separated: water flushing organic layer, with dried over sodium sulfate and be evaporated to drying.The oiliness residue is dissolved in the acetone of 30ml, introduce HCl gas until the pH value less than 1.Reaction mixture is heated to 60 ℃, and refluxed 20 minutes.It is cooled to 30-35 ℃, filters then and with 20ml washing with acetone filter cake.Again it was reduced pressure down at 50-55 ℃ (0.08～-0.1MPa) dry 8 hours.Obtain the levocetirizine dihydrochloride of 720mg.
Embodiment 7
The recrystallize of levocetirizine dihydrochloride
The levocetirizine dihydrochloride that 75g is contained 0.17% formula II compound under 80 ℃ is dissolved in the acetic acid of 225mL.Solution is cooled to 50 ℃, and under this temperature, in 1.5 hours, adds the acetone of 562mL gradually.Add after the acetone, suspension is cooled to 0 ℃, and under this temperature, stirred at least 1 hour.The product levocetirizine dihydrochloride is leached.Under 50 ℃, product is carried out vacuum-drying.Obtain the product of 58g, its HPLC purity (area) is 99.9%.The content of formula II compound is lower than detection limit, is 0.005%.
Analytical procedure: HPLC; Post RP18; Phosphoric acid buffer (pH 7), acetonitrile/methanol; Gradient method; UV-detector, 230nm.
The preparation of the acetic acid solvent thing of levocetirizine dihydrochloride
The levocetirizine dihydrochloride of 50g is suspended in the acetic acid of 100mL, and is heated to substance dissolves.Then, under agitation it slowly being cooled to 50 ℃, until occur suspending, under this temperature, adding the acetone of 100mL afterwards in the suspension.Acetone is cooled to room temperature with suspension after adding, and filters out precipitation and uses the washing with acetone product.With vacuum drier at 50 ℃ of following desciccates.Obtain the product of 43.1g, its HPLC purity (area) is 99.9%.
Analytical procedure: HPLC; Post RP18; Phosphoric acid buffer (pH 7), acetonitrile/methanol; Gradient method; UV-detector, 230nm.
Embodiment 9
Preparation levocetirizine disalt from the acetic acid solvent thing of levocetirizine dihydrochloride
Hydrochlorate
The solvate of 10g levocetirizine dihydrochloride and acetic acid is suspended in the acetone of 60mL, at room temperature stirred 1 hour.After 1 hour, filtering suspension liquid is also used the washing with acetone filter cake, and is dry in vacuum drier.The weight of desciccate is 8.9g.HPLC purity (area) is 99.9%.
Claims (13)
1. method for preparing levocetirizine or its pharmacy acceptable salt comprises step:
I) make the intermediate of formula II
With structural formula be
Diglycollic acid derivative or X-CO-CH
2-O-CH
2-R reacts,
Wherein, X is OH or halogen; And
R is COX, and X wherein is halogen; COOM, M wherein are basic metal or alkaline-earth metal or N (R
1)
4COOR
1, or CN, R wherein
1Be independently selected from H, C
1-C
6Alkyl, aryl;
With the intermediate of acquisition formula IV,
R definition wherein is the same;
Ii) use the intermediate of selective reduction agent reduction-type (IV), obtain the product of formula V,
R definition wherein is the same;
If iii) R is not COOH, then intermediate (V) is converted into levocetirizine,
Iv) randomly, levocetirizine is converted into its pharmacy acceptable salt.
2. according to the process of claim 1 wherein reactions steps i) in aprotic solvent, carry out.
3. method according to claim 1 and 2 also comprises the steps:
V) purifying levocetirizine or its pharmacy acceptable salt to obtain pure levocetirizine or its pharmacy acceptable salt, randomly pass through to form solvate.
4. method according to claim 3, the intermediate of the formula II that pure levocetirizine wherein or its pharmacy acceptable salt contain is less than 0.2%.
5. method according to claim 2, aprotic solvent wherein is acetonitrile.
6. method according to claim 1 and 2, wherein formula (IV) intermediate that at first prepares in step (i) is that wherein R is the intermediate (IV) of COOH, and wherein step (i) also comprises and is converted into described intermediate (IV) wherein that R is the intermediate (IV) that can be converted into the group of COOH.
7. according to claim 1 or 6 described methods, selective reduction agent wherein is selected from: NaBH
4, choose wantonly and exist under the situation of carboxylic acid, or under the situation that sulfonic acid exists; NaBH
3CN chooses wantonly and exists under the situation of carboxylic acid; NaBH
3OCOR
3Or NaBH (COOR
3)
3, R wherein
3Be methyl or trifluoromethyl; Borine; (R
4)
3OBF
4/ NaBH
4, R wherein
4Be methyl, ethyl or propyl group.
8. method according to claim 7, selective reduction agent wherein is NaBH
4, be selected from existence under the situation of carboxylic acid of acetic acid, trifluoroacetic acid and formic acid.
9. method according to claim 7, selective reduction agent wherein is NaBH
3CN is selected from existence under the situation of carboxylic acid of acetic acid, propionic acid and trifluoroacetic acid.
10. method according to claim 7, selective reduction agent wherein is borine-solvent mixture, solvent wherein is selected from tetrahydrofuran (THF), dimethyl thioether and diethyl ether.
11. the compound of a formula (IV)
Described in the definition such as claim 1 of R wherein.
12. according to the compound of claim 11, R wherein is COOH, and it is characterized in that its X-ray powder diffraction pattern is under ° 2 θ about 7.1; 14.2; 16.5; 18.2; 19.2; 19.9; 21.1; With 23.1 places the peak is arranged.
13. the application of the compound of claim 11 or 12 in the preparation levocetirizine.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200700055A SI22489A (en) | 2007-03-12 | 2007-03-12 | New procedure for preparation of levocetirizine and its intermediates |
| SIP-200700055 | 2007-03-12 | ||
| SIP200700055 | 2007-03-12 | ||
| SIP200700191 | 2007-07-30 | ||
| SIP-200700191 | 2007-07-30 | ||
| SI200700191A SI22586A (en) | 2007-07-30 | 2007-07-30 | New procedure for preparation of levocetirizine and its intermediates |
| PCT/EP2008/052970 WO2008110586A2 (en) | 2007-03-12 | 2008-03-12 | New process for the preparation of levocetirizine and intermediates thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101657437A CN101657437A (en) | 2010-02-24 |
| CN101657437B true CN101657437B (en) | 2013-09-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200880008231.XA Expired - Fee Related CN101657437B (en) | 2007-03-12 | 2008-03-12 | New procedure for preparation of levocetirizine and its intermediates |
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| Country | Link |
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| SI (1) | SI22489A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044356A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | New method for synthesizing levocetirizine and key intermediate thereof |
| CN103044355A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | Key intermediate for synthesizing levocetirizine and preparation method thereof |
| CN110845442B (en) * | 2019-12-09 | 2023-06-23 | 湖北美林药业有限公司 | Levocetirizine hydrochloride compound and preparation method thereof |
| CN111205247B (en) * | 2020-04-22 | 2020-08-14 | 湖南九典宏阳制药有限公司 | Preparation method of levocetirizine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2225321A (en) * | 1988-11-23 | 1990-05-30 | Ucb Sa | Process for preparation of a 1-piperazine-ethoxyacetic acid |
| WO2001029016A1 (en) * | 1999-10-20 | 2001-04-26 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
-
2007
- 2007-03-12 SI SI200700055A patent/SI22489A/en not_active IP Right Cessation
-
2008
- 2008-03-12 CN CN200880008231.XA patent/CN101657437B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2225321A (en) * | 1988-11-23 | 1990-05-30 | Ucb Sa | Process for preparation of a 1-piperazine-ethoxyacetic acid |
| WO2001029016A1 (en) * | 1999-10-20 | 2001-04-26 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101657437A (en) | 2010-02-24 |
| SI22489A (en) | 2008-10-31 |
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