CN101633657B - Preparation method of palonosetron and palonosetron hydrochloride and injection - Google Patents
Preparation method of palonosetron and palonosetron hydrochloride and injection Download PDFInfo
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- MWBULQNPGVGHKO-SSDOTTSWSA-N C[C@H]1C(CC2)CCN2C1 Chemical compound C[C@H]1C(CC2)CCN2C1 MWBULQNPGVGHKO-SSDOTTSWSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of palonosetron and palonosetron hydrochloride and an injection, which belongs to the pharmaceutical chemical field. The invention provides the preparation method of the palonosetron, and the preparation method comprises the steps of reacting (1-aza-3(S)-bicyclo [2,2,2] octane base)-(1,2,3,4-tetralin-1S-methyl) amine with Bis(trichloromethyl)carbonate, and adding boron trifluoride to perform the reflux reaction to obtain the palonosetron. The preparation method has the advantages of simple process as well as high yield, good purity and low cost of the obtained products.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly the preparation method of Palonosetron, PalonosetronHydrochloride and injection.
Background technology
PalonosetronHydrochloride (English name Palonosetron Hydrochloride, chemical name: (3aS)-2-[(S)-1-nitrogen heterocyclic two [2,2,2] oct-3-yl]-2,3,3a, 4,5,6-, six hydrogen-1-ketone-1H benzene [also] isoquinoline hydrochloride) be white crystalline powder, fusing point＞290 ℃, molecular formula is C
19H
24N
2OHCl, molecular weight are 332.9; Easily molten in water, in propylene glycol, methyl alcohol and trichloromethane, dissolve slightly soluble in ethanol and 2-propyl alcohol.PalonosetronHydrochloride is the 5-HT of a kind of novel highly selective, high-affinity
3Receptor antagonist is used for causing the acute and retardance nausea and vomiting that telling property chemotherapeutics causes to severe clinically.Itself and 5-HT act on 5-HT competitively
3Acceptor, thereby blocking-up vomiting, its structure is suc as formula shown in the I:
Formula I
The preparation method of existing PalonosetronHydrochloride has following several:
1, No. 200610156874.1 patent applications disclose (S)-tetrahydro-naphthoic acid and thionyl chloride and (S)-3 amino-quinine cyclic amine reaction and have obtained (s, s)-rubane naphthane methane amide, (s, s)-rubane naphthane methane amide obtains (s with the reaction of reductive agent and boron trifluoride diethyl etherate again, s)-naphthane methyl quinuclidine cyclammonium, (s, s)-naphthane methyl quinuclidine cyclammonium and superpalite reaction, add boron trifluoride diethyl etherate, add hydrochloric acid and water in the product again, obtain PalonosetronHydrochloride.
The finished product in this method the first step, second step dewaters after with ethyl acetate extraction and is not easy thoroughly to cause productive rate lower; Adopt the isopropyl alcohol and water during the finished product recrystallization, productive rate is not high.
2, disclosed method one synthetic route is as follows among synthesis 1,996 7 816-818:
This method needs-70 ℃ cold condition with the reduction of boron sodium cyanide the time, and condition is difficult to control during hydrogenation, and Fan Ying selectivity is not high simultaneously.
3, disclosed method two synthetic routes are as follows among synthesis 1,996 7 816-818:
Condition is difficult to control during this method hydrogenation, and the selectivity of reaction is not high; The metal that contains in the naphthoic acid raw material during hydrogenolysis makes poisoning of catalyst easily.
4, US Patent No. 5510486 disclosed synthetic routes are:
This method first step needs the cold condition of anhydrous and oxygen-free and-30 ℃, the conditional request harshness, all the other each step operations are relatively simple, do not need special reaction unit, be easy to suitability for industrialized production, the PalonosetronHydrochloride crude product that obtains is once removed impurity with the Virahol recrystallization.But after adopting the crude product recrystallization that this method prepares, also have more impurity in the product, and repeatedly behind the recrystallization purity of finished product just can reach 99%, single foreign matter content also surpasses 0.1%, if it is very difficult further to improve the quality of product.
In sum, the preparation method of existing PalonosetronHydrochloride exists that product purity is low, processing requirement is high, production cost is than problems such as height.
Summary of the invention
First technical problem to be solved by this invention provides the preparation method of the simple Palonosetron of a kind of technology.
Solving the problems of the technologies described above the technical scheme that adopts is: the preparation method of Palonosetron is (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) behind amine and the trimerization phosgene reaction, extraction namely gets Palonosetron after the adding boron trifluoride back flow reaction.
Wherein the consumption mol ratio of (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine, three surpalites, boron trifluoride is 1: 6～8: 8～10, is preferably 1: 7: 9.When using, boron trifluoride is dissolved in the solution of ether as boron trifluoride.Overflow because three surpalites gasify easily when refluxing, may cause reaction not exclusively, three surpalites add (1-azepine-3 (S)-dicyclo [2 at twice, 2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) in the toluene solution of amine, guarantees that reaction thoroughly, elder generation adds 60～70% three surpalites, in room temperature reaction 8h～12h, back flow reaction 3～6h adds remaining three surpalites again, in room temperature reaction 0.5～1.5h, back flow reaction 3～6h.Add boron trifluoride ether solution under the room temperature, back flow reaction 5～8h.Carry out extraction step after reacting completely: add hydrochloric acid reflux, water phase separated and organic phase, the organic phase hcl as extraction agent, receive water regulate pH=9～11, use chloroform extraction, merge the trichloromethane layer and wash with saturated nacl aqueous solution, desolventizing is namely.
The beneficial effect of the inventive method is:
This preparation method is atmospheric operation, the reaction conditions gentleness, and technology is easy, and equipment is simple, and cost is low, is fit to large-scale commercial production.
Do not use virulent reagent among this preparation method, the recycling of reagent is easy, is conducive to environment protection.
Second technical problem to be solved by this invention provides a kind of preparation method of PalonosetronHydrochloride, and this method is that Palonosetron that aforesaid method obtains is dissolved in the saturated hydrogen chloride solution that drips ethanol behind the Virahol and obtains PalonosetronHydrochloride.PalonosetronHydrochloride obtains the highly finished product of PalonosetronHydrochloride with Virahol/methyl alcohol mixed liquor recrystallization; The volume ratio of Virahol/methyl alcohol mixed liquor is preferably 3: 1.
PalonosetronHydrochloride crude product Virahol and recrystallizing methanol purifying, productive rate is higher, purity is better.
The 3rd technical problem to be solved by this invention provides a kind of PalonosetronHydrochloride injection of stable in properties.
Contain PalonosetronHydrochloride (with C in every milliliter of PalonosetronHydrochloride injection of described PalonosetronHydrochloride injection
19H
24N
2The O meter) 0.05mg, N.F,USP MANNITOL 41.2～41.8mg, Sodium Citrate 1.8～1.92mg, Citric Acid 0.7～0.82mg and Calcium Disodium Edetate 0.46～0.54mg.
Wherein N.F,USP MANNITOL is isotonic regulator, and sodium citrate and citric acid is buffer system, regulates the pH value of injection liquid.Heavy metal ion in the Calcium Disodium Edetate energy complexing injection liquid plays antioxidant, function of stabilizer.
Contain PalonosetronHydrochloride (with C in preferred every milliliter of PalonosetronHydrochloride injection
19H
24N
2The O meter) 0.05mg, N.F,USP MANNITOL 41.5mg, Sodium Citrate 1.86mg, Citric Acid 0.77mg and Calcium Disodium Edetate 0.50mg.
PalonosetronHydrochloride injection preparation unit is 0.05mg/5ml.
The 4th technical problem to be solved by this invention provides the preparation method of above-mentioned PalonosetronHydrochloride injection, specifically may further comprise the steps:
A, take by weighing N.F,USP MANNITOL 206～209g, Sodium Citrate 9～9.6g, Citric Acid 3.5～4.1g and Calcium Disodium Edetate 2.3～2.7g respectively in proportion, the water for injection that adds 1500～3000ml, stirring and dissolving, the medicinal carbon that adds solution total amount 0.04～0.06% (W/V) again, 55～65 ℃ of insulations were adsorbed 10～20 minutes, filtered;
B, take by weighing the 250mg PalonosetronHydrochloride (with C
19H
24N
2The O meter) in the water for injection of 800～1500ml, dissolving fully;
C, two kinds of solution that steps A, B are obtained mix, and add the injection water and are settled to 5000ml, regulate pH value 4.5～5.5, and are extremely clear and bright with the millipore filtration filtration of 0.18～0.26 μ m;
The filled with solution that D, step C make is sealed in ampoule, and in 114～118 ℃ of pressure sterilizing 30～50min, cooling namely.
Preferably, steps A raw material consumption is among the preparation method of PalonosetronHydrochloride injection: N.F,USP MANNITOL 207.5g, Sodium Citrate 9.32g, Citric Acid 3.85g and Calcium Disodium Edetate 2.5g.The medicinal carbon add-on is solution total amount 0.05% (W/V), and the charcoal absorption condition is 60 ℃ of insulation absorption 15 minutes.
Step C millipore filtration specification is 0.22 μ m.
Step D ampoule is brown, and the pressure sterilizing condition is 116 ℃ of pressure sterilizing 40min.
The PalonosetronHydrochloride injection that adopts preparation method of the present invention to make, foreign matter content is few, stable in properties.
Embodiment
Used (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3, the 4-naphthane-1S-methyl) amine of the present invention can be bought by market and obtain, and also can prepare by the following method, comprising:
A, (S)-1,2,3, the toluene solution of 4-tetrahydrochysene-1-naphthoyl chloride adds 1-azepine-3 (S)-dicyclo [2,2,2] react in the chloroform soln of octyl amine, obtain N-(1-azepine-3 (S)-dicyclo [2,2,2] 4-naphthane-1S-methane amide octyl)-1,2,3;
B, N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1,2, after 3,4-naphthane-1S-methane amide and sodium borohydride and the boron trifluoride ether solution reaction, add hydrochloric acid reaction and obtain (1-azepine-3 (S)-dicyclo [2,2,2] amine octyl)-(1,2,3,4-naphthane-1S-methyl).
Wherein, described (S)-1,2,3 of step a, 4-tetrahydrochysene-1-naphthoyl chloride obtains after can being reacted by 1,2,3,4-tetrahydrochysene-1S-naphthoic acid and thionyl chloride, and the mol ratio of 1,2,3,4-tetrahydrochysene-1S-naphthoic acid and thionyl chloride is 1: 5; Reaction solvent is toluene, and the toluene consumption is 9～11 times of 1,2,3,4-tetrahydrochysene-1S-naphthoic acid weight; DMF is catalyzer, and consumption is 0.055～0.07 times of 1,2,3,4-tetrahydrochysene-1S-naphthoic acid weight.After reaction conditions is room temperature reaction 0.5～1.5h, again in 45～55 ℃ of reaction 2～5h.
After the described 1-azepine-3 of step a (S)-dicyclo [2,2,2] octyl amine can be dissolved in alcohol by 1-azepine-3 (S)-dicyclo [2,2,2] octyl amine hydrochloride, regulate pH=9～11, prepare after vaporing away solvent; Preferably, described alcohol is methyl alcohol or ethanol, regulates pH=10.
Step a (S)-1,2,3, the mol ratio of 4-tetrahydrochysene-1-naphthoyl chloride and 1-azepine-3 (S)-dicyclo [2,2,2] octyl amine is 1: 1.3～1.7, is preferably 1: 1.5; During reaction, earlier with (S)-1,2,3,4-tetrahydrochysene-1-naphthoyl chloride is dissolved in toluene, 1-azepine-3 (S)-dicyclo [2,2,2] octyl amine mixes after being dissolved in trichloromethane, and reaction conditions is 45～55 ℃ of reaction 8～12h, after reacting completely, reaction solution is transferred pH=9～11 (transferring pH reagent to be preferably 50%NaOH (wt%) solution), adds water and isolate water, the water chloroform extraction, receive organic phase with the desolventizing of saturated nacl aqueous solution washing back, resistates with toluene wash after namely.
Step b N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1,2,3, the mol ratio of 4-naphthane-1S-methane amide and sodium borohydride and boron trifluoride is 1: 4～5: 7～9, be preferably 1: 4.6: 8, reaction solvent is tetrahydrofuran (THF), is dissolved in the solution of ether when boron trifluoride uses as boron trifluoride, reaction conditions is to react 0.5～1.5h below 20 ℃, 60 ℃ of reaction 3～6h.After reacting completely, in below 10 ℃, add hydrochloric acid and make solid dissolving in the reaction solution, solvent evaporated adds hydrochloric acid and intensification and makes reaction solution become clarification, conditioned reaction liquid pH=9～11, use chloroform extraction, the chloroform soln of collection washs with saturated nacl aqueous solution, and solvent evaporated namely.
Two starting raw materials of aforesaid method be easy to get, cheap and split 1,2,3,4-tetrahydrochysene-1S-naphthoic acid and 1-azepine-3 (S)-dicyclo [2,2,2] octyl amine hydrochloride, intermediate and the finished product separation and purification are easy, and quality product is controlled easily.
The invention will be further elaborated below in conjunction with embodiment.Embodiment only is used for explanation the present invention, rather than limits the present invention by any way.
Embodiment 1
Step 1, N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1,2,3,4-naphthane-1S-methane amide synthetic
1,2,3,4-tetrahydrochysene-1S-naphthoic acid 300g is dropped in the reaction flask of 5L, add the toluene of the fresh distillation of 3L, be stirred to dissolving fully, reaction solution clarification.Under the ice bath cooling conditions, drip adding 20ml N, dinethylformamide.Keep temperature of reaction system below 20 ℃, slowly drip thionyl chloride 0.56L, dropwise back stirring at room reaction 1h.Continue to stir in 50 then, TLC (thin-layer chromatography) follows the tracks of reaction process, and (developping agent is sherwood oil: ethyl acetate=3: 1), approximately the 3h afterreaction is complete.The concentrating under reduced pressure desolventizing, the toluene of adding the fresh distillation of 0.5L continues to be evaporated to solvent-free outflow, and is standby behind the adding 0.5L toluene in the resistates ((S)-1,2,3,4-tetrahydrochysene-1-naphthoyl chloride).
The processing of 1-azepine-3 (S)-dicyclo [2,2,2] octyl amine hydrochloride:
With 408g 1-azepine-3 (S)-dicyclo [2,2,2] the octyl amine hydrochloride drops in the reaction flask of 10L, add 3L methyl alcohol, regulate about pH=10 with saturated sodium hydroxide solution under the room temperature, concentrating under reduced pressure is done, add 0.3L * 3 dehydrated alcohols more respectively, 0.3L toluene concentrates band water, residue adds the dissolving of 6L trichloromethane, and the ice bath cooling is standby.
Keeping temperature of reaction system is below 20 ℃, with (S)-1,2,3,4-tetrahydrochysene-1-naphthoyl chloride solution slowly is added drop-wise in the chloroform soln of above-mentioned 1-azepine-3 (S)-dicyclo [2,2, the 2] octyl amine for preparing, dropwise back stirring at room reaction 30min, be warming up to then about 50 ℃ of stirring reaction 10h, TLC follows the tracks of reaction process and makes (S)-1,2, (developping agent is trichloromethane: methyl alcohol=5: 1) till 3,4-tetrahydrochysene-1-naphthoyl chloride complete reaction.After reacting completely, in transferring about reaction solution pH=10 with 50%NaOH solution under the ice bath, add 2L water, water phase separated and organic phase, water 1L chloroform extraction 3 times merge organic phase, with 1L saturated nacl aqueous solution washing 2 times, anhydrous magnesium sulfate drying. filter the concentrating under reduced pressure desolventizing, resistates adds the ice-cold toluene of 0.5L, shakes up, and filters, filter cake is with the ice-cold toluene wash of 0.2L, 60 ℃ of drying under reduced pressure 6h get light yellow solid 350g, yield 85.8%.
Synthesizing of step 2, (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine
With N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1,2,3,4-naphthane-1S-methane amide (350g) drops in the reaction flask of 20L, adds the tetrahydrofuran (THF) of the fresh distillation of 7.5L, is stirred to dissolving fully.Under the ice bath cooling conditions, keep temperature of reaction system≤10 ℃, add sodium borohydride 168g, slowly drip the 1.15L boron trifluoride ether solution then (with BF
3Meter, the boron trifluoride weight percent content is 47.0-47.7%), dropwise the back in stirring reaction 1h below 20 ℃.
(little the boiling of reaction solution got final product, and the reaction times disappears with actual TLC or HPLC monitoring raw material and is as the criterion, and the TLC developping agent is trichloromethane: methyl alcohol=5: 1) to be warming up to 60 ℃ of insulated and stirred reaction 4h.
The previous reaction bottle is placed ice bath, keep the interior temperature of bottle below 10 ℃, slowly drip the hydrochloric acid 2L (producing a large amount of gases) of 6mol/L, stir and make the most of dissolving of white solid in the bottle.Concentrating under reduced pressure is removed tetrahydrofuran (THF), and resistates adds 6mol/L hydrochloric acid 2L, is warming up to 80 ℃ and reacts to reaction solution change clarification.Add 50% (wt%) sodium hydroxide solution conditioned reaction liquid pH=10 under the ice bath, with 1L chloroform extraction 3 times, merge the chloroform soln of collecting, with 0.5L saturated nacl aqueous solution washing 2 times, add an amount of anhydrous magnesium sulfate drying, filter the concentrating under reduced pressure desolventizing, get light yellow oily product (240g), yield 68.6%.
Synthesizing of step 3, Palonosetron
Under nitrogen protection, (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine (220g) is dropped in the reaction flask of 20L, add the toluene of the fresh distillation of 5L, be stirred to dissolving fully.The control temperature of reaction is under 5 ℃, slowly drip the toluene solution that 1L has dissolved 510g three surpalites, dropwise the back stirring reaction 20 minutes, and be warming up to room temperature (more than 25 ℃) stirring reaction 10h, then temperature rising reflux 4h, reaction system is cooled under 5 ℃, slowly drip the toluene solution that 0.5L has dissolved 255g three surpalites, dropwise back stirring reaction 20min, be warming up to room temperature (more than 25 ℃) stirring reaction 1h then, about temperature rising reflux reaction 4h, HPLC monitoring reaction process.After treating that (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine reacts completely, reaction solution is cooled to room temperature, drips the 0.84L boron trifluoride ether solution, temperature rising reflux reaction 6h (HPLC monitoring reaction process).
After reacting completely, add 2mol/L hydrochloric acid 3L under the ice bath, reflux 1h, reaction solution is cooled to room temperature, water phase separated (abandoning) and organic phase, organic phase is respectively with 2mol/L hydrochloric acid 0.5L extraction 2 times, merge 2 times the extraction receive water, regulate about pH=10 with 50% sodium hydroxide solution under the ice bath, use the 1L chloroform extraction respectively 3 times, merge the trichloromethane layer and wash 2 times an amount of anhydrous magnesium sulfate drying with the 0.5L saturated nacl aqueous solution, filter, resistates is Palonosetron after the concentrating under reduced pressure desolventizing.
The preparation of step 4, PalonosetronHydrochloride
The Palonosetron that makes with 400ml Virahol dissolving step three, the ice bath cooling drips the saturated hydrogen chloride solution 1.5L of ethanol down, separate out the PalonosetronHydrochloride product, below 5 ℃ about crystallisation by cooling 10h, filter, 0.2L cold isopropanol washs, drains, and gets thick product (118g), yield 53.6%.
Making with extra care of step 5, PalonosetronHydrochloride
Recrystallization for the first time:
The PalonosetronHydrochloride crude product (118g) that step 3 is made drops in the 5L reaction flask, add 3.6L Virahol/methyl alcohol (3: 1) mixed solution, stir, be heated to backflow, add 3g gac reflux decolour 20min, filtered while hot, filtrate are put into refrigerator (5 ℃) cooling 10h after leaving standstill naturally and being cooled to room temperature.Filter, filter cake with the ice-cold washed with isopropyl alcohol of 0.2L, drain, get crystal (93g).
Recrystallization for the second time:
The PalonosetronHydrochloride crystal that the first time, recrystallization made is dropped in the 5L reaction flask, add 2L Virahol/methyl alcohol (3: 1) mixed solution, stir, be heated to backflow, add 3g gac reflux decolour 20min, filtered while hot, filtrate are put into about refrigerator (5 ℃) cooling 10h after leaving standstill naturally and being cooled to room temperature.Filter, filter cake with the ice-cold washed with isopropyl alcohol of 0.2L, drain, get white crystalline powder (65g).
Dry:
The highly finished product that the second time, recrystallization made are sent in the vacuum drying oven, carried out drying, 60 ± 5 ℃ of control drying temperatures, dry 4～6h is dried to weight loss on drying and is not more than 0.5%, gets white crystalline powder (45g).It is 99.72% that HPLC measures purity, yield 55.1%, and fusing point: greater than 290 ℃, all the other physico-chemical property parameters are as follows:
EI-MS M/Z：296，109。
UV(CH
3OH)λ
max：208nm。
Specific rotatory power
Chloroform (C=0.1).
Ultimate analysis: C 68.48, H 7.47, and N 8.53, and Cl 10.66, and O 4.86.
IR (KBr compressing tablet) v
Max(cm
-1): 3023.9,2924.6,2877.3,2506.4,2456.9,1647.8,1590.3,1476.56,1445.4,1408.5,768.5,695.2.
1H NMR(CDCl
3，400MHz)δ(ppm)：1.402-1.314(1H，m，8-Hb)，1.821-1.714(1H，m，8-Ha)，2.034-1.894(2H，m，7-H)，2.276-2.079(4H，m，16-H，18-H)，2.385-2.339(1H，m，17-H)，2.908-2.748(2H，m，14-H)，3.025-2.922(1H，m，9-H)，3.327-3.244(3H，m，11-Hb，6-H)，3.421-3.369(1H，m，11-Ha)，3.840-3.668(4H，t，15-H，19-H)，4.972-4.929(1H，t，13-H)，7.268-7.248(2H，m，2-H，4-H)，7.848-7.830(1H，t，3-H)，12.235(1H，s，20-H)。
13C NMR(CDCl
3，400MHz)δ(ppm)：19.652(1C，18-C)，21.738(1C，16-C)，24.195(1C，8-C)，25.617(1C，17-C)，25.935(1C，7-C)，27.998(1C，6-C)，34.845(1C，9-C)，45.941(2C，11-C，14-C)，49.167(2C，15-C，19-C)，49.314(1C，13-C)，125.971(1C，3-C)，126.570(1C，4-C)，128.274(1C，1-C)，132.624(1C，2-C)，134.939(1C，10-C)，136.973(1C，5-C)，165.994(1C，12-C)。
The treating process of PalonosetronHydrochloride needs to operate in 300,000 grades of clean areas.
Filter in the recrystallization process crystal mother liquor can collect in 5 ℃ of preservations, focus on when equivalent is big.During processing mother liquor is concentrated into about 1/3 volume, cools off (5 ℃) back suction filtration.Filter solid in 60 ± 2 ℃ of oven dry 4～6h, measure weight loss on drying≤1.0%, get white crystalline powder, be the PalonosetronHydrochloride crude product, crude product can obtain highly finished product after through twice recrystallization.
Test example 1 PalonosetronHydrochloride injection liquid pH buffer reagent is selected and the screening of pH value
The constant of pH value of blood is the prerequisite of cell physiological activity, if pH overruns, not only changes the excitability of neurocyte, and can influence the activity of enzyme, and the Metabolic activity of all cells and physiological function all are affected.General injection pH value requires control between 4～9, otherwise the too high or mistake end of pH value all can cause stimulation or the necrosis of local organization.
Compound concentration is 0.01mol/L respectively, and pH is each 1000ml of Sodium Citrate-citrate buffer solution of 4.0,4.5,5.0,5.5,6.0, adds PalonosetronHydrochloride 56mg respectively (with C
19H
24N
2O counts 50mg) and 0.5g Calcium Disodium Edetate stirring and dissolving, with 0.45 μ m filtering with microporous membrane, be sub-packed in the brown ampoule of 5ml, seal, in 100 ℃ of flowing steam sterilizations 30 minutes.Proterties, pH value, related substance and content to injection detect, and the results are shown in Table 1.
Table 1pH buffer reagent is selected and the screening of pH value
Data can be found out in the table 1, and behind 100 ℃ of flowing steam sterilization 30min, each pH value injection liquid PalonosetronHydrochloride content down is more or less the same, but related substance is low in pH value 4.5～5.5 scopes.Above result shows: the injection liquid of pH value in 4.5～5.5 scopes is behind 100 ℃ of flowing steam sterilization 30min, and its related substance and PalonosetronHydrochloride content are not obvious.
The test of test example 2 PalonosetronHydrochloride injection liquid antioxidant consumptions
When containing trace metal ion in the soup, regular meeting accelerates oxidation, the degraded of medicine.These metal ions may be from pharmacy apparatus in raw material, auxiliary material and the process for preparation etc.Except above factors were controlled in strictness, the normal employing added the complexing of metal ion agent, made with metal ion and generated stable water soluble complex, to stop the injection liquid deterioration by oxidation.
Test method: get four parts of PalonosetronHydrochloride 56mg (with C
19H
24N
2O counts 50mg), with 1000ml water for injection stirring and dissolving, add 0,0.1,0.3,0.5 and the Calcium Disodium Edetate of 0.7g respectively, it is that 0.01mol/L, pH are 5.0 buffer system that the Sodium Citrate that adds 770mg Citric Acid and 1860mg again makes it to become concentration, with 0.45 μ m filtering with microporous membrane, be sub-packed in the brown ampoule of 5ml, seal, in 100 ℃ of flowing steam sterilizations 30 minutes.Proterties, pH value, content and related substance to injection detect, and the results are shown in Table 2.
The anti-oxidant result of the different amount of table 2 antioxidant
Table 2 data as seen, consumption is that the Calcium Disodium Edetate of 0.5g has tangible antioxygenation.In the presence of the Calcium Disodium Edetate of 0.5g, the pH of sample, visible foreign matters, related substance is less, content is higher, shows that the Calcium Disodium Edetate consumption that every 1000ml adds 0.5g namely meets the demands, so determine that the Calcium Disodium Edetate consumption is 2.5g.
The test of N.F,USP MANNITOL consumption in the test example 3 PalonosetronHydrochloride injection liquids
People's blood plasma has certain osmotic pressure, on average is about 7.4 normal atmosphere.The solution that all and blood plasma have identical osmotic pressure is called " isotonic solution ".Chang Yong isotonic solution is 0.278molL clinically
-1Glucose solution, mosm strength of solution are 278mOsmL
-1(be similar to 280mOsmL
-1).This test adds N.F,USP MANNITOL and does osmotic pressure regulator, needs the every 1000ml of PalonosetronHydrochloride injection liquid to add 41.5 grams as calculated, just can be adjusted to " isotonic solution ", thus in the prescription N.F,USP MANNITOL add high-volume for every 1000ml with N.F,USP MANNITOL 41.5g.
The selection of gac adding method and consumption in the test example 4 PalonosetronHydrochloride injection liquids
Gac is the very strong material of a kind of adsorptivity, is usually used in preparing injection liquid.It can adsorb particulate matter, can adsorb impurity, pyrogen, pigment again, therefore can improve the injection liquid quality.But it also can adsorb main ingredient in absorption impurity, and the excessive filtration difficulty that causes of consumption, so activated carbon dosage directly influences the quality of injection liquid.The consumption of gac does not have concrete regulation, should decide on the quality of bulk drug, soup visible foreign matters etc., and general activated carbon dosage scope is 0.01～0.3% (W/V).If use quantity not sufficient, do not reach expected effect; If consumption is excessive, except the waste that causes gac, its contained water-soluble impurity can pollute soup.Therefore we are 0,0.01%, 0.05%, 0.1% (W/V) with activated carbon dosage, test, and concrete operations are as follows:
Take by weighing PalonosetronHydrochloride 56mg (with C
19H
24N
2O counts 50mg) with the dissolving of an amount of water for injection and be diluted to 1000ml, be divided into 4 groups, 1 group does not add gac, in addition 3 groups to add gac respectively be that 0.01%, 0.05%, 0.1% (W/V) of solution total amount stirs, insulation (about 60 ℃) absorption 15min, composite microporous filter film filter with 0.45 μ m～0.22 μ m is extremely clear and bright, is sub-packed in the brown ampoule of 5ml 100 ℃ of flowing steam sterilization 30min.Put cold back and check its visible foreign matters and content, the results are shown in Table 3.
Table 3 activated carbon dosage shaker test
The result shows: the PalonosetronHydrochloride injection liquid is from adding 0.01% gac, qualified substantially but its content of its visible foreign matters is in continuous decline, with do not add gac relatively, descend more (comparing under the same condition determination), because PalonosetronHydrochloride content pettiness in this product, only 0.25mg/5ml according to these characteristics, therefore only uses 0.05% activated carbon adsorption auxiliary material solution in actual production technology.
The research of test example 5 PalonosetronHydrochloride injection liquid sterilization process
(1) preparation of sample:
Raw material is: PalonosetronHydrochloride 280mg is (with C
19H
24N
2O counts 250mg), auxiliary material is N.F,USP MANNITOL 207.5g, Sodium Citrate 9.32g, Citric Acid 3.85g and Calcium Disodium Edetate 2.5g, and water for injection adds to 5000ml, makes 1000, and specification: 5ml:0.25mg is (with C
19H
24N
2The O meter).
Take by weighing Sodium Citrate, Citric Acid, N.F,USP MANNITOL and the Calcium Disodium Edetate of above-mentioned weight, add the water for injection of 2000ml, stirring and dissolving adds the medicinal carbon of solution total amount 0.05% (W/V) again, 60 ℃ of insulation absorption 15 minutes, and it is standby to filter the back.
Take by weighing the PalonosetronHydrochloride of above-mentioned weight in the water for injection of 1000ml, dissolving fully, and is standby.
After aforementioned two kinds of solution mixing, add the injection water and be settled to 5000ml, regulate pH value 4.5～5.5, extremely clear and bright with the millipore filtration filtration of 0.22 μ m.
Get aforesaid liquid and detect its content, pH value, treat that the can of qualified back in the brown ampoule of 5ml, seals, prepared lot number and be 06031901 in the middle of 1000 (specifications: 5ml:0.25mg), carry out the screening of sterilising conditions of product.
(2) sterilising conditions is investigated:
Adopt moist heat sterilization, get 100 of 06031901 batch of middle product, each 4 parts, respectively at 100 ℃ of flowing steam sterilization 40min, 116 ℃ of sterilization 30min, 116 ℃ of sterilization 40min, 116 ℃ of sterilization 45min.Check proterties, pH value, visible foreign matters, related substance and content under each condition.Concrete outcome sees Table 4:
Table 406031901 batch middle product sterilization back detected result
The result shows: along with the increase of sterilising temp and time, above-mentioned projects check result is close, and the related substance of sample and content are all little.
For guaranteeing sterilising effect, estimate the sterilization process except adopting above index, also adopted F
0Value judges to this technology, each sterilising conditions F
0Value sees Table 5:
Calculation formula F
0=Δ t ∑ 10 (T-121)/10
F
0---the standard sterilization time
Δ t---measure by the timed interval of sterilization thing temperature
T---each timed interval Δ t is measured by sterilization thing temperature
Each sterilising conditions F of table 5
0The value table
| Sterilising conditions | F 0Value |
| 100 ℃ of sterilization 40min | 0.32 |
| 116 ℃ of sterilization 30min | 9.48 |
| 116 ℃ of sterilization 40min | 12.64 |
| 116 ℃ of sterilization 45min | 14.22 |
In sum, when adopting 116 ℃ of sterilization 40min, F
0Value reaches 12, as seen from Table 4, compares after this sterilising conditions sterilization with before the sterilization, related substance and content are little, therefore, and in order to control quality product effectively well, can ensure the safety of this injection liquid again, determine that best sterilising conditions is 116 ℃ of sterilization 40min.
(3) sterility test:
Product carry out sterility test in the middle of getting behind 116 ℃ of sterilization 40min, the results are shown in Table 6.
Table 6 sterility test result
| Sterilising conditions | Aseptic |
| Aseptic | Up to specification |
| 116 ℃ of sterilization 40min | Up to specification |
By last table result as can be known, adopt the sample sterility test after this condition is sterilized up to specification.
(4) interaction of auxiliary material and PalonosetronHydrochloride
The method of (1) is made PalonosetronHydrochloride injection liquid samples solution set by step, the method of (1) does not add PalonosetronHydrochloride and makes auxiliary material solution set by step, the method of (1) does not add auxiliary material preparation reference substance solution set by step, and three kinds of solution are all in 116 ℃ of sterilization 40min.Accurate each the 20 μ l of above three kinds of solution that draw, inject high performance liquid chromatograph respectively, the record color atlas, the retention time of auxiliary material solution is about 2 minutes, and the main peak retention time of sample solution is about 9 minutes, and reference substance solution main peak retention time is about 9 minutes.This shows that auxiliary material and PalonosetronHydrochloride do not have interaction.
The preparation of embodiment 2 PalonosetronHydrochloride injection liquids
Raw material is: PalonosetronHydrochloride 280mg is (with C
19H
24N
2O counts 250mg), auxiliary material is N.F,USP MANNITOL 207.5g, Sodium Citrate 9.32g, Citric Acid 3.85g and Calcium Disodium Edetate 2.5g, and water for injection adds to 5000ml, makes 1000, and specification: 5ml:0.25mg is (with C
19H
24N
2The O meter).
Take by weighing Sodium Citrate, Citric Acid, N.F,USP MANNITOL and the Calcium Disodium Edetate of above-mentioned weight, add the water for injection of 2000ml, stirring and dissolving adds the medicinal carbon of solution total amount 0.05% (W/V) again, 60 ℃ of insulation absorption 15 minutes, and it is standby to filter the back.
Take by weighing the PalonosetronHydrochloride of above-mentioned weight in the water for injection of 1000ml, dissolving fully, and is standby.
After aforementioned two kinds of solution mixing, add the injection water and be settled to 5000ml, regulate pH value 4.5～5.5, extremely clear and bright with the millipore filtration filtration of 0.22 μ m.
Get aforesaid liquid and detect its content, pH value, treat that the can of qualified back in the brown ampoule of 5ml, seals, in 116 ℃ of pressure sterilizing 40min, cooling checks its visible foreign matters, labels packing.
The pilot scale of embodiment 3 PalonosetronHydrochloride injection liquids
Press three batches of table 7 prescription preparation pilot products, each 10000, yield sees Table 7.
Three batches of pilot scale sample ligands of table 7 are yield when
Table 8 has been listed the assay of middle test agent:
Table 8 three batch sample assays
As seen from the above table, three batches of (06040301,06040501,06040701) samples that pilot scale is prepared, each index is all up to specification.
The exposure experiments to light of test example 6 PalonosetronHydrochloride injection liquids
The injection liquid of embodiment 2 preparation was put under the high light that illumination is 4500 ± 500LX irradiation 10 days, respectively at sampling in the 5th, 10 day with 0 day relatively, the results are shown in Table 9.
The injection liquid of embodiment 2 preparation is put 60 ℃ placed 10 days down, respectively at sampling in the 5th, 10 day with 0 day relatively, the results are shown in Table 9.
The injection liquid of embodiment 2 preparation put under 2～4 ℃ of conditions placed 10 days, respectively at sampling in the 5th, 10 day with 0 day relatively, the results are shown in Table 9.
Table 9 sample effects factor is investigated the result
As seen from the above table, this product through 10 days related substances of high temperature and strong illumination and assay and 0 day relatively, related substance increases (related substance increases maximum behind the high temperature) to some extent, content descends to some extent, illustrates that this product is to the equal less stable of light and heat.Place 10 days related substances and assay and comparison in 0 day under the cold condition, related substance does not have obvious increase, and content is little, illustrates that this product is more stable to low temperature.
The freezing and thawing test of test example 7 PalonosetronHydrochloride injection liquids
Get the injection liquid of embodiment 2 preparations, place-15 ℃ to place 2 days, take out, put under 40 ℃ of conditions and placed 2 days, 3 times repeatedly, sampling detects by stable high spot reviews project in the time of the 12nd day, the results are shown in Table 10.
Table 10 freezing and thawing test result
Conclusion: this product related substance after freezing and thawing test slightly increases, and content descends to some extent, so this product should be avoided excessive temperature differentials in the process of storage transportation.
Investigate and freezing and thawing test by influence factor test, can be observed PalonosetronHydrochloride injection liquid less stable under high temperature and illumination condition, and should not be positioned over lesser temps, with this product holding conditions is tentative be: lucifuge, 20～25 ℃ of preservations, avoid freezing.
The selection of test example 8 PalonosetronHydrochloride injection containers
According to the physico-chemical property of the result of influence factor and this bulk drug as can be known, PalonosetronHydrochloride needs lucifuge to store to photo-labile.So the PalonosetronHydrochloride injection liquid of our preparation, selecting container is brown ampoule still, takes to keep in Dark Place.
Claims (3)
1. the preparation method of PalonosetronHydrochloride is characterized in that: behind (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine and the trimerization phosgene reaction, extract after the adding boron trifluoride back flow reaction and namely get Palonosetron; Palonosetron is dissolved in the saturated hydrogen chloride solution that drips ethanol behind the Virahol and obtains PalonosetronHydrochloride; Obtain the highly finished product of PalonosetronHydrochloride with Virahol/methyl alcohol mixed liquor recrystallization; The consumption mol ratio of described (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine, three surpalites, boron trifluoride is 1: 6～8: 8～10; Described (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine adds 60～70% three surpalites earlier, in room temperature reaction 8h～12h, back flow reaction 3～6h adds remaining three surpalites again, in room temperature reaction 0.5～1.5h, back flow reaction 3～6h; Add boron trifluoride ether solution under the room temperature, extraction namely gets Palonosetron behind back flow reaction 5～8h; The volume ratio of described Virahol/methyl alcohol mixed liquor is 3: 1.
2. the preparation method of PalonosetronHydrochloride according to claim 1, it is characterized in that: described extraction is for adding hydrochloric acid reflux, water phase separated and organic phase, the organic phase hcl as extraction agent, receive water regulate pH=9～11, use chloroform extraction, merge the trichloromethane layer with saturated nacl aqueous solution washing back desolventizing.
3. according to the preparation method of each described PalonosetronHydrochloride of claim 1～2, it is characterized in that: (1-azepine-3 (S)-dicyclo [2,2,2] octyl)-(1,2,3,4-naphthane-1S-methyl) amine is by N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1,2,3, behind 4-naphthane-1S-methane amide and sodium borohydride and the boron trifluoride reaction, add hydrochloric acid reaction and obtain; N-(1-azepine-3 (S)-dicyclo [2,2,2] octyl)-1, the mol ratio of 2,3,4-naphthane-1S-methane amide and sodium borohydride and boron trifluoride is 1: 4～5: 7～9, reaction solvent is tetrahydrofuran (THF), and reaction conditions is to react 0.5～1.5h below 20 ℃, 60 ℃ of reaction 3～6h; After reacting completely, in below 10 ℃, add hydrochloric acid and make solid dissolving in the reaction solution, solvent evaporated adds hydrochloric acid and intensification and makes reaction solution become clarification, conditioned reaction liquid pH=9～11, use chloroform extraction, the chloroform soln of collection washs with saturated nacl aqueous solution, and solvent evaporated namely.
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| CN101103982A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Palonosetron hydrochloride intravenous injection medicinal composition and preparation method thereof |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103982A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Palonosetron hydrochloride intravenous injection medicinal composition and preparation method thereof |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| 朱阳等.盐酸帕洛诺司琼的合成.《中国医药工业杂志》.2009,第40卷(第4期),241-243. |
| 盐酸帕洛诺司琼的合成;朱阳等;《中国医药工业杂志》;20090410;第40卷(第4期);241-243 * |
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Effective date of registration: 20160728 Address after: 611830, Sichuan, Dujiangyan province Chengdu science and Technology Industrial Development Zone Rainbow Road No. 802 Yangzi Pharmaceutical Group Sichuan Hai Rong Pharmaceutical Co., Ltd. Patentee after: Sichuan Hairong Pharmaceutical Industry Co., Ltd. of Yangzijiang Pharmaceutical Patentee after: Yangtze River Pharmaceutical Co., Ltd. Patentee after: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group Address before: 611830, Sichuan, Dujiangyan province Chengdu science and Technology Industrial Development Zone Rainbow Road No. 802 Yangzi Pharmaceutical Group Sichuan Hai Rong Pharmaceutical Co., Ltd. Patentee before: Sichuan Hairong Pharmaceutical Industry Co., Ltd. of Yangzijiang Pharmaceutical Patentee before: Yangtze River Pharmaceutical Co., Ltd. |