CN104003985B - A kind of preparation method of PalonosetronHydrochloride and intermediate thereof - Google Patents
A kind of preparation method of PalonosetronHydrochloride and intermediate thereof Download PDFInfo
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Abstract
nullThe present invention relates to pharmaceutical formulating art，The preparation method being specifically related to a kind of PalonosetronHydrochloride，Including (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent，Within the scope of temperature 0～40 DEG C, N-[1-azabicyclo (2.2.2) octyl-3S-base]-1 it is obtained by reacting with condensing agent,2,3,4-naphthane-1S-Methanamide，This product reacts with metallic boron hydrides，Obtain [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine，React with double; two (trichloromethyl) carbonic ester again，Add acidic alcohol and obtain PalonosetronHydrochloride crude product，PalonosetronHydrochloride fine work is obtained then through recrystallization.The present invention efficiently solve that prior art exists product yield is low and equipment corrosion problem.
Description
Technical field
The present invention relates to pharmaceutical formulating art, the preparation method being specifically related to a kind of PalonosetronHydrochloride and intermediate thereof.
Background technology
PalonosetronHydrochloride (palonosetron, trade name: A Lexi), researched and developed by HeLsinn company of Switzerland, in July, 2003 lists in the U.S. first, it it is the 5-HT3 acceptor inhibitor of a kind of novel high selectivity, high-affinity, be clinically used in treatment, severe causes acute, the retardance nausea and vomiting that telling property chemotherapeutics causes, and receives much concern because it has the features such as curative effect height, toxic and side effects is little, long half time (about 40h), dosage are little.
Currently, the synthetic route of three PalonosetronHydrochlorides has been reported.
Document Synthesis, 1996, (7), p816-818 reports two lines:
Article 1, route, with 1,8-naphthalene dicarboxylic anhydride for initiation material, through urethane exchange, catalytic hydrogenation, reduction, dehydration, the reaction of catalytic hydrogenation five step, obtains PalonosetronHydrochloride.Article 2 route, with 1-naphthoic acid for initiation material, obtains PalonosetronHydrochloride through catalytic hydrogenation, amidatioon, cyclization, catalytic hydrogenation four-step reaction.But, all use catalytic hydrogenation in these two lines, this reaction condition is difficult to control to, and selectivity is poor, is not suitable for industrialized production.
Article 3 route, synthesis technique disclosed in US5510486, with 1,2,3,4-tetrahydrochysene-1-naphthoic acid for initiation material, obtain PalonosetronHydrochloride through amidatioon, fractionation, reduction, cyclization, one-tenth salt, recrystallization.It is simple that this route often walks operation, it does not have uses specific response device.But, the initiation material 1 used in this route, 2,3,4-tetrahydrochysene-1-naphthoic acids are racemies, need obtaining N-[1-azabicyclo (2.2.2) octyl-3S-base]-1, split after 2,3,4-naphthane Methanamides, but it is relatively low to split the intermediate optical purity obtained, and the refining impact of PalonosetronHydrochloride crude product is bigger.Such as, Chinese invention patent CN101157691A points out, " after adopting the crude product recrystallization for preparing of the method; product also has more impurity; and repeatedly the purity of finished product can be only achieved 99% after recrystallization; single contaminant content is also above 0.1%, and the quality to improve product further is highly difficult ".
Meanwhile, CN101157691A reports with commercial (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid as initiation material, is purified by the method for column chromatography, it is possible to obtain purity more than 99.0%, the single impurity < technique of the PalonosetronHydrochloride of 0.1%.Compared with US5510486 total recovery 6%, this process recovery ratio is 24.8%, improves very notable.
While it is true, the technique of CN101157691A still suffers from some problems:
First, first step reaction employs the thionyl chloride of severe corrosive, point out in reporting such as CN101413762A " seal nipple is had strong corrosivity by thionyl chloride; the rubber washer that such as butt joint seals; and once after packing ring is corroded; the thionyl chloride of effusion and air combine the chloride ion produced can produce stronger corrosion to rubber packing material and piping material (such as, stainless steel tube).", thus large-scale commercial production is adversely affected.
Secondly, although it adopts the method product quality of column chromatography to significantly improve, but column chromatography yield is relatively low, and solvent cost is high, and the operating time is long, still not ideal enough as industrial method, limits the application in production.
Summary of the invention
For the shortcoming and defect that above-mentioned prior art exists, the preparation method that it is an object of the invention to provide the PalonosetronHydrochloride of a kind of high yield, by controlling the optical purity of initiation material, and ensure that course of reaction does not have new optical isomer to generate with gentle reactive mode, the PalonosetronHydrochloride crude product obtained passes through simple recrystallizing and refining, can reach content more than 99.8%, the single impurity<quality standard of 0.10%, total recovery>35%, thus being more applicable for industrialized production.
Particularly, inventor provides following technical scheme:
The preparation method of a kind of PalonosetronHydrochloride, in the steps below operation:
(1) formula III compound (i.e. N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide) is prepared
Formula II compound (i.e. (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid) and (S)-3-amino-1-azabicyclo [2.2.2] octane is in organic solvent, within the scope of temperature 0～40 DEG C, formula III compound (i.e. N-[1-azabicyclo (2.2.2) octyl-3S-base]-1 it is obtained by reacting with condensing agent, 2,3,4-naphthane-1S-Methanamide), wherein: formula II compound (i.e. (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acids), the mol ratio of (S)-3-amino-1-azabicyclo [2.2.2] octane and condensing agent be: 1.0 ~ 2.0:1.0:1.05 ~ 2.1；Organic solvent is selected from one or more in normal hexane, toluene, oxolane, 2-methyltetrahydrofuran, dichloromethane and chloroform；Condensing agent one in DCC, DCC and DMAP mixed liquor, DIC, EDCI and HOBt and triethylamine mixed liquor, CDI, HATU etc., wherein EDCI and HOBt mixed liquor is the equimolar ratio mixed liquor of the two.
Symbol description: DCC refers to N, N '-dicyclohexylcarbodiimide, DIC refers to N, N'-DIC, and EDCI refers to 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, HOBt refers to I-hydroxybenzotriazole, CDI refers to that carbonyl dimidazoles, HATU refer to 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester.
(2) formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine) is prepared
Formula III compound (i.e. N-[1-azabicyclo (2.2.2) octyl-3S-base]-1, 2, 3, 4-naphthane-1S-Methanamide) in organic solvent, it is react with metallic boron hydrides within the scope of 60～70 DEG C in temperature under lewis acidic catalysis, obtain formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-base]-(1, 2, 3, 4-naphthane-1S-methyl) amine), wherein: formula III compound (i.e. N-[1-azabicyclo (2.2.2) octyl-3S-base]-1, 2, 3, 4-naphthane-1S-Methanamide), the mol ratio of lewis acid and metallic boron hydrides is: 1:2.0 ~ 6.1:1.0 ~ 4.8；Described organic solvent is: oxolane or 2-methyltetrahydrofuran；Described metallic boron hydrides is: sodium borohydride, potassium borohydride or lithium borohydride,
(3) preparationⅠcompound (i.e. PalonosetronHydrochloride)
Formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-base]-(1, 2, 3, 4-naphthane-1S-methyl) amine) in organic solvent, it is react with double, two (trichloromethyl) carbonic esters within the scope of 20～60 DEG C in temperature under lewis acidic catalysis, add acidic alcohol and obtain type I compound (i.e. PalonosetronHydrochloride) crude product, PalonosetronHydrochloride fine work is obtained then through recrystallization, wherein: IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-base]-(1, 2, 3, 4-naphthane-1S-methyl) amine), the mol ratio of lewis acid and double, two (trichloromethyl) carbonic esters is: 1:2.0 ~ 7.1:1.0 ~ 1.5；Described organic solvent is: normal hexane, benzene or toluene,
General chemical structure formula is as follows:
,,,。
Preferably, the reaction temperature in step of the present invention (1) is 20～30 DEG C.
Preferably, the organic solvent in step of the present invention (1) selects chloroform.
Preferably, the condensing agent in step of the present invention (1) selects DCC(and N, N '-dicyclohexylcarbodiimide).
Preferably, the response time in step of the present invention (1) is 2～24 hours.
Preferably, the organic solvent in step of the present invention (2) is oxolane.
Preferably, the metallic boron hydrides in step of the present invention (2) is sodium borohydride.
Preferably, the response time in step of the present invention (2) is 1～5 hour.
Preferably, in step of the present invention (3), reaction temperature is 30～50 DEG C.
Preferably, the recrystallization solvent in step of the present invention (3) is: absolute methanol, dehydrated alcohol, isopropanol, and the mixed solvent of the mixed solvent of methanol/water, ethanol/water.The preferred scheme of recrystallization solvent is dehydrated alcohol.
The dominant response formula of the present invention has:
,
,
。
The preparation method that present invention also offers a kind of PalonosetronHydrochloride intermediate, in the steps below operation:
Formula II compound and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent, it is obtained by reacting, within the scope of temperature 0～40 DEG C, the compound meeting formula III structure with condensing agent, i.e. PalonosetronHydrochloride intermediate, wherein: the mol ratio of formula II compound, (S)-3-amino-1-azabicyclo [2.2.2] octane and condensing agent is: 1.0 ~ 2.0:1.0:1.05 ~ 2.1；Organic solvent is selected from one or more in normal hexane, toluene, oxolane, 2-methyltetrahydrofuran, dichloromethane and chloroform；Condensing agent one in DCC, DCC and DMAP mixed liquor, DIC, EDCI and HOBt and triethylamine mixed liquor, CDI, HATU,
General chemical structure formula is as follows:
,。
Preferably, the preparation method according to described a kind of PalonosetronHydrochloride intermediate, wherein, the described response time is 2～24 hours.
Key intermediate N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3, the 4-naphthane-1S-Methanamide of the present invention, it is possible to prepare as follows:
Under nitrogen protection, by (S)-1,2,3; 4-tetrahydrochysene-1-naphthoic acid dissolves in dichloromethane, adds DCC, is incubated 1 ~ 2 hour at 18 ~ 25 DEG C; subsequently below 30 DEG C, add the dichloromethane solution of (S)-3-amino-1-azabicyclo [2.2.2] octane, be incubated 3 hours at 25 ~ 30 DEG C；The consumption mol ratio of described (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid, DCC and (S)-3-amino-1-azabicyclo [2.2.2] octane is 1.0 ~ 2.0:1.0:1.05 ~ 2.1；After reaction, generate intermediate N [1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide.After reaction, wash organic facies, aqueous phase discarded with water, wash organic facies with aqueous hydrochloric acid solution again, discard organic facies, between the pH value of sodium hydrate aqueous solution water transfer phase to 9-10, with dichloromethane extraction, with anhydrous sodium sulfate dry methylene chloride extracting solution, concentration, obtain intermediate N [1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide white solids, yield 95.0-98.8%, HPLC > 98.0%.
The product present invention obtained carries out HPLC detection, detection method: CHIRALCELAD-H post；Mobile phase: normal hexane (containing 0.05% diethylamine): ethanol (92:8)；Detection wavelength: 220nm.PalonosetronHydrochloride fine work HPLC purity>99.90%, single impurity<0.10%.
Compared with prior art, the invention have the advantages that
PalonosetronHydrochloride fine work yield in the present invention is more than 35%, hence it is evident that higher than the yield of existing bibliographical information.
The present invention selects the one in DCC, DIC, EDCI, CDI and HATU as condensing agent, compared with prior art, abandon the thionyl chloride of etching apparatus, intermediate N [1-azabicyclo (2.2.2) octyl-3S-base]-1 can be made simultaneously, 2, the impurity of 3,4-naphthane-1S-Methanamides reduces.
Accompanying drawing explanation
Fig. 1 is N-in embodiment 1 [1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (formula III compound)1HNMR collection of illustrative plates.
Fig. 2 is PalonosetronHydrochloride (compound of formula I) in embodiment 11HNMR collection of illustrative plates.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, further illustrate present disclosure.
In the present invention, all of equipment and raw material etc. all can be buied from market or the industry is conventional.Method in following embodiment, if no special instructions, is the conventional method of this area.
Primary raw material and reagent illustrate:
(S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid AR(content>=98.0%, R type isomer<1.0%): Hangzhou Rui De Chemical Co., Ltd.,
(S)-3-amino-1-azabicyclo [2.2.2] octane AR(content>=95.0%, R type isomer<2.0%): ShanghaiBirchChemicalTechnologyCo, Ltd,
N, N '-dicyclohexylcarbodiimide (DCC) AR: Zhejiang Tianyu Pharmaceutical Co., Ltd.,
1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) AR(content >=98.0%): Chemical Reagent Co., Ltd., Sinopharm Group,
I-hydroxybenzotriazole (HOBt) AR(content >=98.0%): Suzhou Highfine Biotech Co., Ltd.,
Double; two (trichloromethyl) carbonic ester AR: Youbang Chemical Co., Ltd., Lishui, Zhejiang Prov.,
Boron trifluoride diethyl etherate AR: Jiangsu Yonghua Fine Chemical Co., Ltd.,
Other reagent is commercially available conventional product.
Embodiment 1
The preparation method of a kind of PalonosetronHydrochloride, in the steps below operation:
(1) N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (formula III compound) is prepared
Under nitrogen protection, (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid (10g, 56.8mmol) is put in 100mL chloroform, after stirring and dissolving, adds DCC(11.7g, 56.8mmol), at 25 DEG C, it is incubated 1.5 hours.TLC determines reaction end.Subsequently below 30 DEG C, adding the chloroformic solution of (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) free for 50mL, be incubated 3 hours at 25 DEG C, after completion of the reaction, by 50mL water washing organic facies, aqueous phase discards.Fully washing organic facies with 10% aqueous hydrochloric acid solution again, each 50mL, organic facies discards.Between the pH value of 10% sodium hydrate aqueous solution water transfer phase to 9-10, with chloroform extraction three times, each 50mL, merges organic facies, dries with anhydrous sodium sulfate, concentration, obtaining white solid 15.9g, this white solid is N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2 after testing, 3,4-naphthane-1S-Methanamides.Yield 98.8%, HPLC98.04%, (R, S) content of isomer 1.47%.mp:190-191℃,[α]D 20=-54.4°(c=1.0,CH2Cl2).1H-NMR(CDCl3): δ 1.2150-1.3790 (m, 2H), 1.5720-1.5972
(m,2H),1.7410-1.8590(m,3H),1.9333-1.9796(m,1H),2.2151-2.2967(m,2H),2.5210-2.6090(m,1H),2.7175-2.8706(m,5H),3.2132-3.2587(m,1H),3.6511-3.6715(t,1H),
3.8750-3.9550(m,1H),5.4712-5.4837(d,1H,J=6.25Hz),7.0772-7.0928(m,1H),7.1375-
7.1520(m,2H),7.1821-7.2111(m,1H)。
(2) [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound) is prepared
By N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (10g, 35.2mmol), sodium borohydride (6.4g, 168.4mmol) join in oxolane 100mL, stirring be cooled to 10 DEG C, dropping boron trifluoride diethyl etherate (27mL, 211.5mmol).Finish, be warming up to 70 DEG C after being warming up to 25 DEG C of insulations 30 minutes and react 2 hours.Cooling, temperature rising reflux 1 hour after dropping 2N hydrochloric acid 150mL, air-distillation, to more than 75 DEG C, is lowered the temperature, is dripped 50% potassium hydroxide aqueous solution 50mL, finish, and adds ethyl acetate 100mL and stirs 30 minutes.Filtering, organic over anhydrous dried over sodium sulfate, filter, be evaporated to dry grease, this grease is [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine, and HPLC96.33% directly throws next step.
(3) palonosetron (type I compound) is prepared
[1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (in step (2) all) is joined in toluene 100mL, stirs 5 minutes, be warming up to backflow.Lower the temperature less than 30 DEG C, be dividedly in some parts double; two (trichloromethyl) carbonic ester (12g, 40.4mmol), be warming up to about 50 DEG C insulation reaction 18 hours.Lower the temperature 40 DEG C, dropping boron trifluoride diethyl etherate (30mL, 237.7mmol), it is warming up to back flow reaction 5 hours, lowers the temperature 40 DEG C, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lower the temperature 40 DEG C, layering.Water layer is joined in reaction bulb, lower the temperature less than 30 DEG C, drip 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, filter after stirring 10 minutes, layering, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain grease, add isopropanol 120mL, be warming up to 70 DEG C, add acidic alcohol 20mL, reflux 1 hour.It is cooled to 5 DEG C after 2 hours stirred below and puts into refrigerator freezing overnight.Filter, after drying under reduced pressure put into flask, with dehydrated alcohol 120mL be back to molten clearly, add activated carbon (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, cool down 1 hour with frozen water again, filtering, dry 6 hours at 60 DEG C, the product obtained is detected as PalonosetronHydrochloride.Total recovery 35.3%.HPLC99.91%, (R, S) content of isomer 0.05%.Mp > 297 DEG C (dec), [α]D 20=-90.2°(c=1.0,CHCl3).1H-NMR(DMSO-d6):δ1.2390-1.2187(m,1H),1.6280-2.0899(m,7H),2.1840-2.1888(m,1H),2.7084-2.7790(m,1H),2.8256-2.8703(m,1H),
2.9843-3.0332(m,1H),3.1775-3.2337(m,4H),3.4480-3.4882(m,2H),3.6042-3.6558
(m,1H),3.7722-3.8053(dd,1H,J=11.83Hz,4.75Hz),4.7671-4.8019(t,1H),7.2504-
7.3036(m,2H),7.6961-7.7103(d,1H,J=7.10Hz),10.8054(brs,1H)。
Embodiment 2
The preparation method of a kind of PalonosetronHydrochloride, in the steps below operation:
(1) N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (formula III compound) is prepared
Under nitrogen protection; by (S)-1,2,3; 4-tetrahydrochysene-1-naphthoic acid (10g; 56.8mmol) put in 100mL dichloromethane, after stirring and dissolving, it is sequentially added into EDCI(12.0g; 62.5mmol), HOBt(8.5g; 62.5mmol), triethylamine (15.8mL, 113.6mmol), at 25 DEG C be incubated 1 ~ 2 hour.TLC determines reaction end.Subsequently below 30 DEG C, add the dichloromethane solution of (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) free for 50mL, it is incubated 8 hours, after completion of the reaction, by 50mL water washing organic facies at 25 DEG C, aqueous phase, with dichloromethane extraction secondary, each 50mL, merges organic facies, dry with anhydrous sodium sulfate, concentration, obtains white solid N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide 14.4g.Yield 89.4%, HPLC97.52%, (R, S) content of isomer 2.85%.
(2) [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound) is prepared
By N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (10g, 35.2mmol), sodium borohydride (5.4g, 140.8mmol) join in oxolane 100mL, stirring be cooled to 10 DEG C, dropping boron trifluoride diethyl etherate (22.5mL, 176.0mmol).Finish, be warming up to 70 DEG C after being warming up to 25 DEG C of insulations 30 minutes and react 2 hours.Cooling, temperature rising reflux 1 hour after dropping 2N hydrochloric acid 150mL, air-distillation, to more than 75 DEG C, is lowered the temperature, is dripped 50% potassium hydroxide aqueous solution 50mL, finish, and adds ethyl acetate 100mL and stirs 30 minutes.Filter, organic over anhydrous dried over sodium sulfate, filter, be evaporated to dry grease [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine, HPLC95.58%, directly throw next step.
(3) palonosetron (type I compound) is prepared
[1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (in step (2) all) is joined in toluene 100mL, stirs 5 minutes, be warming up to backflow.Lower the temperature less than 30 DEG C, be dividedly in some parts double; two (trichloromethyl) carbonic ester (15.7g, 52.8mmol), be warming up to about 50 DEG C insulation reaction 18 hours.Lower the temperature 40 DEG C, dropping boron trifluoride diethyl etherate (31.5mL, 250.0mmol), it is warming up to back flow reaction 5 hours, lowers the temperature 40 DEG C, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lower the temperature 40 DEG C, layering.Water layer is joined in reaction bulb, lower the temperature less than 30 DEG C, drip 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, filter after stirring 10 minutes, layering, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain grease, add isopropanol 120mL, be warming up to 70 DEG C, add acidic alcohol 20mL, reflux 1 hour.It is cooled to 5 DEG C after 2 hours stirred below and puts into refrigerator freezing overnight.Filter, after drying under reduced pressure put into flask, with dehydrated alcohol 120mL be back to molten clearly, add activated carbon (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, cool down 1 hour with frozen water again, filter, dry 6 hours at 60 DEG C, obtain PalonosetronHydrochloride.Total recovery 29.7%.HPLC99.82%, (R, S) content of isomer 0.07%.
Embodiment 3
The preparation method of a kind of PalonosetronHydrochloride, in the steps below operation:
(1) N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (formula III compound) is prepared
Under nitrogen protection, (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid (20g, 113.6mmol) is put in 100mL chloroform, after stirring and dissolving, adds DCC(23.4g, 113.6mmol), at 25 DEG C, it is incubated 20 hours.TLC determines reaction end.Subsequently below 30 DEG C, adding the chloroformic solution of (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) free for 50mL, be incubated 3 hours at 25 DEG C, after completion of the reaction, by 50mL water washing organic facies, aqueous phase discards.Fully washing organic facies with 10% aqueous hydrochloric acid solution again, each 50mL, organic facies discards.Between the pH value of 10% sodium hydrate aqueous solution water transfer phase to 9-10, with chloroform extraction three times, each 50mL, merge organic facies, dry with anhydrous sodium sulfate, concentration, obtain white solid N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide 15.7g.Yield 98.7%, HPLC97.49%, (R, S) content of isomer 1.46%.
(2) [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound) is prepared
By N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (10g, 35.2mmol), sodium borohydride (4.0g, 105.6mmol) join in oxolane 100mL, stirring be cooled to 10 DEG C, dropping boron trifluoride diethyl etherate (13.5mL, 105.6mmol).Finish, be warming up to 70 DEG C after being warming up to 25 DEG C of insulations 30 minutes and react 5 hours.Cooling, temperature rising reflux 1 hour after dropping 2N hydrochloric acid 150mL, air-distillation, to more than 75 DEG C, is lowered the temperature, is dripped 50% potassium hydroxide aqueous solution 50mL, finish, and adds ethyl acetate 100mL and stirs 30 minutes.Filter, organic over anhydrous dried over sodium sulfate, filter, be evaporated to dry grease [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine, HPLC95.30%, directly throw next step.
(3) palonosetron (type I compound) is prepared
[1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (in step (2) all) is joined in toluene 100mL, stirs 5 minutes, be warming up to backflow.Lower the temperature less than 30 DEG C, be dividedly in some parts double; two (trichloromethyl) carbonic ester (10.5g, 35.2mmol), be warming up to about 50 DEG C insulation reaction 18 hours.Lower the temperature 40 DEG C, dropping boron trifluoride diethyl etherate (13.3mL, 105.6mmol), it is warming up to back flow reaction 8 hours, lowers the temperature 40 DEG C, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lower the temperature 40 DEG C, layering.Water layer is joined in reaction bulb, lower the temperature less than 30 DEG C, drip 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, filter after stirring 10 minutes, layering, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain grease, add isopropanol 120mL, be warming up to 70 DEG C, add acidic alcohol 20mL, reflux 1 hour.It is cooled to 5 DEG C after 2 hours stirred below and puts into refrigerator freezing overnight.Filter, after drying under reduced pressure put into flask, with dehydrated alcohol 120mL be back to molten clearly, add activated carbon (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, cool down 1 hour with frozen water again, filter, dry 6 hours at 60 DEG C, obtain PalonosetronHydrochloride.Total recovery 35.0%.HPLC99.78%, (R, S) content of isomer 0.07%.
Comparative example 1
The preparation method of a kind of PalonosetronHydrochloride, in the steps below operation:
(1) N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (formula III compound) is prepared
Under nitrogen protection, by (S)-1,2,3; 4-tetrahydrochysene-1-naphthoic acid (10g, 56.8mmol) puts in 100mL chloroform, after stirring and dissolving, is sequentially added into DMF(0.08mL; 1.0mmol), thionyl chloride (8.0mL, 110.3mmol), at 50 DEG C be incubated 1.5 hours.It is evaporated to dry, add chloroform to dissolve, it is transferred in reaction bulb, it is cooled to 20 DEG C and adds free (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g of 50mL, 54.0mmol) chloroformic solution, 50 DEG C be incubated 1 hour, TLC follow the tracks of after completion of the reaction, by 50mL water washing organic facies, aqueous phase discards.Wash with organic facies with 10% sodium hydrate aqueous solution, each 50mL, merge organic facies, dry with anhydrous sodium sulfate, concentration, obtain white solid N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide 15.6g.Yield 97.1%, HPLC96.15%, (R, S) content of isomer 1.47%.
(2) [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound) is prepared
By N-[1-azabicyclo (2.2.2) octyl-3S-base]-1,2,3,4-naphthane-1S-Methanamide (10g, 35.2mmol), sodium borohydride (6.4g, 168.4mmol) join in oxolane 100mL, stirring be cooled to 10 DEG C, dropping boron trifluoride diethyl etherate (27mL, 211.5mmol).Finish, be warming up to 70 DEG C after being warming up to 25 DEG C of insulations 30 minutes and react 2 hours.Cooling, temperature rising reflux 1 hour after dropping 2N hydrochloric acid 150mL, air-distillation, to more than 75 DEG C, is lowered the temperature, is dripped 50% potassium hydroxide aqueous solution 50mL, finish, and adds ethyl acetate 100mL and stirs 30 minutes.Filter, organic over anhydrous dried over sodium sulfate, filter, be evaporated to dry grease [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine, HPLC93.53%, directly throw next step.
(3) palonosetron (type I compound) is prepared
(1) [1-azabicyclo (2.2.2) octyl-3S-base]-(1,2,3,4-naphthane-1S-methyl) amine (in step (2) all) is joined in toluene 100mL, stir 5 minutes, be warming up to backflow.Lower the temperature less than 30 DEG C, be dividedly in some parts double; two (trichloromethyl) carbonic ester (12g, 40.4mmol), be warming up to about 50 DEG C insulation reaction 18 hours.Lower the temperature 40 DEG C, dropping boron trifluoride diethyl etherate (30mL, 237.7mmol), it is warming up to back flow reaction 5 hours, lowers the temperature 40 DEG C, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lower the temperature 40 DEG C, layering.Water layer is joined in reaction bulb, lower the temperature less than 30 DEG C, drip 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, filter after stirring 10 minutes, layering, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain grease, add isopropanol 120mL, be warming up to 70 DEG C, add acidic alcohol 20mL, reflux 1 hour.It is cooled to 5 DEG C after 2 hours stirred below and puts into refrigerator freezing overnight.Filtering, after drying under reduced pressure, carry out post separation, adopt 160 ~ 200 order silica gel, gradient elution (pure chloroform, chloroform: methanol=95:5), collect single product solution, put in 45 DEG C of water-baths, decompression is steamed to without fraction, obtaining PalonosetronHydrochloride.Total recovery 27.4%.HPLC99.69%, (R, S) content of isomer 0.08%.
Finally it is pointed out that above example is only the more representational example of the present invention.Obviously, technical scheme is not limited to above-described embodiment, it is also possible to have many deformation.Every all deformation directly derived from present disclosure or associate, are all considered as protection scope of the present invention.
Claims (5)
1. the preparation method of a PalonosetronHydrochloride, it is characterised in that operation in the steps below:
(1) formula III compound is prepared
Formula II compound and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent, within the scope of temperature 0～40 DEG C, it is obtained by reacting formula III compound with condensing agent, response time is 2～24 hours, wherein: the mol ratio of formula II compound, (S)-3-amino-1-azabicyclo [2.2.2] octane and condensing agent is: 1.0 ~ 2.0:1.0:1.05 ~ 2.1；Organic solvent selects chloroform；DCC selected by condensing agent,
(2) formula IV compound is prepared
Formula III compound is in organic solvent, it is react with metallic boron hydrides within the scope of 60～70 DEG C in temperature under lewis acidic catalysis, response time is 1～5 hour, obtain formula IV compound, wherein: the mol ratio of formula III compound, lewis acid and metallic boron hydrides is: 1:2.0 ~ 6.1:1.0 ~ 4.8；Described organic solvent is: oxolane or 2-methyltetrahydrofuran；Described metallic boron hydrides is: sodium borohydride, potassium borohydride or lithium borohydride,
(3) preparationⅠcompound
Formula IV compound is in organic solvent, it is react with double; two (trichloromethyl) carbonic esters within the scope of 20～60 DEG C in temperature under lewis acidic catalysis, add acidic alcohol and obtain type I compound crude product, type I compound fine work is obtained then through recrystallization, namely type I compound is PalonosetronHydrochloride, wherein: the mol ratio of formula IV compound, lewis acid and double; two (trichloromethyl) carbonic ester is: 1.0:2.0 ~ 7.1:1.0 ~ 1.5；Described organic solvent is: normal hexane, benzene or toluene, and recrystallization solvent is dehydrated alcohol,
General chemical structure formula is as follows:
,,,。
2. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, it is characterised in that the described reaction temperature in step (1) is 20～30 DEG C.
3. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, it is characterised in that the described organic solvent in step (2) is oxolane；Metallic boron hydrides is sodium borohydride.
4. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, it is characterised in that in described step (3), reaction temperature is 30～50 DEG C.
5. the preparation method of a PalonosetronHydrochloride intermediate, it is characterised in that operation in the steps below:
Formula II compound and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent, it is obtained by reacting, within the scope of temperature 0～40 DEG C, the compound meeting formula III structure with condensing agent, i.e. PalonosetronHydrochloride intermediate, response time is 2～24 hours, wherein: the mol ratio of formula II compound, (S)-3-amino-1-azabicyclo [2.2.2] octane and condensing agent is: 1.0 ~ 2.0:1.0:1.05 ~ 2.1；Organic solvent selects chloroform；DCC selected by condensing agent,
General chemical structure formula is as follows:
,。
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510486A (en) * | 1994-07-26 | 1996-04-23 | Syntex (U.S.A.) Inc. | Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one |
| CN101157691A (en) * | 2007-10-18 | 2008-04-09 | 杭州九源基因工程有限公司 | Production technique of hydrochloric acid palonosetron |
| CN101186607A (en) * | 2006-11-15 | 2008-05-28 | 深圳海王药业有限公司 | Method for synthesizing palonosetron hydrochloride |
| CN101314601A (en) * | 2008-06-30 | 2008-12-03 | 江苏先声药物研究有限公司 | Preparation process of high-purity palonosetron Hcl |
| CN103183670A (en) * | 2011-12-30 | 2013-07-03 | 昆明积大制药股份有限公司 | Synthetic method of palonosetron hydrochloride |
| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
-
2014
- 2014-06-24 CN CN201410285980.4A patent/CN104003985B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510486A (en) * | 1994-07-26 | 1996-04-23 | Syntex (U.S.A.) Inc. | Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one |
| CN101186607A (en) * | 2006-11-15 | 2008-05-28 | 深圳海王药业有限公司 | Method for synthesizing palonosetron hydrochloride |
| CN101157691A (en) * | 2007-10-18 | 2008-04-09 | 杭州九源基因工程有限公司 | Production technique of hydrochloric acid palonosetron |
| CN101314601A (en) * | 2008-06-30 | 2008-12-03 | 江苏先声药物研究有限公司 | Preparation process of high-purity palonosetron Hcl |
| CN103183670A (en) * | 2011-12-30 | 2013-07-03 | 昆明积大制药股份有限公司 | Synthetic method of palonosetron hydrochloride |
| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸帕洛诺司琼合成路线图解;杨新华 等;《中国医药工业杂志》;20090331;第40卷(第3期);第231-233页 * |
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