CN104003985A - Preparation method for palonosetron hydrochloride and intermediate thereof - Google Patents
Preparation method for palonosetron hydrochloride and intermediate thereof Download PDFInfo
- Publication number
- CN104003985A CN104003985A CN201410285980.4A CN201410285980A CN104003985A CN 104003985 A CN104003985 A CN 104003985A CN 201410285980 A CN201410285980 A CN 201410285980A CN 104003985 A CN104003985 A CN 104003985A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- palonosetronhydrochloride
- formula
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Abstract
The invention relates to the field of medicine preparation, in particular to a preparation method for palonosetron hydrochloride. The method comprises the steps that (S)-1, 2, 3, 4-tetrahydrophthalic anhydride-1-naphthoic acid and (S)-3-amidogen-1-aza-bicyclic[2. 2. 2] octane are put into an organic solvent and react with a condensing agent in the temperature range of 0-40 DEG C to obtain N-[1-aza-bicyclic(2. 2. 2)octyl-3S-radical]-1, 2, 3, 4-tetrahydronaphthalene-1S-formamide, the product reacts with metal hydronoron to obtain [1-aza-bicyclic(2. 2. 2)octyl-3S-radical]-(1, 2, 3, 4-tetrahydronaphthalene-1S-methyl) amine to be react with bis(trichloromethyl) carbonic ester, hydrochloric acid alcohol is added, crude products of the palonosetron hydrochloride are obtained, and then recrystallization is carried out to obtain high-quality products of the palonosetron hydrochloride. The preparation method for the palonosetron hydrochloride effectively solves the problems that product yield is low and equipment is corroded in the prior art.
Description
Technical field
The present invention relates to medicine preparation field, be specifically related to the preparation method of a kind of PalonosetronHydrochloride and intermediate thereof.
Background technology
PalonosetronHydrochloride (palonosetron, trade(brand)name: A Lexi), by Switzerland HeLsinn company, researched and developed, go on the market in the U.S. in July, 2003 first, it is the 5-HT3 acceptor inhibitor of a kind of novel highly selective, high-affinity, in clinical being used for the treatment of, severe causes acute, the retardance nausea and vomiting that telling property chemotherapeutics causes, because it has that curative effect is high, toxic side effect is little, long half time (about 40h), dosage be little etc., and feature receives much concern.
Current, reported the synthetic route of three PalonosetronHydrochloride.
Document Synthesis, 1996, (7), in p816-818, reported two lines:
Article one, route, for starting raw material, through ammonia transesterify, catalytic hydrogenation, reduction, dehydration, catalytic hydrogenation five step reactions, obtains PalonosetronHydrochloride with 1,8-naphthalene dicarboxylic anhydride.Second route, take 1-naphthoic acid as starting raw material, through catalytic hydrogenation, amidation, pass ring, catalytic hydrogenation four-step reaction, obtains PalonosetronHydrochloride.But, in these two lines, all used catalytic hydrogenation, this reaction conditions is difficult to control, and selectivity is poor, is not suitable for suitability for industrialized production.
A Third Way line, is the disclosed synthesis technique of US5510486, with 1,2,3,4-tetrahydrochysene-1-naphthoic acid, for starting raw material, through amidation, fractionation, reduction, pass ring, salify, recrystallization, obtains PalonosetronHydrochloride.The every step operation of this route is simple, does not use special reaction device.But, the starting raw material 1 using in this route, 2,3,4-tetrahydrochysene-1-naphthoic acid is raceme, need to obtain N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1, after 2,3,4-naphthane methane amide, split, but it is lower to split the intermediate optical purity obtaining, larger on the refining impact of PalonosetronHydrochloride crude product.Such as, in Chinese invention patent CN101157691A, point out, " adopt after the crude product recrystallization that the method prepares; in product, also have more impurity; and repeatedly after recrystallization the purity of finished product just can reach 99%; single contaminant content also surpasses 0.1 %, if it is very difficult further to improve the quality of product ".
Meanwhile, CN101157691A has reported with commercial (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid is starting raw material, by the method for column chromatography, carries out purifying, can obtain purity more than 99.0%, the technique of the PalonosetronHydrochloride of single impurity <0.1%.Compare with US5510486 total recovery 6%, this process recovery ratio is 24.8%, improves very remarkable.
However, the technique of CN101157691A still exists some problems:
First, in the first step reaction, used the sulfur oxychloride of severe corrosive, as in CN 101413762A report, point out " sulfur oxychloride has strong corrodibility to sealing connection; the rubber cradle of butt junction sealing for example; once and after packing ring is corroded; the sulfur oxychloride of effusion and air can for example, produce stronger corrosion to rubber packing material and piping material (, stainless steel tube) in conjunction with the chlorion producing.", thereby large-scale industrial production is caused to disadvantageous effect.
Secondly, although it adopts the method quality product of column chromatography obviously to improve, column chromatography yield is lower, and solvent cost is high, and the operating time is long, still not ideal enough as industrial method, has limited the application in producing.
Summary of the invention
The shortcoming and defect existing for above-mentioned prior art, the object of the present invention is to provide a kind of preparation method of PalonosetronHydrochloride of high yield, by controlling the optical purity of starting raw material, and guarantee do not have new optical isomer to generate in reaction process with gentle reactive mode, the PalonosetronHydrochloride crude product obtaining is by simple recrystallizing and refining, can reach content more than 99.8%, the quality standard of single impurity <0.10%, total recovery >35%, thus be more applicable for suitability for industrialized production.
Particularly, contriver provides following technical scheme:
A preparation method for PalonosetronHydrochloride, in the steps below operation:
(1) preparation formula III compound (be N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide)
Formula II compound (i.e. (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid) and (S)-3-amino-1-azabicyclo [2.2.2] octane in organic solvent, react within the scope of 0～40 ℃ of temperature with condensing agent obtain formula III compound (be N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide), wherein: formula II compound (i.e. (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid), the mol ratio of (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, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and chloroform; Condensing agent is selected from a kind of in DCC, DCC and DMAP mixed solution, DIC, EDCI and HOBt and triethylamine mixed solution, CDI, HATU etc., the equimolar ratio mixed solution that wherein EDCI and HOBt mixed solution are the two.
Nomenclature: 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 carbonyl dimidazoles, and HATU refers to 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester.
(2) preparation formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine)
Formula III compound (be N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1, 2, 3, 4-naphthane-1S-methane amide) in organic solvent, under lewis acidic catalysis, in temperature, be to react with metal borohydride within the scope of 60～70 ℃, obtain formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-yl]-(1, 2, 3, 4-naphthane-1S-methyl) amine), wherein: formula III compound (be N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1, 2, 3, 4-naphthane-1S-methane amide), the mol ratio of Lewis acid and metal borohydride is: 1:2.0 ~ 6.1:1.0 ~ 4.8, described organic solvent is: tetrahydrofuran (THF) or 2-methyltetrahydrofuran, described metal borohydride is: sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride,
(3) preparationⅠcompound (being PalonosetronHydrochloride)
Formula IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-yl]-(1, 2, 3, 4-naphthane-1S-methyl) amine) in organic solvent, under lewis acidic catalysis, in temperature, be to react with two (trichloromethyl) carbonic ethers within the scope of 20～60 ℃, add again acidic alcohol to obtain formula I compound (being PalonosetronHydrochloride) crude product, through recrystallization, obtain PalonosetronHydrochloride fine work again, wherein: IV compound (i.e. [1-azabicyclo (2.2.2) octyl-3S-yl]-(1, 2, 3, 4-naphthane-1S-methyl) amine), Lewis acid with the mol ratio of two (trichloromethyl) carbonic ethers is: 1:2.0 ~ 7.1:1.0 ~ 1.5, described organic solvent is: normal hexane, benzene or toluene,
Main chemical structural formula is as follows:
，
，
，
。
As preferred version, the temperature of reaction in step of the present invention (1) is 20～30 ℃.
As preferred version, the organic solvent in step of the present invention (1) is selected chloroform.
As preferred version, it is N that the condensing agent in step of the present invention (1) is selected DCC(, N '-dicyclohexylcarbodiimide).
As preferred version, the reaction times in step of the present invention (1) is 2～24 hours.
As preferred version, the organic solvent in step of the present invention (2) is tetrahydrofuran (THF).
As preferred version, the metal borohydride in step of the present invention (2) is sodium borohydride.
As preferred version, the reaction times in step of the present invention (2) is 1～5 hour.
As preferred version, in step of the present invention (3), temperature of reaction is 30～50 ℃.
As preferred version, the recrystallization solvent in step of the present invention (3) is: anhydrous methanol, dehydrated alcohol, Virahol, and the mixed solvent of methanol/water is, the mixed solvent of ethanol/water.The preferred scheme of recrystallization solvent is dehydrated alcohol.
Principal reaction formula of the present invention has:
，
，
。
The present invention also provides a kind of preparation method 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, within the scope of 0～40 ℃ of temperature, react the compound that obtains meeting formula III structure with condensing agent, be 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, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and chloroform; Condensing agent is selected from a kind of in DCC, DCC and DMAP mixed solution, DIC, EDCI and HOBt and triethylamine mixed solution, CDI, HATU,
Main chemical structural formula is as follows:
，
。
As preferred version, according to the preparation method of described a kind of PalonosetronHydrochloride intermediate, wherein, the described reaction times is 2～24 hours.
Key intermediate N-[1-azabicyclo of the present invention (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide, can prepare as follows:
Under nitrogen protection, by (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid dissolves in methylene dichloride, adds DCC, at 18 ~ 25 ℃, is incubated 1 ~ 2 hour, below 30 ℃, add the dichloromethane solution of (S)-3-amino-1-azabicyclo [2.2.2] octane subsequently, 25 ~ 30 ℃ of insulations 3 hours; Described (S)-1,2,3, the consumption mol ratio of 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-yl]-1,2,3,4-naphthane-1S-methane amide.After reaction, wash organic phase with water, aqueous phase discarded, with aqueous hydrochloric acid, wash organic phase again, discard organic phase, by the pH value of aqueous sodium hydroxide solution water transfer phase between 9-10, with dichloromethane extraction, with anhydrous sodium sulfate drying dichloromethane extract, concentrated, obtain intermediate N [1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide white solid, yield 95.0-98.8%, HPLC>98.0%.
The product that the present invention is obtained carries out HPLC detection, detection method: CHIRALCEL AD-H post; Moving phase: normal hexane (containing 0.05% diethylamine): ethanol (92:8); Detect wavelength: 220nm.PalonosetronHydrochloride fine work HPLC purity >99.90%, single impurity <0.10%.
Compared with prior art, the present invention has the following advantages:
PalonosetronHydrochloride fine work yield in the present invention is greater than 35%, apparently higher than the yield of existing bibliographical information.
The present invention selects a kind of as condensing agent in DCC, DIC, EDCI, CDI and HATU, compared with prior art, abandon the thionyl chloride of etching apparatus, can make intermediate N [1-azabicyclo (2.2.2) octyl-3S-yl]-1 simultaneously, 2, the impurity of 3,4-naphthane-1S-methane amide reduces.
Accompanying drawing explanation
Fig. 1 is N-[1-azabicyclo (2.2.2) octyl-3S-yl in embodiment 1]-1,2,3,4-naphthane-1S-methane amide (formula III compound)
1hNMR collection of illustrative plates.
Fig. 2 is PalonosetronHydrochloride in embodiment 1 (formula I compound)
1hNMR collection of illustrative plates.
Embodiment
Below in conjunction with embodiment and accompanying drawing, be described more specifically content of the present invention.
In the present invention, all 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 ordinary method of this area.
Main raw material and reagent explanation:
(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%): Shanghai Birch Chemical Technology Co, 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.,
Two (trichloromethyl) carbonic ether AR: Youbang Chemical Co., Ltd., Lishui, Zhejiang Prov.,
Boron trifluoride diethyl etherate AR: Jiangsu Yong Hua fine chemicals company limited,
Other reagent is commercially available conventional product.
embodiment 1
A preparation method for PalonosetronHydrochloride, in the steps below operation:
(1) prepare N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (formula III compound)
Under nitrogen protection, by (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid (10g, 56.8mmol) drops in 100mL chloroform, after stirring and dissolving, adds DCC(11.7g, 56.8mmol), at 25 ℃, be incubated 1.5 hours.TLC determines reaction end.Below 30 ℃, add the chloroformic solution of free (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) of 50mL subsequently, 25 ℃ of insulations 3 hours, after completion of the reaction, by 50mL water washing organic phase, water discarded.With 10% aqueous hydrochloric acid, fully wash organic phase again, each 50mL, organic phase discards.By the pH value of 10% aqueous sodium hydroxide solution water transfer phase between 9-10, with chloroform extraction three times, each 50mL, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtain white solid 15.9g, this white solid is N-[1-azabicyclo (2.2.2) octyl-3S-yl after testing]-1,2,3,4-naphthane-1S-methane amide.Yield 98.8%, HPLC 98.04%, (R, S) content of isomer 1.47%.mp:190-191℃,[α]
D 20=-54.4°(c=1.0,CH
2Cl
2).
1H-NMR(CDCl
3)：δ1.2150-1.3790(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) preparation [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound)
By N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (10g, 35.2mmol), sodium borohydride (6.4g, 168.4mmol) joins in tetrahydrofuran (THF) 100mL, stir and be cooled to 10 ℃, drip boron trifluoride diethyl etherate (27mL, 211.5mmol).Finish, be warming up to 25 ℃ of insulations and after 30 minutes, be warming up to 70 ℃ of reactions 2 hours.Cooling, drips after 2N hydrochloric acid 150mL temperature rising reflux 1 hour, and more than air distillation to 75 ℃, cooling, drips 50% potassium hydroxide aqueous solution 50mL, finishes, and adds ethyl acetate 100mL to stir 30 minutes.Filter, organic layer anhydrous sodium sulfate drying, filtration, is evaporated to dry oily matter, and this oily matter is [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine, and HPLC 96.33%, directly throws next step.
(3) prepare Palonosetron (formula I compound)
[1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (whole in step (2)) is joined in toluene 100mL, stir 5 minutes, be warming up to backflow.Cooling, below 30 ℃, adds two (trichloromethyl) carbonic ethers (12g, 40.4mmol) in batches, is warming up to 50 ℃ of left and right insulation reaction 18 hours.Lower the temperature 40 ℃, drip boron trifluoride diethyl etherate (30mL, 237.7mmol), be warming up to back flow reaction 5 hours, lower the temperature 40 ℃, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lowers the temperature 40 ℃, layering.Water layer is joined in reaction flask, and cooling, below 30 ℃, drips 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, stir after 10 minutes and filter, layering, organic layer anhydrous sodium sulfate drying, filter, concentrate to obtain oily matter, add Virahol 120mL, be warming up to 70 ℃, add acidic alcohol 20mL, reflux 1 hour.Being cooled to 5 ℃ of following stirrings puts into refrigerator freezing after 2 hours and spends the night.Filter, after drying under reduced pressure, drop into flask, with dehydrated alcohol 120mL, be back to molten clearly, add gac (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, use again frozen water cooling 1 hour, filter, at 60 ℃ dry 6 hours, the product obtaining was PalonosetronHydrochloride after testing.Total recovery 35.3%.HPLC 99.91%, (R, S) content of isomer 0.05%.mp?>297℃?(dec)?，?[α]
D 20=-90.2°(c=1.0,CHCl
3).
1H-NMR(DMSO-d
6):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
A preparation method for PalonosetronHydrochloride, in the steps below operation:
(1) prepare N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (formula III compound)
Under nitrogen protection; by (S)-1,2,3; 4-tetrahydrochysene-1-naphthoic acid (10g; 56.8mmol) drop in 100mL methylene dichloride, after stirring and dissolving, add successively EDCI(12.0g; 62.5mmol), HOBt(8.5g; 62.5mmol), triethylamine (15.8mL, 113.6mmol), at 25 ℃, be incubated 1 ~ 2 hour.TLC determines reaction end.Below 30 ℃, add the dichloromethane solution of free (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) of 50mL subsequently, 25 ℃ of insulations 8 hours, after completion of the reaction, by 50mL water washing organic phase, water is with dichloromethane extraction secondary, and each 50mL, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtain white solid N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide 14.4g.Yield 89.4%, HPLC 97.52%, (R, S) content of isomer 2.85%.
(2) preparation [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound)
By N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (10g, 35.2mmol), sodium borohydride (5.4g, 140.8mmol) joins in tetrahydrofuran (THF) 100mL, stir and be cooled to 10 ℃, drip boron trifluoride diethyl etherate (22.5mL, 176.0mmol).Finish, be warming up to 25 ℃ of insulations and after 30 minutes, be warming up to 70 ℃ of reactions 2 hours.Cooling, drips after 2N hydrochloric acid 150mL temperature rising reflux 1 hour, and more than air distillation to 75 ℃, cooling, drips 50% potassium hydroxide aqueous solution 50mL, finishes, and adds ethyl acetate 100mL to stir 30 minutes.Filter, organic layer anhydrous sodium sulfate drying, filtration, is evaporated to dry oily matter [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine, and HPLC 95.58%, directly throws next step.
(3) prepare Palonosetron (formula I compound)
[1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (whole in step (2)) is joined in toluene 100mL, stir 5 minutes, be warming up to backflow.Cooling, below 30 ℃, adds two (trichloromethyl) carbonic ethers (15.7g, 52.8mmol) in batches, is warming up to 50 ℃ of left and right insulation reaction 18 hours.Lower the temperature 40 ℃, drip boron trifluoride diethyl etherate (31.5mL, 250.0mmol), be warming up to back flow reaction 5 hours, lower the temperature 40 ℃, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lowers the temperature 40 ℃, layering.Water layer is joined in reaction flask, and cooling, below 30 ℃, drips 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, stir after 10 minutes and filter, layering, organic layer anhydrous sodium sulfate drying, filter, concentrate to obtain oily matter, add Virahol 120mL, be warming up to 70 ℃, add acidic alcohol 20mL, reflux 1 hour.Being cooled to 5 ℃ of following stirrings puts into refrigerator freezing after 2 hours and spends the night.Filter, after drying under reduced pressure, drop into flask, with dehydrated alcohol 120mL be back to molten clearly, add gac (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, use again frozen water cooling 1 hour, filter, at 60 ℃ dry 6 hours, obtain PalonosetronHydrochloride.Total recovery 29.7%.HPLC 99.82%, (R, S) content of isomer 0.07%.
embodiment 3
A preparation method for PalonosetronHydrochloride, in the steps below operation:
(1) prepare N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (formula III compound)
Under nitrogen protection, by (S)-1,2,3,4-tetrahydrochysene-1-naphthoic acid (20g, 113.6mmol) drops in 100mL chloroform, after stirring and dissolving, adds DCC(23.4g, 113.6mmol), at 25 ℃, be incubated 20 hours.TLC determines reaction end.Below 30 ℃, add the chloroformic solution of free (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g, 54.0mmol) of 50mL subsequently, 25 ℃ of insulations 3 hours, after completion of the reaction, by 50mL water washing organic phase, water discarded.With 10% aqueous hydrochloric acid, fully wash organic phase again, each 50mL, organic phase discards.By the pH value of 10% aqueous sodium hydroxide solution water transfer phase, between 9-10, with chloroform extraction three times, each 50mL, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtain white solid N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide 15.7g.Yield 98.7%, HPLC 97.49%, (R, S) content of isomer 1.46%.
(2) preparation [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound)
By N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (10g, 35.2mmol), sodium borohydride (4.0g, 105.6mmol) joins in tetrahydrofuran (THF) 100mL, stir and be cooled to 10 ℃, drip boron trifluoride diethyl etherate (13.5mL, 105.6mmol).Finish, be warming up to 25 ℃ of insulations and after 30 minutes, be warming up to 70 ℃ of reactions 5 hours.Cooling, drips after 2N hydrochloric acid 150mL temperature rising reflux 1 hour, and more than air distillation to 75 ℃, cooling, drips 50% potassium hydroxide aqueous solution 50mL, finishes, and adds ethyl acetate 100mL to stir 30 minutes.Filter, organic layer anhydrous sodium sulfate drying, filtration, is evaporated to dry oily matter [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine, and HPLC 95.30%, directly throws next step.
(3) prepare Palonosetron (formula I compound)
[1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (whole in step (2)) is joined in toluene 100mL, stir 5 minutes, be warming up to backflow.Cooling, below 30 ℃, adds two (trichloromethyl) carbonic ethers (10.5g, 35.2mmol) in batches, is warming up to 50 ℃ of left and right insulation reaction 18 hours.Lower the temperature 40 ℃, drip boron trifluoride diethyl etherate (13.3mL, 105.6mmol), be warming up to back flow reaction 8 hours, lower the temperature 40 ℃, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lowers the temperature 40 ℃, layering.Water layer is joined in reaction flask, and cooling, below 30 ℃, drips 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, stir after 10 minutes and filter, layering, organic layer anhydrous sodium sulfate drying, filter, concentrate to obtain oily matter, add Virahol 120mL, be warming up to 70 ℃, add acidic alcohol 20mL, reflux 1 hour.Being cooled to 5 ℃ of following stirrings puts into refrigerator freezing after 2 hours and spends the night.Filter, after drying under reduced pressure, drop into flask, with dehydrated alcohol 120mL be back to molten clearly, add gac (1g), reflux 30 minutes, filtered while hot, filtrate is concentrated into 2 times of volumes, is cooled to room temperature, use again frozen water cooling 1 hour, filter, at 60 ℃ dry 6 hours, obtain PalonosetronHydrochloride.Total recovery 35.0%.HPLC 99.78%, (R, S) content of isomer 0.07%.
comparative example 1
A preparation method for PalonosetronHydrochloride, in the steps below operation:
(1) prepare N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (formula III compound)
Under nitrogen protection, by (S)-1,2,3; 4-tetrahydrochysene-1-naphthoic acid (10g, 56.8mmol) drops in 100mL chloroform, after stirring and dissolving, adds successively DMF(0.08mL; 1.0mmol), sulfur oxychloride (8.0mL, 110.3mmol), at 50 ℃, be incubated 1.5 hours.Be evaporated to dry, add chloroform to dissolve, be transferred in reaction flask, be cooled to 20 ℃ and add free (S)-3-amino-1-azabicyclo [2.2.2] octane (8.8g of 50mL, chloroformic solution 54.0mmol), 50 ℃ of insulations 1 hour, TLC followed the tracks of after completion of the reaction, by 50mL water washing organic phase, water discards.By 10% aqueous sodium hydroxide washes, wash with organic phase, each 50mL, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtains white solid N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide 15.6g.Yield 97.1%, HPLC 96.15%, (R, S) content of isomer 1.47%.
(2) preparation [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (formula IV compound)
By N-[1-azabicyclo (2.2.2) octyl-3S-yl]-1,2,3,4-naphthane-1S-methane amide (10g, 35.2mmol), sodium borohydride (6.4g, 168.4mmol) joins in tetrahydrofuran (THF) 100mL, stir and be cooled to 10 ℃, drip boron trifluoride diethyl etherate (27mL, 211.5mmol).Finish, be warming up to 25 ℃ of insulations and after 30 minutes, be warming up to 70 ℃ of reactions 2 hours.Cooling, drips after 2N hydrochloric acid 150mL temperature rising reflux 1 hour, and more than air distillation to 75 ℃, cooling, drips 50% potassium hydroxide aqueous solution 50mL, finishes, and adds ethyl acetate 100mL to stir 30 minutes.Filter, organic layer anhydrous sodium sulfate drying, filtration, is evaporated to dry oily matter [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine, and HPLC 93.53%, directly throws next step.
(3) prepare Palonosetron (formula I compound)
(1) [1-azabicyclo (2.2.2) octyl-3S-yl]-(1,2,3,4-naphthane-1S-methyl) amine (whole in step (2)) is joined in toluene 100mL, stir 5 minutes, be warming up to backflow.Cooling, below 30 ℃, adds two (trichloromethyl) carbonic ethers (12g, 40.4mmol) in batches, is warming up to 50 ℃ of left and right insulation reaction 18 hours.Lower the temperature 40 ℃, drip boron trifluoride diethyl etherate (30mL, 237.7mmol), be warming up to back flow reaction 5 hours, lower the temperature 40 ℃, add 2N hydrochloric acid 50mL, water 60mL, temperature rising reflux 1 hour, lowers the temperature 40 ℃, layering.Water layer is joined in reaction flask, and cooling, below 30 ℃, drips 50% potassium hydroxide aqueous solution 40mL, add ethyl acetate 120mL, stir after 10 minutes and filter, layering, organic layer anhydrous sodium sulfate drying, filter, concentrate to obtain oily matter, add Virahol 120mL, be warming up to 70 ℃, add acidic alcohol 20mL, reflux 1 hour.Being cooled to 5 ℃ of following stirrings puts into refrigerator freezing after 2 hours and spends the night.Filter, after drying under reduced pressure, carry out post separation, adopt 160 ~ 200 order silica gel, gradient elution (pure chloroform, chloroform: methyl alcohol=95:5), collect single product solution, put in 45 ℃ of water-baths, decompression is steamed to without cut, obtains PalonosetronHydrochloride.Total recovery 27.4%.HPLC 99.69%, (R, S) content of isomer 0.08%.
Finally, it should be pointed out that above embodiment is only the more representational example of the present invention.Obviously, technical scheme of the present invention is not limited to above-described embodiment, can also have many distortion.Every all distortion of directly deriving or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (10)
1. a preparation method for PalonosetronHydrochloride, is characterized in that operating in the steps below:
(1) preparation formula III compound
Formula II compound and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent, react and obtain formula III compound within the scope of 0～40 ℃ of temperature with condensing agent, 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, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and chloroform; Condensing agent is selected from a kind of in DCC, DCC and DMAP mixed solution, DIC, EDCI and HOBt and triethylamine mixed solution, CDI, HATU,
(2) preparation formula IV compound
Formula III compound is in organic solvent, under lewis acidic catalysis, in temperature, be to react with metal borohydride within the scope of 60～70 ℃, obtain formula IV compound, wherein: the mol ratio of formula III compound, Lewis acid and metal borohydride is: 1:2.0 ~ 6.1:1.0 ~ 4.8; Described organic solvent is: tetrahydrofuran (THF) or 2-methyltetrahydrofuran; Described metal borohydride is: sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride,
(3) preparationⅠcompound
Formula IV compound is in organic solvent, under lewis acidic catalysis, in temperature, be to react with two (trichloromethyl) carbonic ethers within the scope of 20～60 ℃, add again acidic alcohol to obtain formula I compound crude product, through recrystallization, obtain formula I compound fine work again, formula I compound is PalonosetronHydrochloride, wherein: the mol ratio of IV compound, Lewis acid and two (trichloromethyl) carbonic ethers is: 1.0:2.0 ~ 7.1:1.0 ~ 1.5; Described organic solvent is: normal hexane, benzene or toluene,
Main chemical structural formula is as follows:
，
，
，
。
2. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, the temperature of reaction in described step (1) is 20～30 ℃.
3. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, the organic solvent in described step (1) is selected chloroform; Condensing agent is selected DCC.
4. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, the reaction times in described step (1) is 2～24 hours.
5. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, the organic solvent in described step (2) is tetrahydrofuran (THF); Metal borohydride is sodium borohydride.
6. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, the reaction times in described step (2) is 1～5 hour.
7. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, is characterized in that, in described step (3), temperature of reaction is 30～50 ℃.
8. the preparation method of a kind of PalonosetronHydrochloride according to claim 1, it is characterized in that, recrystallization solvent in described step (3) is: anhydrous methanol, dehydrated alcohol, Virahol, and the mixed solvent of methanol/water is, the mixed solvent of ethanol/water.
9. a preparation method for PalonosetronHydrochloride intermediate, is characterized in that operating in the steps below:
Formula II compound and (S)-3-amino-1-azabicyclo [2.2.2] octane are in organic solvent, within the scope of 0～40 ℃ of temperature, react the compound that obtains meeting formula III structure with condensing agent, be 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, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and chloroform; Condensing agent is selected from a kind of in DCC, DCC and DMAP mixed solution, DIC, EDCI and HOBt and triethylamine mixed solution, CDI, HATU,
Main chemical structural formula is as follows:
，
。
10. the preparation method of a kind of PalonosetronHydrochloride intermediate according to claim 9, is characterized in that, the described reaction times is 2～24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410285980.4A CN104003985B (en) | 2014-06-24 | 2014-06-24 | A kind of preparation method of PalonosetronHydrochloride and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410285980.4A CN104003985B (en) | 2014-06-24 | 2014-06-24 | A kind of preparation method of PalonosetronHydrochloride and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104003985A true CN104003985A (en) | 2014-08-27 |
| CN104003985B CN104003985B (en) | 2016-07-06 |
Family
ID=51364918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410285980.4A Active CN104003985B (en) | 2014-06-24 | 2014-06-24 | A kind of preparation method of PalonosetronHydrochloride and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104003985B (en) |
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 |
|---|
| 杨新华 等: "盐酸帕洛诺司琼合成路线图解", 《中国医药工业杂志》, vol. 40, no. 3, 31 March 2009 (2009-03-31), pages 231 - 233 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104003985B (en) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI715658B (en) | Crystal form of fused dihydropyrimidine compound and preparation method and intermediate thereof | |
| CN111875517B (en) | Intermediate for synthesizing camptothecin derivative, preparation method and application thereof | |
| CN108947891A (en) | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene | |
| CN105294653B (en) | The preparation technology of Vonoprazan fumarate | |
| CN105330582B (en) | (R) preparation method of-Esomeprazole | |
| CN109293592A (en) | A method of preparing Gadobutrol | |
| CN102399166B (en) | The Stopholidine of optical siomerism and the preparation method of derivative thereof | |
| CN108794351A (en) | A kind of preparation method of Mo Fanselin key intermediate | |
| CN109867673B (en) | Method for synthesizing palbociclib | |
| CN112062767A (en) | Preparation method and intermediate of rumepilone | |
| CN103864674B (en) | (R) preparation method of-3-amino piperidine dihydrochloride | |
| CN105358529B (en) | A kind of new method of synthesis Eliquis important intermediate | |
| CN107118161B (en) | Synthesis method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid | |
| CN115417802A (en) | Preparation method of sepiatinib and intermediate thereof | |
| CN106543144A (en) | A kind of industrialized process for preparing of dabigatran etcxilate | |
| CN104003985A (en) | Preparation method for palonosetron hydrochloride and intermediate thereof | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN104529960A (en) | Preparation method of prucalopride intermediate | |
| CN108503586B (en) | Process for the preparation of tolvaptan intermediates | |
| CN107935909B (en) | Synthesis method of nintedanib and intermediate thereof | |
| CN102241617A (en) | Synthesis method of 1-tert-butoxycarbonyl-3-pyrrolidone | |
| CN113956183B (en) | Boc-Ser (Bzl) -OH and preparation method thereof | |
| CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
| CN104262340A (en) | Method for preparing Tadalafil | |
| CN116178473A (en) | Preparation method of obeticholic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230314 Address after: Room 301, Building C, Phase III Project (Military and Civilian Integration Industrial Park), Headquarters of Zhejiang Tsinghua Yangtze River Delta Research Institute, No. 4659, Youquan Road, Daqiao Town, Nanhu District, Jiaxing City, Zhejiang Province, 314006 Patentee after: Xianju (Jiaxing) Pharmaceutical Technology Co.,Ltd. Patentee after: Zhejiang Xianju Pharmaceutical Co.,Ltd. Address before: A county of Taizhou City, Zhejiang province 317300 Xianju Road No. 1 Patentee before: Zhejiang Xianju Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |