CN104892595B - Production method of palonosetron hydrochloride - Google Patents
Production method of palonosetron hydrochloride Download PDFInfo
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- SBYHFKPVCBCYGV-UHFFFAOYSA-N C(C1)C2CCN1CC2 Chemical compound C(C1)C2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 2
- YABTYLPBLUXORV-JTQLQIEISA-N NC([C@@H]1c2ccccc2CCC1)=O Chemical compound NC([C@@H]1c2ccccc2CCC1)=O YABTYLPBLUXORV-JTQLQIEISA-N 0.000 description 1
- AKARIZHKZBLDNW-JTQLQIEISA-N O=C([C@@H]1c2ccccc2CCC1)Cl Chemical compound O=C([C@@H]1c2ccccc2CCC1)Cl AKARIZHKZBLDNW-JTQLQIEISA-N 0.000 description 1
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- 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
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a production method of high-purity and high-yield palonosetron hydrochloride. Chiral compounds, namely, (S)-(-)-1,2,3,4-tetrahedro-naphthoic acid and S-3-aminoquinuclidine, are taken as raw materials, and an intermediate is obtained; the intermediate has a reduction reaction in the presence of NaBH4 and BF3*CH3OH, a product is added to a hydrochloric acid aqueous solution for a reflux reaction after the reaction, and a transparent oily substance is obtained through extraction after the reflux reaction; toluene is added to the substance, a toluene solution of triphosgene is dropwise added again at the temperature ranging from 10 DEG C to 15 DEG C, white solids are separated out, a reaction is performed under the condition of heating reflux, and the toluene solution of the triphosgene is dropwise added again under the reflux condition; then a system is cooled to the temperature ranging from 10 DEG C to 15 DEG C, BF3*CH3OH is added, the system is added to water and the hydrochloric acid aqueous solution at the reflux temperature after addition, then a reflux reaction is performed at the heating reflux temperature, and then a crude product is obtained through washing, extraction and crystallization; the crude product is dissolved in acetone, repeated crystallization is performed after dissolution, and the refined palonosetron hydrochloride is obtained. Steps are simple and convenient, reaction conditions are mild, and the production method is easy to operate and suitable for industrial production.
Description
Technical field
The invention belongs to organic synthesis field, and in particular to be a kind of life of the palonosetron Hcl of high-purity high-yield
Product method.
Background technology
Palonosetron Hcl, is the selective serotonin receptor antagonist of Helsinn companies of Switzerland research and development.2003
July 25, U.S. FDA approval is obtained, for, to the acute and delayed nausea and vomiting that vomitting property of height chemotherapy causes, having in prevention
Curative effect height, little toxic and side effect, long half time (about 40h), consumption dosage are little, are other 5-hydroxytryptamine receptors with the affinity of acceptor
More than 100 times of antagonist the features such as.
United States Patent (USP) US5510486 discloses a kind of synthesis technique of new palonosetron Hcl, and its synthetic route is：
The technique has been provided with simple to operate, the advantage of suitable production, but the hydrochloric acid Pa Luonuosi obtained by the technique
Containing the related impurities produced in other three kinds of isomers and other synthesis techniques, chemical purity and optical purity in fine jade crude product
All relatively low, after with isopropanol repeated recrystallize, total recovery but only has 6%, and single contaminant is wayward, and subtractive process needs
A large amount of isopropanols are expended, and refining effect is unsatisfactory.Therefore, it is badly in need of the production work of a kind of total recovery height of exploitation and low cost
Skill.
The content of the invention
It is an object of the invention to provide a kind of production method of palonosetron Hcl.
For achieving the above object, the present invention adopt technical scheme for：
A kind of production method of palonosetron Hcl：
1) obtained as raw material with chipal compounds (S)-(-) -1,2,3,4- tetrahydrochysene -1- naphthoic acids and S-3- amino quinine cyclammonium
Obtain intermediate 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium；
2) gained intermediate 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium is in NaBH4And BF3·
CH3Reduction reaction in the presence of OH, adding after reaction carries out back flow reaction into aqueous hydrochloric acid solution, extracts thoroughly after back flow reaction
Bright grease 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium；
3) add toluene that three light are added dropwise at 10-15 DEG C in 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium
The toluene solution of gas, separates out white solid, is warming up to 105 DEG C of backflows and is reacted, and under counterflow condition, triphosgene is added dropwise again
Toluene solution；Then system is cooled to 10-15 DEG C of addition BF3·CH3OH, adds system under 105 DEG C of reflux temperature after addition
In entering water and aqueous hydrochloric acid solution, then it is warming up to 105 DEG C of reflux temperature and carries out back flow reaction, then washing, extraction crystallization is obtained
Crude product；
4) crude product Jing acetone solutions, by the palonosetron Hcl of methyl tertiary butyl ether(MTBE) crystallization after dissolving, then Jing again
Acetone solution, methyl tertiary butyl ether(MTBE) crystallization obtains final product refined palonosetron Hcl.
The step 1) reaction equation is：
Toluene and SOCl are added in compound 22, 30-35 DEG C is stirred until homogeneous, then is warming up to 65-70 DEG C of stirring 1.0-
1.5h；70-80 DEG C of backflow 5-10min is risen to after stirring, air-distillation to system is changed into yellow solution, and ice bath is cooled down, then
The toluene solution (S-3- amino quinine cyclammonium) of compound 4 is added dropwise, rate of addition is suitably fast, and into little thread shape, 25min is dripped off.
70-80 DEG C of reaction 1-1.5h is warming up to after addition, room temperature is down to after reaction, water management system temperature is added at 40-50 DEG C, ice bath
It is lower addition 50% sodium hydroxide solution, separate out solid room temperature under stir, suction filtration, solid it is dry white powdery solids A；
Filtrate stands after suction filtration, and by the excessive saturated common salt water washing of organic layer, anhydrous sodium sulfate drying, suction filtration obtains clear
Clear solution B；Dried solid A is added in solution B, 70-80 DEG C of backflow 0.5-1h of intensification is down in ice bath after backflow and analyses
Crystalline substance, filters, and filtration cakes torrefaction obtains intermediate 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium 5 to constant weight.
The S-3- amino quinines cyclammonium is S-3- amino quinines cyclammonium hydrochloride (4HCl) to be added in methyl alcohol, ice bath
0-10 DEG C is cooled to, adding KOH makes system be warming up to 70-80 DEG C of stirring 2-2.5h；Room temperature, suction filtration, filter cake are down to after stirring
Air-distillation after washing, adds anhydrous sodium sulfate drying overnight, and next day filters to obtain S-3- amino quinine cyclammonium.
The step 2) reaction equation is：
CH is added in midbody compound 53OH, is cooled to 0 DEG C, adds NaBH4, add and be added dropwise at 0-5 DEG C
BF3·CH3OH, about 1h are dripped off, and are then warmed to room temperature stirring 30-40min, and the reflux temperature for being warming up to 105-110 DEG C after stirring is anti-
2.5-3.5h is answered, room temperature is down to after reaction, then above-mentioned reactant liquor is added in 2N aqueous hydrochloric acid solutions under ice bath cooling condition, then
105-110 DEG C of reflux temperature is warming up to, normal pressure concentration, ice bath cooling after concentration adds the dissolving of 50%KOH solution, 25-35
At DEG C Jing ethyl acetate extraction, collected organic layer be dried, filter, be concentrated to dryness the clear oil thing 3S-N- of intermediate 6 (1,2,
3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium.
30-40min is stirred after the normal pressure concentration, ice bath cooling adds KOH solution dissolving, the Jing second at 25-35 DEG C
Acetoacetic ester stands and separates organic layer, and, again by ethyl acetate extraction merging organic layer, organic layer is by saturated common salt water washing, nothing for water layer
Aqueous sodium persulfate is dried, and filters, and is concentrated to dryness to obtain clear oil thing.
The step 3) reaction equation is：
Intermediate 6 and toluene are mixed, triphosgene toluene solution (being added dropwise to complete in 30min) is added dropwise at 10-15 DEG C and is separated out
White solid, is warming up to 40-50 DEG C of reaction 1-1.5h；Temperature rises to 105-120 DEG C of back flow reaction 1.5-2h after reaction, and is returning
Triphosgene toluene solution (being added dropwise to complete in 20min) is added dropwise under the conditions of stream again, system is down to 40-50 DEG C, adds BF3·CH3OH,
Then system temperature maintains 105-120 DEG C of back flow reaction 3.5-4.5h；System temperature is sequentially added at 30-40 DEG C after reaction
Water and 2N aqueous hydrochloric acid solutions reaction 0.5-1h, are then cooled to room temperature and add 50%KOH solution and ethyl acetate agitation and filtration,
Filter cake is washed by ethyl acetate, and cleaning solution is collected by ethyl acetate extraction, is dried, and suction filtration, filtrate is concentrated to dryness, and obtains brown oil
Thing, above-mentioned brown oil is dissolved in acetone, adds concentrated hydrochloric acid to wait to separate out a large amount of white solids under water-bath, then is warming up to
55-60 DEG C of system is molten clear, is cooled to 15-20 DEG C of crystallization, continues to stir after solid is separated out, and ice bath is cooled to 0-5 DEG C of stirring analysis
Crystalline substance, suction filtration, filter cake obtains crude product 1HCl, hydrochloric acid Pa Luonuo by the acetone washing for freezing, 70-80 DEG C of vacuum drying 3.5-4.0h
Department's fine jade (1HCl).
The step 4) crude product 1HCl is added in acetone, being warming up to 55-60 DEG C of backflow makes solid molten clear, molten clear rear heat
Filter, and the washing of Jing hot acetones, heat filter, filtrate is warming up to 55-60 DEG C of backflow 0.5-1h, is then down to 10-15 DEG C and adds methyl
Tertbutyl ether crystallization, continues to stir after solid is separated out, ice bath is cooled to 0-5 DEG C of stirring and crystallizing, suction filtration, and filter cake was by freezing
Methyl tertiary butyl ether(MTBE) is simultaneously vacuum dried to obtain white solid 1HCl at 50-60 DEG C；By it is above-mentioned it is refined after 1HCl Jing acetone again
Dissolving, methyl tertiary butyl ether(MTBE) crystallization obtains final product refined palonosetron Hcl.
Advantage for present invention：
The palonosetron Hcl of high-purity high-yield, low cost, step letter can be obtained using the preparation method of the present invention
Victory, simple and safe operation, reaction condition is gentle, is adapted to industrialized production, obtains palonosetron Hcl crude product Jing after recrystallization,
Chemical purity and optical purity can reach more than 99.9%, and total recovery is 37%.
Specific embodiment
Embodiment 1
1) S-3- amino quinines cyclammonium (4) prepares reaction equation：
20g (0.1mol) S-3- amino quinines cyclammonium hydrochloride (4HCl) is added in 100ml methyl alcohol, ice bath is cooled to
5℃.Add system temperature after 15.2g (0.23mol) KOH to be warming up to 70 DEG C of stirring 2h, room temperature, suction filtration, filter cake are down to after stirring
Washed with 20ml methyl alcohol 2 times, cleaning solution is poured in reaction bulb, air-distillation then adds 80ml to solvent residue about 30-40ml
Toluene, air-distillation is to solvent residue about 30-40ml, then adds 100ml toluene, continues normal pressure and steams about 20ml solvents, makes anti-
Answer bottle internal solvent amount about 130ml, then with anhydrous sodium sulfate drying overnight, next day filter compound 4 toluene solution, directly
Feed intake for lower step.
2) 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium (5) prepares reaction equation：
15.84g (0.09mol) (S)-(-) -1,2,3,4- tetrahydrochysenes -1- naphthoic acids are sequentially added in 0.5L reaction bulbs
Raw material 2,160ml toluene and 12.8g (0.108mol) SOCl2, 35 DEG C of stirring 1h.70 DEG C are warming up to after stirring and are stirred for 1.5h.
Then rise to 110 DEG C of backflow normal pressures and steam about 30ml, steam ice bath after solvent and be cooled to about 0 DEG C, step 1 is added dropwise at a slow speed) obtain
Compound 4 toluene solution, 25min drips off, and is warming up to 70 DEG C of reaction 1h.Room temperature is down to after reaction, 120ml water, control is added
35 DEG C of temperature, adds 50wt% NaOH 9g (0.108mol) under ice bath.A large amount of solids are separated out, 20min is stirred at room temperature, suction filtration,
Filter cake is washed 2 times by 30ml water loggings, be placed in convection oven be dried (70 DEG C) of 5h 21g white powdery solids A；Filtrate stands and separates
Organic layer, water layer extracts (50ml*2) by dichloromethane, merges organic layer, and the saturated common salt water washing of organic layer Jing 30ml is washed
Again by anhydrous sodium sulfate drying after washing, suction filtration obtains settled solution B.Dried solid A is added in solution B, 80 DEG C are warming up to
Backflow 1h, is down to ice bath moderate-speed mixer crystallization 1h, filters, and filter cake is washed 2 times by 20ml toluene, is placed in 70 DEG C of dryings of convection oven
To constant weight, 22g white powdery solids 5, yield are obtained：86%.
3) 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium (6) prepares reaction equation：
11.36g (0.04mol) intermediate 5 is added in the reaction bulb equipped with drying tube, 200ml CH are added3OH, cooling
To 0 DEG C, 4.72g (0.12mol) NaBH is added4., 10.0g (0.10mol) BF is added dropwise3·CH3OH, temperature control during dropwise addition
Finish in -5 DEG C of about 20min, be warmed to room temperature stirring 30min, be warming up to 105 DEG C of back flow reactions 2.5h.Room temperature is down to, then in ice
During above-mentioned reactant liquor to be added to the 2N aqueous hydrochloric acid solutions of 120ml under bath cooling, 70 DEG C of backflow 1h are warming up to, normal pressure is steamed about
200ml CH3OH, used time about 2h, steam and make after organic solvent system temperature and maintain 70 DEG C, stir 30min.Then ice bath is cold
But to 10 DEG C, 70.4g 50%KOH solution is added dropwise, controls below 35 DEG C, to add 150ml ethyl acetate during dropwise addition, it is quiet
Put and separate organic layer, water layer is extracted 2 times by 75ml ethyl acetate, merge organic layer, washed once by 40ml saturated aqueous common salts, nothing
Aqueous sodium persulfate is dried, and filters, and is concentrated to dryness to obtain 11.3g clear oil things, quantitative yield.
4) palonosetron Hcl (1HCl) prepares reaction equation
11.3g (0.04mol) intermediate 6 and 160ml toluene are added in 0.5L reaction bulbs, 15 DEG C are cooled to, is added dropwise
Toluene solutions of the 35ml containing 4.16g (0.014mol) triphosgene, under conditions of remaining temperature-resistant, about 15min completion of dropping, analysis
Go out white solid, system is warming up to 40 DEG C of reaction 1h；System rises to 105 DEG C of back flow reactions 2.5h after reaction, while in backflow temperature
Under degree, toluene solutions of the 25ml containing 1.8g (0.006mol) triphosgene, about 20min completion of dropping, backflow 8h is added dropwise.Then system
40 DEG C are down to, 10.0g (0.10mol) BF is disposably added3·CH3OH, is warming up to 105 DEG C of back flow reactions 3.5h after addition；Backflow
63ml water and 63ml 2N aqueous hydrochloric acid solutions are sequentially added after reaction, is finished, system is warming up to 105 DEG C of back flow reactions 0.5h.Reaction
After be cooled to room temperature, add 68g 50%KOH and 85ml ethyl acetate, temperature control stirs 5min less than 35 DEG C, filtration,
Filter cake is washed 2 times by 20ml ethyl acetate, and water layer is extracted 2 times by 40ml ethyl acetate, and combining extraction liquid uses 30ml saturated common salts
Water washing once, adds anhydrous sodium sulfate drying, suction filtration, filtrate to be concentrated to dryness to obtain 12.7g brown oils.By above-mentioned grease
In being dissolved in 120ml acetone, water-bath cooling is lower to add 1.9ml concentrated hydrochloric acids, and a large amount of white solids are separated out after 5min.It is warming up to 55
DEG C, system is molten clear, it is molten it is clear after be cooled to 15 DEG C of crystallizations, continue to stir 0.5h after solid is separated out, ice bath is cooled to 0-5 DEG C of stirring
Crystallization 1h, suction filtration, filter cake is washed 2 times by the acetone that 5ml was freezed, and is vacuum dried 3.5h in 70 DEG C and is obtained 9g crude product 1HCl, is
Off-white powder, crude yield：67.6% (chemical purity：99.89%；Optical purity：99.27%, isomers：0.70%).
5) palonosetron Hcl (1HCl) is refined
Primary purification：9g crude products 1HCl is added in 50ml acetone, 105 DEG C of back flow reactions 0.5h are warming up to, solid is made
Molten clear, molten clear rear stopping heating, heat filter, the acetone of reaction bulb 50 DEG C of 10ml of addition is washed, heat filter.Filtrate is warming up to 105 DEG C and returns
Stream steams 30ml solvents, and residue is down to room temperature, adds 20ml methyl tertiary butyl ether(MTBE) crystallizations, continues to stir after solid is separated out
0.5h, ice bath is cooled to 5 DEG C of stirring and crystallizings 3h, and suction filtration, filter cake is washed 2 times by the methyl tertiary butyl ether(MTBE) that 7ml was freezed, in 50 DEG C
Vacuum drying 2h obtains 7.3g white solid the 1HCl, (chemical purity of yield 81%：99.93%；Optical purity：99.87%, it is different
Structure body：0.10%).
Secondary refining：1HCl after 7.3g primary purifications is added in 45ml acetone, 105 DEG C of backflow 0.5h are warming up to,
Solid is molten clear, it is molten it is clear after be down to room temperature crystallization, continue to stir 0.5h after solid is separated out, ice bath is cooled to 5 DEG C of stirring and crystallizings 3h,
Suction filtration, filter cake is washed 2 times by the methyl tertiary butyl ether(MTBE) that 5ml was freezed, and is vacuum dried 3h in 60 DEG C and is obtained 6.1g white products (1
HCl), (chemical purity of yield 83.5%：99.97%；Optical purity：99.96%, isomers：0.02%).
Embodiment 2
1) S-3- amino quinines cyclammonium (4) prepares reaction equation：
2.0kg (10mol) S-3- amino quinines cyclammonium hydrochloride (4HCl) is added in 10L methyl alcohol, ice bath is cooled to 5
℃.Add system temperature after 1.52kg (23mol) KOH to be warming up to 70 DEG C of stirring 2h, room temperature is down to after stirring, suction filtration, filter cake is used
2L methyl alcohol is washed 2 times, and cleaning solution is poured in reaction bulb, air-distillation to solvent residue about 3-4L, then adds 8L toluene, normal pressure
Distill to solvent residue about 3-4L, then add 10L toluene, continue normal pressure and steam about 2L solvents, make reaction bulb internal solvent amount about
13L, then with anhydrous sodium sulfate drying overnight, next day filter compound 4 toluene solution, be directly used in lower step and feed intake.
2) 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium (5) prepares reaction equation：
Sequentially add in 50L glass kettles 1.6kg (9mol) (S)-(-) raw material 2 of -1,2,3,4- tetrahydrochysenes -1- naphthoic acids,
16L toluene and 1.3kg (10.8mol) SOCl2, 35 DEG C of stirring 1h.70 DEG C are warming up to after stirring and are stirred for 1.5h.Then rise to
110 DEG C of backflow normal pressures steam about 3L, steam ice bath after solvent and are cooled to about 0 DEG C, and step 1 is added dropwise at a slow speed) compound 4 that obtains
Toluene solution, 30min is dripped off, and is warming up to 70 DEG C of reaction 1h.Room temperature is down to after reaction, 12L water, 40 DEG C of temperature control, under ice bath is added
Add 50% NaOH 0.9kg (10.8mol).A large amount of solids are separated out, 20min is stirred at room temperature, suction filtration, filter cake is washed by 3L water loggings
2 times, be placed in convection oven be dried (70 DEG C) of 5h 2.1kg white powdery solids A；Filtrate stands and separates organic layer, water layer by
Dichloromethane extracts (5L*2), merges organic layer, the saturated common salt water washing of organic layer Jing 3L, again by anhydrous sodium sulfate after washing
It is dried, suction filtration obtains settled solution B.Dried solid A is added in solution B, 80 DEG C of backflow 1h are warming up to, ice bath middling speed is down to
Stirring and crystallizing 1h, filters, and filter cake is washed 2 times by 2L toluene, is placed in 70 DEG C of dryings of convection oven to constant weight, obtains 2.3kg white powder
Last shape solid 5, yield：90%.
3) 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium (6) prepares reaction equation：
1.14kg (4.0mol) intermediate 5 is added in glass kettle, 20L CH are added3OH, is cooled to 0 DEG C, adds 472g
(12.0mol)NaBH4.- 5 DEG C of temperature control, is added dropwise 1.0kg (10.0mol) BF3·CH3OH, about 20min is finished, and is warmed to room temperature stirring
30min, is warming up to 105 DEG C of back flow reactions 2.5h.Room temperature is down to, then under ice cooling, 4 above-mentioned reactant liquor is added to into 1.2L's
In 2N aqueous hydrochloric acid solutions, 70 DEG C of backflow 1h are warming up to, normal pressure steams about 20L CH3OH, used time about 2h, steams and made after organic solvent
System temperature maintains 70 DEG C, stirs 30min.Then ice bath is cooled to 10 DEG C, and 7.0kg 50%KOH solution, temperature control is added dropwise<35
DEG C, 15L ethyl acetate is added, standing separates organic layer, and water layer is extracted 2 times by 7.5L ethyl acetate, merges organic layer, by 4L
Saturated aqueous common salt washed once, anhydrous sodium sulfate drying, filter, and be concentrated to dryness to obtain 1.2kg clear oil things, quantitative yield.
4) palonosetron Hcl (1HCl) prepares reaction equation
1.2kg (4.2mol) intermediate 6 and 17.0L toluene are added in 50L glass kettles, 12 DEG C are cooled to, 3.7L is added dropwise
Toluene solution containing 441g (1.5mol) triphosgene, under conditions of remaining temperature-resistant, about 15min completion of dropping separates out white
Solid, system is warming up to 40 DEG C of reaction 1h；System rises to 105 DEG C of back flow reactions 2.5h after reaction, while at a reflux temperature, drop
Plus toluene solutions of the 2.65L containing 190g (0.6mol) triphosgene, about 20min completion of dropping, flow back 8h.Then system is down to 40
DEG C, disposably add 1.06kg (10.0mol) BF3·CH3OH, is warming up to 105 DEG C of back flow reactions 3.5h after addition；Back flow reaction
After sequentially add 6.68L water and 6.68L 2N aqueous hydrochloric acid solutions, finish, system is warming up to 105 DEG C of back flow reactions 0.5h.After reaction
Room temperature is cooled to, 7.2kg 50%KOH and 9.0L ethyl acetate, temperature control is added<35 DEG C, 5min is stirred, filtered, filter cake is by 2.1L
Ethyl acetate is washed 2 times, and water layer is extracted 2 times by 4.2L ethyl acetate, combining extraction liquid, with 3.2L saturated common salts water washing one
It is secondary, add anhydrous sodium sulfate drying, suction filtration, filtrate to be concentrated to dryness to obtain 1.4kg brown oils.Above-mentioned grease is dissolved in
In 13.2L acetone, water-bath cooling is lower to add 200ml concentrated hydrochloric acids, and a large amount of white solids are separated out after 5min.55 DEG C are warming up to, system
It is molten clear, it is molten it is clear after be cooled to 15 DEG C of crystallizations, continue to stir 0.5h after solid is separated out, ice bath is cooled to 0-5 DEG C of stirring and crystallizing 1h,
Suction filtration, filter cake is washed 2 times by the acetone that 500ml was freezed, and is vacuum dried 3.5h in 70 DEG C and is obtained 1.0kg crude product 1HCl, is class
White solid, crude yield：75.1% (chemical purity：99.87%；Optical purity：99.19%, isomers：0.77%).
5) palonosetron Hcl (1HCl) is refined
Primary purification：1.0kg crude products 1HCl is added in 5.5L acetone, 105 DEG C of back flow reactions 0.5h are warming up to, is made solid
Body is molten clear, and molten clear rear stopping heating, heat filter, the acetone of reaction bulb 50 DEG C of 1.1L of addition is washed, heat filter.Filtrate is warming up to 105 DEG C
Backflow steams 3.3L solvents, and residue is down to room temperature, adds 2.2L methyl tertiary butyl ether(MTBE) crystallizations, continues to stir after solid is separated out
0.5h, ice bath is cooled to 5 DEG C of stirring and crystallizings 3h, and suction filtration, filter cake is washed 2 times by the methyl tertiary butyl ether(MTBE) that 770ml was freezed, in 50
DEG C vacuum drying 2h obtain 800g white solid the 1HCl, (chemical purity of yield 88%：99.95%；Optical purity：99.85%,
Isomers：0.10%).
Secondary refining：1HCl after 800g primary purifications is added in 5.0L acetone, 105 DEG C of backflow 0.5h are warming up to,
Solid is molten clear, it is molten it is clear after be down to room temperature crystallization, continue to stir 0.5h after solid is separated out, ice bath is cooled to 5 DEG C of stirring and crystallizings 3h,
Suction filtration, filter cake is washed 2 times by the methyl tertiary butyl ether(MTBE) that 550ml was freezed, and is vacuum dried 3h in 60 DEG C and is obtained 650g white products
(1HCl), (chemical purity of yield 88.5%：99.97%；Optical purity：99.96%, isomers：0.02%).
Claims (3)
1. a kind of production method of palonosetron Hcl, it is characterised in that：
1) in chipal compounds (S)-(-) -1,2,3,4- tetrahydrochysene -1- naphthoic acids and S-3- amino quinines cyclammonium as raw material acquisition
Mesosome 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium；
The step 1) reaction equation is：
Toluene and SOCl are added in compound 22, 30-35 DEG C is stirred until homogeneous, then is warming up to 65-70 DEG C of stirring 1.0-1.5h；
70-80 DEG C of backflow 5-10min is risen to after stirring, air-distillation to system is changed into yellow solution, and ice bath is cooled down, then dropwise additionization
The toluene solution (S-3- amino quinine cyclammonium) of compound 4, is warming up to 70-80 DEG C of reaction 1-1.5h after addition, room is down to after reaction
Temperature, adds water management system temperature at 40-50 DEG C, and 50% sodium hydroxide solution is added under ice bath, separates out and stirred under solid room temperature,
Suction filtration, solid it is dry white powdery solids A；
Filtrate stands after suction filtration, and by the excessive saturated common salt water washing of organic layer, anhydrous sodium sulfate drying, suction filtration must be clarified molten
Liquid B；Dried solid A is added in solution B, 70-80 DEG C of backflow 0.5-1h of intensification is down to crystallization in ice bath, mistake after backflow
Filter, filtration cakes torrefaction obtains intermediate 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium 5 to constant weight；
2) gained intermediate 3S-N- (1,2,3,4- tetrahydrochysene -1S- naphthoyls)-quinine cyclammonium is in NaBH4And BF3·CH3OH's
In the presence of reduction reaction, adding after reaction carries out back flow reaction into aqueous hydrochloric acid solution, and clear oil is extracted to obtain after back flow reaction
Thing 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium；
The step 2) reaction equation is：
CH is added in midbody compound 53OH, is cooled to 0 DEG C, adds NaBH4, add and BF be added dropwise at 0-5 DEG C3·
CH3OH, is then warmed to room temperature stirring 30-40min, 105-110 DEG C of reflux temperature reaction 2.5-3.5h is warming up to after stirring, instead
Should after be down to room temperature, then above-mentioned reactant liquor is added in 2N aqueous hydrochloric acid solutions under ice bath cooling condition, then be warming up to 105-110
DEG C reflux temperature, normal pressure concentration, ice bath cooling after concentration adds the dissolving of 50%KOH solution, the Jing acetic acid second at 25-35 DEG C
Ester is extracted, and collected organic layer is dried, and is filtered, and is concentrated to dryness to obtain clear oil thing 3S-N- (1,2,3, the 4- tetrahydrochysene -1S- of intermediate 6
Menaphthyl)-quinine cyclammonium；
3) add toluene that triphosgene is added dropwise at 10-15 DEG C in 3S-N- (1,2,3,4- tetrahydrochysene -1S- menaphthyls)-quinine cyclammonium
Toluene solution, separates out white solid, is warming up to 105-120 DEG C of backflow and is reacted, and under counterflow condition, triphosgene is added dropwise again
Toluene solution；Then system is cooled to 40-50 DEG C of addition BF3·CH3OH, adds system under 105 DEG C of reflux temperature after addition
In entering water and aqueous hydrochloric acid solution, then it is warming up to 105 DEG C of reflux temperature and carries out back flow reaction, then washing, extraction crystallization is obtained
Crude product；
The step 3) reaction equation is：
Intermediate 6 and toluene are mixed, triphosgene toluene solution is added dropwise at 10-15 DEG C, be added dropwise to complete in 30min, separate out white
Solid, is warming up to 40-50 DEG C of reaction 1-1.5h；Temperature rises to 105-120 DEG C of back flow reaction 1.5-2h after reaction, and in reflux condition
Triphosgene toluene solution is added dropwise under part again, system is down to 40-50 DEG C, adds BF3·CH3OH, then system temperature maintain 105-
120 DEG C of back flow reactions 3.5-4.5h；Water and 2N aqueous hydrochloric acid solutions are sequentially added after back flow reaction, then is warming up to 105 DEG C of backflows instead
05-1h is answered, room temperature is then cooled to and is added 50%KOH solution and ethyl acetate agitation and filtration, filter cake is washed by ethyl acetate,
Cleaning solution is collected by ethyl acetate extraction, is dried, and suction filtration, filtrate is concentrated to dryness, and brown oil is obtained, by above-mentioned brown oil
In being dissolved in acetone, concentrated hydrochloric acid is added to wait to separate out a large amount of white solids under water-bath, then molten clear, the cooling that is warming up to 55-60 DEG C of system
To 15-20 DEG C of crystallization, continue to stir after solid is separated out, ice bath is cooled to 0-5 DEG C of stirring and crystallizing, suction filtration, filter cake was by freezing
Acetone washing, 70-80 DEG C vacuum drying 3.5-4.0h obtain crude product 1HCl, palonosetron Hcl (1HCl)；
4) crude product Jing acetone solutions, palonosetron Hcl is obtained after dissolving by methyl tertiary butyl ether(MTBE) crystallization, then Jing acetone again
Dissolving, methyl tertiary butyl ether(MTBE) crystallization obtains final product refined palonosetron Hcl；
The step 4) crude product 1HCl is added in acetone, being warming up to 55-60 DEG C of backflow makes solid molten clear, molten clear rear heat filter,
And Jing hot acetones are washed, heat filter, filtrate is warming up to 55-60 DEG C of backflow 0.5-1h, is then down to 10-15 DEG C and adds methyl- tert fourth
Base ether crystallization, continues to stir after solid is separated out, and ice bath is cooled to 0-5 DEG C of stirring and crystallizing, suction filtration, and filter cake is by the methyl for freezing
Tertbutyl ether is simultaneously vacuum dried to obtain white solid 1HCl at 50-60 DEG C；By it is above-mentioned it is refined after 1HCl Jing acetone solutions again,
Methyl tertiary butyl ether(MTBE) crystallization, obtains final product refined palonosetron Hcl.
2. the production method of the palonosetron Hcl as described in claim 1, it is characterised in that：The S-3- amino quinines ring
Amine is S-3- amino quinines cyclammonium hydrochloride (4HCl) to be added in methyl alcohol, and ice bath is cooled to 0-10 DEG C, and adding KOH makes body
System is warming up to 70-80 DEG C of stirring 2-2.5h；Room temperature is down to after stirring, suction filtration, air-distillation after Washing of Filter Cake adds anhydrous slufuric acid
Sodium is dried overnight, and next day filters to obtain S-3- amino quinine cyclammonium.
3. the production method of the palonosetron Hcl as described in claim 1, it is characterised in that：Stir after the normal pressure concentration
30-40min, ice bath cooling adds KOH solution dissolving, and Jing ethyl acetate stands and separates organic layer at 25-35 DEG C, and water layer is again
By ethyl acetate extraction merging organic layer, organic layer is filtered by saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated to dryness
Obtain clear oil thing.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO2011001400A2 (en) * | 2009-06-30 | 2011-01-06 | Ranbaxy Laboratories Limited | Processes for the preparation of form i and form ii of palonosetron hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO2011001400A2 (en) * | 2009-06-30 | 2011-01-06 | Ranbaxy Laboratories Limited | Processes for the preparation of form i and form ii of palonosetron hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸帕洛诺司琼的合成;杜有国等;《当代化工》;20100228;第39卷(第1期);第14页图1，第14页1.2-第15页1.7 * |
| 盐酸帕洛诺司琼的合成;郑德强等;《食品与药品》;20101231;第12卷(第3期);第88页2.4，右栏第6段 * |
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