CN103214453A - Separation and purification method of zuclopenthixol - Google Patents

Separation and purification method of zuclopenthixol Download PDF

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Publication number
CN103214453A
CN103214453A CN2013101253826A CN201310125382A CN103214453A CN 103214453 A CN103214453 A CN 103214453A CN 2013101253826 A CN2013101253826 A CN 2013101253826A CN 201310125382 A CN201310125382 A CN 201310125382A CN 103214453 A CN103214453 A CN 103214453A
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zuclopenthixol
acid
organic solvent
isomer
ether
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赵金召
张梅
彭学东
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ZHANGJIAGANG WEISHENG BIOLOGICAL PHARMACEUTICAL CO Ltd
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ZHANGJIAGANG WEISHENG BIOLOGICAL PHARMACEUTICAL CO Ltd
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Abstract

The invention relates to an improved method for separating and purifying zuclopenthixol. The method comprises the specific following steps of: dissolving a mixture of an alpha-isomer (i.e. zuclopenthixol) and a beta isomer of 2-chloro-9-[3'-(N'-2-ethoxy piperazine-N)-allyl]-thiaxanthene into an organic solvent, adding an active benzoic acid derivative, and esterifying with the mixture so as to remove the beta-isomer; subsequently carrying out alkali hydrolysis on the residual substances so as to obtain relatively pure zuclopenthixol; and further recrystallizing by using organic solvent so as to obtain zuclopenthixol which meets the United States pharmacopeia standards. In addition, the invention further relates to preparation of a carboxylic ester and pharmaceutically acceptable acid salt of zuclopenthixol. The method has the advantages that the content of zuclopenthixol is improved by optimizing the reaction of different steps when the raw material, namely, alpha/beta-chlorine thiaxanthene, is prepared, a novel and effective method for purifying a single isomer is provided, and high-yield and high-purity zuclopenthixol is obtained by using the method.

Description

The separation purification method of zuclopenthixol
Technical field
The present invention relates to a kind of method of improved separation antipsychotic drug diuril ton isomer, be specifically related to the method for its alpha-isomer zuclopenthixol of purifying and carboxylicesters thereof, belong to the pharmaceutical chemistry technical field.
Background technology
Diuril ton (Clopenthixol), chemistry 2-chloro-9-[3 ' by name-(N '-the 2-hydroxyethyl piperazine-N)-allyl group]-thioxanthene, this product is a kind of Thiaxanthene derivative, has significant antipsycholic action and special sedative effect, is particularly useful for the schizophrenia patient.Its activeconstituents is its alpha-isomer, i.e. zuclopenthixol (structural formula is seen Fig. 1); Have the stereotypy effect that anti-Ritalin causes, and the effect of anti-Apomorphine is arranged, this product energy rejection condition avoiding reaction and catalepsy are stronger 10 times than chlorpromazine.A little less than the cholinolytic effect, and antihistamine effect is strong.Zuclopenthixol is applicable to that treatment has psychosis, class Paranoia-illusion type schizophrenia, hebephrenia, the manic and anxiety periodic psychosis of anxiety and illusion symptom; The uneasiness that mental element causes, excitement, psychiatric disorder, the encephalatrophy process, post-traumatic psychosis, the proverb of trembling are absurd etc.Be particularly useful for elderly patients.
Recorded the quality standard of zuclopenthixol sheet, zuclopenthixol dihydrochloride, Ciatyl Depot and zuclopenthixol acetic ester etc. in the British Pharmacopoeia, wherein the zuclopenthixol quality standard has stipulated that its content should be 95%-105%.But in actual industrial production, guarantee that zuclopenthixol reaches pharmaceutically acceptable purity, and β-isomer (structural formula is seen Fig. 2) content being limited in 5%, is a very thing of difficulty.
About the preparation method of zuclopenthixol, mainly containing of bibliographical information is following several:
As if the general separation of having described diuril ton isomer can be undertaken by the fractional crystallization of dihydrochloride among the BE585338A of nineteen fifty-nine application, and still, this separation method yield is extremely low, and complicated operation does not also have actual industrial use.
Described the preparation method of diuril ton isomer mixture among the US3116291, wherein alpha-isomer is that the content of zuclopenthixol is 30%-35%.Obtain purer zuclopenthixol by diuril ton alkali being carried out fractional separation in the literary composition with ether organic solvent, but, instructed crystallization to come the purifying zuclopenthixol can not obtain good result, especially in isomer mixture, had under the situation of a large amount of impurity existence by diuril ton alkali.
Summary of the invention
The object of the invention provides the method for a kind of improved separation, purifying diuril ton isomer, relates to a kind of method for preparing pure state zuclopenthixol and carboxylicesters thereof more specifically.
The present invention finds pleasantly surprisedly, and the crystallization of the certain esters by the diuril ton comes the separating isomerism body obtaining optimal results aspect productive rate and the purity.
In fact, have been found that some ester derivatives of diuril ton have been formed the intermediate that is used in fractional crystallization especially, described ester derivative obtains pure zuclopenthixol ester easily.Hydrolysis or reduction reaction by routine can obtain pure zuclopenthixol again.
Therefore, preparation and purifying 2-chloro-9-[3 '-(N '-2-hydroxyethyl piperazine-N)-allyl group]-method of the alpha-isomer of thioxanthene is characterized in that:
(a) make raw material α/β-diuril ton and active benzoic acid derivative in organic solvent, carry out benzoyl by reacting by heating;
(b) make reaction mixture cooling, precipitation separation from the mother liquor that contains α-diuril ton benzoic ether;
(c) mother liquor in the above-mentioned steps is heated, and add hydrochloric acid;
(d) make the reaction mixture cooling, to reclaim the hydrochloride of sedimentary thus zuclopenthixol benzoic ether;
(e) ester hydrolysis is to obtain purer zuclopenthixol;
(f) with the further crystallization of organic solvent, obtain qualified zuclopenthixol.
Raw material α/β-diuril the ton that uses in step (a) can prepare (the building-up reactions formula is seen Fig. 3) by 2-chloro-9-(allyl group) thioxanthene and N-(2-hydroxyethyl) piperazine generation condensation reaction, or prepares by other method.Wherein the content of α-diuril ton is between 37%-50%.
The used active benzoic acid derivative of step (a) is phenylformic acid, benzoyl oxide, Benzoyl chloride, benzoyl bromide, 2-chloro-benzoic acid or Chlorodracylic acid etc.; The mol ratio of benzoic acid derivative and raw material is 1: 1-1.2: 1.
The used organic solvent of step (a) is selected from a kind of in ether, ethyl acetate, methylene dichloride, chloroform, acetone, tetrahydrofuran (THF), toluene, the dimethylbenzene or their mixture.
Reacting by heating is meant that all reactants all are dissolved in the organic solvent by the mode of heating in the step (a), temperature of reaction be 40 ℃ to reflux temperature, preferred temperature is 70 ℃.
Heating temperature is advisable with 40 ℃-50 ℃ in the step (c); The hydrochloric acid content that adds roughly be half of raw material α/β-diuril ton molar weight for best, for example, every mole of raw material adds the hydrochloric acid that the 0.4-0.6 mole should be arranged.
Normally quite pure in the step (d) as the separated zuclopenthixol benzoic ether of hydrochloride.
The hydrolysis catalyst system therefor is mineral alkali or organic bases in the step (e); Described mineral alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, lithium hydroxide, sodium hydride or potassium hydride KH etc.
The used organic solvent of step (f) is selected from methyl alcohol, ethanol, propyl alcohol, acetone, ether, ethyl acetate, sherwood oil, hexanaphthene, normal hexane or their mixture.
The purity of step (f) gained zuclopenthixol meets the requirement of British Pharmacopoeia (British Pharmacopoeia) to these product greater than 99%.
As required, can by simple esterification the pure product zuclopenthixol of gained be changed into again its carboxylicesters according to known technology.
Therefore, according to a further aspect in the invention, prepare the method for zuclopenthixol carboxylicesters, comprise above-mentioned steps (a) to (f), and then carry out following steps:
(g) with the pure zuclopenthixol of gained in organic solvent, with carboxylic acid or derivatives thereof reacting by heating.
Used organic solvent is selected from a kind of in ether, ethyl acetate, methylene dichloride, chloroform, acetone, tetrahydrofuran (THF), toluene, the dimethylbenzene or their mixture in the step (g).
Used carboxylic acid and derivative thereof are aliphatic acid in the step (g), as, acetate, propionic acid, isopropyl acid, valeric acid, caproic acid, enanthic acid, capric acid, palmitinic acid or diacetyl oxide, decanoyl chloride etc.If carry out step (g), then obtain the hydrochloride of Ciatyl Depot with decanoyl chloride.
Have and experiment showed, that the zuclopenthixol after the esterification can prolong the intravital working lipe the people; The hydrochlorate of acceptable zuclopenthixol of pharmacy and ester thereof has: hydrochloride, bromate, vitriol, phosphoric acid salt, Citrate trianion, tartrate, bitartrate, maleate or salicylate.
Advantage of the present invention is: preparation raw material α/β-diuril ton hour, improved the content of α-diuril ton (being zuclopenthixol) in the raw material by optimizing each step reaction; The method of a kind of novelty and effective purifying individual isomer is provided, has obtained higher yields and highly purified zuclopenthixol by this method.
Following example will specify content of the present invention, but content of the present invention not only is confined to the following examples.
Description of drawings
Fig. 1 is the structural formula of zuclopenthixol.
Fig. 2 be 2-chloro-9-[3 '-(N '-2-hydroxyethyl piperazine-N)-allyl group]-structural formula of thioxanthene β-isomer.
Fig. 3 is the building-up reactions formula of zuclopenthixol.
Embodiment
Embodiment 1: the preparation of diuril ton base
1) preparation of 2-chloro-9-allyl group-9-thioxanthene alcohol
100.00g (0.405mol) 2-chloro-9-thioxanthone is dissolved in the 600mL tetrahydrofuran (THF), 20 ℃ of-30 ℃ of stirrings, add magnesium powder 26g then, iodine 1g, splash into chlorallylene 65g (0.855mol), 40 ℃-50 ℃ are reacted 2h down, and the cooling back drips 20% sodium chloride aqueous solution 1000ml in reaction solution, stir 10min, filter insolubles, use dichloromethane extraction then 2 times, each 500ml, merge organic phase, water 500ml washing is told organic layer, dry after-filtration, filtrate is concentrated except that desolvating, obtain 105.40g2-chloro-9-allyl group-9-thioxanthene alcohol.
2) preparation of 2-chloro-9-(2-propenylidene) thioxanthene
100.00g (0.346mol) 2-chloro-9-allyl group-9-thioxanthene alcohol is dissolved in the 100ml toluene, solution is heated to 40 ℃, the Acetyl Chloride 98Min. of 1.34g (0.017mol) is dissolved in the diacetyl oxide of 41.19g (0.403mol) and drops in the above-mentioned solution, temperature is controlled at about 40 ℃, dropwise, it is complete until the TLC monitoring reaction that heating makes temperature of reaction rise to 50 ℃ of-55 ℃ of reactions, and concentrating under reduced pressure steams solvent, obtains 94.01g2-chloro-9-(2-propenylidene) thioxanthene.
3) preparation of clopenthixol base
N-(2-hydroxyethyl) piperazine of getting 90.00g (0.332mol) 2-chloro-9-(2-propenylidene) thioxanthene and 215.21g (1.65mol) adds in the 1L four-hole boiling flask, stirs and is warming up to 100 ℃ of reactions, and TLC monitors to reacting completely.Vacuum oil pump concentrating under reduced pressure excessive N-(2-hydroxyethyl) piperazine, temperature is controlled at 100 ℃-135 ℃, and oil pump vacuum tightness is at 0.2-1mmHg.Distillation finishes, and adds the benzene of 400ml and the water of 100ml in gained oily matter, and 70 ℃ are stirred 15min, and separatory is used the water washing organic phase of 100ml again, and simultaneous temperature is controlled at 60 ℃-70 ℃, separatory; With organic phase concentrate resistates.This resistates is dissolved in the 300ml methylene dichloride, after add 10% hydrochloric acid soln and transfer pH to 2-3, stirring 10min, separatory, water discard dichloromethane extraction liquid with the dichloromethane extraction of 150ml; Above-mentioned water adds ammoniacal liquor and regulates pH=9-10, extract with methylene dichloride (300ml * 2) after stirring 10min, merge organic phase, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression concentrate 109.32g diuril ton base, isomer proportion α/β is that 45/55 (the HPLC area normalization method: analytical column is 4.6 * 250mmAgilent C18 post, moving phase is acetonitrile: methyl alcohol: phosphoric acid buffer=20: 30: 50, flow velocity are 1mL/min; With this understanding, the retention time of zuclopenthixol is 12min, and the retention time of β-isomer is 16min).
Embodiment 2: the preparation of zuclopenthixol Chlorodracylic acid ester 2HCl
100.00g (0.250mol) α/β-diuril ton is dissolved in the ethyl acetate of 500ml, under 40 ℃ of conditions, drips the 100ml ethyl acetate that is dissolved with 52.48g (0.30mol) parachlorobenzoyl chloride, dropwise the back back flow reaction, complete until the TLC monitoring reaction.Remove the 300ml solvent under reduced pressure, be cooled to 4 ℃, remove by filter precipitation.Mother liquor is heated to 40 ℃, drips the concentrated hydrochloric acid aqueous solution of 12.50g (0.125mol) 37%, react about 1h after, cool off, have solid to separate out, filter 56.27g zuclopenthixol Chlorodracylic acid ester 2HCl.Purity (HPLC is the same) is 97.11%, and productive rate is 36.82%.
Embodiment 3: the preparation of zuclopenthixol
2HCl is dissolved in the methanol aqueous solution of 300ml80% with 45.25g (0.074mol) zuclopenthixol Chlorodracylic acid ester, adds the potassium hydroxide of 16.83mol (0.30mol) then.With mixture heating up to 50 ℃, insulation reaction 1h.Underpressure distillation removes and desolvates, and with toluene (200ml * 2) and water extraction, merges organic phase, and concentrating under reduced pressure is removed toluene; Residue obtainedly carry out recrystallization with hexanaphthene, the 25.51g dried crystals.Purity is 99.7%, and productive rate is 86.17%. 1H?NMR(CDCl 3,400MHz),δ:7.10-7.46(7H,m),5.98(1H,t),3.41(2H,t),2.46-2.52(14H,m)。
Embodiment 4: the preparation of Ciatyl Depot 2HCl
The zuclopenthixol of 50.00g (0.125mol) is dissolved in the methylene dichloride of 500ml, and to wherein dripping 28.60g (0.150mol) decanoyl chloride, back flow reaction is complete to the TLC monitoring reaction after dropwising under the room temperature.Underpressure distillation removes and desolvates, and adds the ethyl acetate of 300ml in residue, drips the ethyl acetate solution that contains hydrogenchloride again, is transferred to 3-4 until pH.After the cooling, filter, vacuum-drying gets 70.63g Ciatyl Depot 2HCl.Productive rate is 90.12%.
Embodiment 5: the preparation of Ciatyl Depot
The Ciatyl Depot 2HCl of 60g (0.0957mol) is suspended in the t-butyl methyl ether of 400ml, drips water (250ml) solution of 13.22g (0.0957mol) salt of wormwood, stirring reaction 0.5h.Two are separated, and use 100ml water washing organic phase again, use the anhydrous sodium sulfate drying organic phase, filter, and organic solvent is removed in underpressure distillation, get the 51.29g Ciatyl Depot.Productive rate is 96.58%. 1H?NMR(CDCl 3,400MHz),δ:7.12-7.50(7H,m),5.90(1H,t),4.35(2H,t),3.41(2H,t),2.97(2H,t),2.32-2.57(10H,m),2.06(2H,t),1.64(2H,m),1.30(12H,m),0.88(3H,t)。
Each raw material and solvent that the present invention is cited, and the bound value of each raw material and interval value can both realize the present invention, just do not enumerate embodiment one by one at this.

Claims (10)

1. the separation of a zuclopenthixol and purification process is characterized in that, described method generates ester by diuril ton and benzoic acid derivative, and fractional crystallization obtains pure alpha-isomer again.
2. the method for claim 1 is characterized in that, said method comprising the steps of:
(a) make raw material α/β-diuril ton and active benzoic acid derivative in organic solvent, carry out benzoyl by reacting by heating;
(b) make reaction mixture cooling, precipitation separation from the mother liquor that contains α-diuril ton benzoic ether;
(c) mother liquor in the above-mentioned steps is heated, and add hydrochloric acid;
(d) make the reaction mixture cooling, to reclaim the hydrochloride of sedimentary thus zuclopenthixol benzoic ether;
(e) ester hydrolysis is to obtain purer zuclopenthixol;
(f) with the further crystallization of organic solvent, obtain qualified zuclopenthixol.
3. method as claimed in claim 2 is characterized in that, used active benzoic acid derivative is phenylformic acid, benzoyl oxide, Benzoyl chloride, benzoyl bromide, 2-chloro-benzoic acid or Chlorodracylic acid etc. in the step (a); The mol ratio of benzoic acid derivative and raw material is 1: 1-1.2: 1.
4. method as claimed in claim 2 is characterized in that, organic solvent is selected from a kind of in ether, ethyl acetate, methylene dichloride, chloroform, acetone, tetrahydrofuran (THF), toluene, the dimethylbenzene or their mixture in the step (a).Wherein best with the ethyl acetate effect especially.Described reacting by heating be meant all reactants by the heating mode all be dissolved in the organic solvent, temperature of reaction be 40 ℃ to reflux temperature, preferred temperature is 70 ℃.
5. method as claimed in claim 2 is characterized in that, half the amount that hydrochloric acid is shown the feed molar amount greatly in the step (c) adds; For example, every mole of raw material adds the hydrochloric acid that the 0.4-0.6 mole should be arranged.
6. method as claimed in claim 2 is characterized in that, the hydrolysis catalyst system therefor is mineral alkali or organic bases in the step (e); Described mineral alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, lithium hydroxide, sodium hydride or potassium hydride KH etc.
7. method as claimed in claim 2 is characterized in that, used organic solvent is selected from methyl alcohol, ethanol, propyl alcohol, acetone, ether, ethyl acetate, sherwood oil, hexanaphthene, normal hexane or their mixture in the step (f).Wherein with the hexanaphthene best results.
8. method as claimed in claim 2 is characterized in that, step (f) is carried out following steps afterwards:
(g) with the pure zuclopenthixol of gained in organic solvent, with carboxylic acid or derivatives thereof reacting by heating, obtain carboxylicesters or its pharmaceutically acceptable hydrochlorate of zuclopenthixol.
9. method as claimed in claim 8 is characterized in that, used organic solvent is selected from a kind of in ether, ethyl acetate, methylene dichloride, chloroform, acetone, tetrahydrofuran (THF), toluene, the dimethylbenzene or their mixing in the step (g); Mentioned carboxylic acid is an aliphatic acid, as, acetate, propionic acid, isopropyl acid, valeric acid, caproic acid, enanthic acid, capric acid or palmitinic acid; Carboxylic acid derivative is diacetyl oxide, valeric anhydride, decanoyl chloride etc.
10. method as claimed in claim 9, it is characterized in that the pharmaceutically acceptable hydrochlorate of mentioning in the step (g) is hydrochloride, bromate, vitriol, phosphoric acid salt, Citrate trianion, tartrate, bitartrate, maleate or salicylate etc.
CN2013101253826A 2013-04-12 2013-04-12 Separation and purification method of zuclopenthixol Pending CN103214453A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104628802A (en) * 2013-11-07 2015-05-20 北大方正集团有限公司 Method for extracting and purifying nemadectin from fermentation liquid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3116291A (en) * 1958-12-04 1963-12-31 Kefalas As 9-(propene-3-ylidene-1), and 9-[3'-(nu-hydrox-yalkylpiperazino-nu)-propylidene], xanthenes and thiaxanthenes, and processes for their preparation
US3996211A (en) * 1973-06-25 1976-12-07 Kefalas A/S Alpha-isomer of 2-chloro-9-[3'-(N'-2-hydroxyethylpiperazino-N)-propylidene]-thiaxanthene, carboxylic acid esters thereof and acid addition salts of these compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3116291A (en) * 1958-12-04 1963-12-31 Kefalas As 9-(propene-3-ylidene-1), and 9-[3'-(nu-hydrox-yalkylpiperazino-nu)-propylidene], xanthenes and thiaxanthenes, and processes for their preparation
US3996211A (en) * 1973-06-25 1976-12-07 Kefalas A/S Alpha-isomer of 2-chloro-9-[3'-(N'-2-hydroxyethylpiperazino-N)-propylidene]-thiaxanthene, carboxylic acid esters thereof and acid addition salts of these compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104628802A (en) * 2013-11-07 2015-05-20 北大方正集团有限公司 Method for extracting and purifying nemadectin from fermentation liquid
CN104628802B (en) * 2013-11-07 2017-01-18 北大方正集团有限公司 Method for extracting and purifying nemadectin from fermentation liquid

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