CN103159797A - Fosaprepitant dimeglumine crystal form compound - Google Patents
Fosaprepitant dimeglumine crystal form compound Download PDFInfo
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Abstract
The embodiment of the invention discloses a fosaprepitant dimeglumine crystal form compound of which the molecular formula is C23H22F7N4O6P.2C7H17NO5. The preparation process comprises the following steps: preparing an intermediate compound: reacting aprepitan used as an initial raw material and tetrabenzyl pyrophosphate by taking sodium bis(trimethylsilyl)amide as alkali in anhydrous tetrahydrofuran to prepare a bisbenzyl intermediate compound, and removing one benzyl in absolute methanol to generate a monobenzyl intermediate compound; preparing a fosaprepitant dimeglumine crude product: hydrogenizing the monobenzyl intermediate compound to remove the residual benzyl, and performing salification with meglumine to obtain the fosaprepitant dimeglumine crude product; and preparing a fosaprepitant dimeglumine refined product: dissolving the fosaprepitant dimeglumine crude product in absolute methanol, filtering off insoluble substances, and refining with mixed solvent of anhydrous ethanol and anhydrous acetonitrile to finally obtain the while solid fosaprepitant dimeglumine refined product. The compound has the advantages of accessible raw materials, mild and controllable reaction conditions, simple technical process and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of crystal formation compound field, relate in particular to a kind of fosaprepitant dimeglumine crystal formation compound.
Background technology
fosaprepitant dimeglumine, the chinesization formal name used at school is deoxidation-1-(methylamino-)-D-glucitol [3-[[(2R, 3S)-2-[(1R)-1-[3, 5-two (trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-2, 5-dihydro-5-oxo-1H-1, 2, the 4-triazol-1-yl] phosphoric acid salt (2:1), molecular formula is C23H22F7N4O6P2C7H17NO5, molecular weight is 1004.83, for white to off-white powder, odorless, have draw moist, easily molten in the first alcohol and water, soluble,very slightly in dehydrated alcohol, specific optical rotation is+28 °～+ 33 °, be mainly used in treating the nausea and vomiting that causes in chemotherapy process.
Summary of the invention
Embodiment of the present invention technical problem to be solved is, provides that a kind of raw material is easy to get, the reaction conditions gentleness is controlled, technological process is simple, yield is high and the fosaprepitant dimeglumine crystal formation compound of suitable suitability for industrialized production.
Described fosaprepitant dimeglumine crystal formation compound, molecular formula is as follows:
C23H22F7N4O6P·2C7H17NO5；
The preparation technology of described fosaprepitant dimeglumine crystal formation compound comprises the steps:
(1) preparation intermediate: use Aprepitant as starting raw material, in anhydrous tetrahydro furan, take the silica-based sodium amide of hexamethyl two as alkali, with tetra-sodium four benzyl ester reactions, make two benzyl ester intermediates, slough a benzyl in anhydrous methanol, generate single benzyl ester intermediate;
(2) preparation fosaprepitant dimeglumine crude product: a remaining benzyl ester is sloughed in the hydrogenation of single benzyl ester intermediate, with the meglumine salify, made the smooth two meglumine crude products of the husky pyrrole of good fortune;
(3) preparation fosaprepitant dimeglumine elaboration: the smooth two meglumine crude products of the husky pyrrole of good fortune are dissolved in anhydrous methanol, the elimination insolubles, more refining with the mixed solvent of dehydrated alcohol and anhydrous acetonitrile, obtain at last the smooth two meglumine elaboration of the husky pyrrole of white solid good fortune.
In described preparation process, the preparation intermediate is: prepare the Aprepitant of 1.6 weight parts and the tetra-sodium four benzyl esters of 2.2 weight parts, in kg/L, the anhydrous tetrahydro furan that adds 16 times of volumes, be cooled to-5 ℃, splash into the silica-based sodium amide of hexamethyl two of 4.8 times of volumes, maintenance-5-0 ℃ is stirred 2h, reaction solution is extracted with methyl tertiary butyl ether, i.e. intermediate double benzyl ester; The anhydrous methanol of two benzyl ester intermediates and 16 times of volumes is heated, react 20h under 45 ℃, after cooling, suction filtration and drying process, get single benzyl ester intermediate.
preparation fosaprepitant dimeglumine crude product: in kg/L, intermediate S100902 with 1.55 weight parts, 0.84 the 5%Pd/C of the meglumine of weight part and 0.085 weight part drops in hydriding reactor, add the methyl alcohol of 33 times of volumes and the water of 0.83 times of volume, remain on hydrogenation 10-12h under 2.0MPa, filtering Pd/C, filtrate is at 20 ℃ of lower concentrating under reduced pressure, remove the solvent of 28 times of volumes, the triphenyl phosphorus that adds 4.5 weight parts in resistates, stirring at room 12h, nitrogen protection, splash in the mixed solvent of anhydrous acetonitrile of the dehydrated alcohol of 15 times of volumes of 0-10 ℃ and 15 times of volumes, 1-2h drips off, continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation, discard supernatant liquid, fill into dehydrated alcohol and anhydrous acetonitrile (6 times of volumes: mixing solutions 6 times of volumes) of preparation in advance, stir 30min, the nitrogen press filtration, solid 2L absolute ethanol washing, 25 ℃ of lower vacuum-drying 20h, get the fosaprepitant dimeglumine crude product.
making with extra care of fosaprepitant dimeglumine crude product: in kg/L, under nitrogen protection, the fosaprepitant dimeglumine crude product of 1.8 weight parts is dissolved in the anhydrous methanol of 9 times of volumes, the elimination insolubles, splash in the mixed solvent of anhydrous acetonitrile of the dehydrated alcohol of 28 times of volumes of 0-10 ℃ and 28 times of volumes, 1-2h drips off, continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation, discard supernatant liquid, fill into dehydrated alcohol and anhydrous acetonitrile (7 times of volumes: mixing solutions 7 times of volumes) of preparation in advance, stir 30min, the nitrogen press filtration, after the absolute ethanol washing of solid with 2 times of volumes, at 25 ℃ of lower vacuum-drying 20h, get white solid, pulverize, dry 20h again, get the fosaprepitant dimeglumine product.
Methyl tertiary butyl ether extraction in described step (1) refers to reaction solution is poured in the mixing solutions of cooling in advance methyl tertiary butyl ether and each 32 times of volumes of saturated sodium bicarbonate, stir, standing separatory, it is respectively that the saturated sodium bicarbonate aqueous solution of 20 times of volumes, 8% the sodium pyrosulfate aqueous solution and water wash that organic layer is used successively, organic layer is done at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, the methyl alcohol that adds 3 times of volumes, stirring and dissolving, continuation is at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, be two benzyl ester intermediates.
After cooling, suction filtration in described step (1) and drying process refer to reaction solution is chilled to room temperature, stir 1h under 0-5 ℃, suction filtration, obtain solid, after the methanol wash of solid with 2.5 times of volumes, at 25 ℃ of lower vacuum-drying 12h, namely obtain single benzyl ester intermediate.
Implement the embodiment of the present invention, have following beneficial effect:
Provide that a kind of raw material is easy to get, the reaction conditions gentleness is controlled, technological process is simple, yield is high and the fosaprepitant dimeglumine crystal formation compound of suitable suitability for industrialized production.
Embodiment
For making the purpose, technical solutions and advantages of the present invention clearer, below the present invention is described in further detail.
The present embodiment fosaprepitant dimeglumine molecular formula is: C23H22F7N4O6P2C7H17NO5;
Synthetic method comprises the following steps: the general line of reaction is:
The first step: the preparation technology of starting raw material Aprepitant (SM001):
1, (R)-1-(3,5-two (trifluoromethyl) phenyl) ethyl-1-alcohol is synthetic, and operation steps comprises:
(1) 350mL Dimethyl sulfide borine and 120mL(s)-CBS is dissolved in the 2.5L methyl tertiary butyl ether, is cooled to-5 ℃.
(2) 3 of 1.5kg, 5-two (trifluoromethyl) methyl phenyl ketone is dissolved in the 5L methyl tertiary butyl ether, slowly splashes into above-mentioned system.
(3) drip end, continue to stir after 1 hour, splash into hydrochloric acid and 1.5LN that 1.5L concentration is 1mol/L, the mixing solutions of dinethylformamide keeps temperature of reaction system less than 10 ℃, stirring at room 1 hour.
(4) add the 4L n-hexane extraction, organic layer washing (4L*2), saturated common salt water washing (4L), anhydrous sodium sulfate drying, concentrated, cooling, nitrogen dries up, and gets white solid 1.43kg, productive rate is that 94%, Mp is 52-53 ℃, [α] D25=+23.2 ° (c=1, MeOH).
2,4-benzyl-2-hydroxyl-Isosorbide-5-Nitrae-oxazines-3-ketone is synthetic, and operation steps comprises:
(1) the N-benzyl ethyl alcohol amine of 2.8kg is dissolved in 8.5L tetrahydrofuran (THF), reflux.
(2) splash into the 3.8L50% aqueous glyoxylic acid, drip and finish, reflux 21h.
(3) remove tetrahydrofuran (THF) under reduced pressure, add water 8.5L, be cooled to room temperature, suction filtration, washing, 40 ℃ of lower vacuum-dryings get white solid 2.6kg, and productive rate is that 68%, Mp is 132-134 ℃.
3, (2R, 2 α R)-4-benzyl-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-Isosorbide-5-Nitrae-oxazines-3-ketone synthetic, operation steps comprises:
(1) 1kg4-benzyl-2-hydroxyl-Isosorbide-5-Nitrae-oxazines-3-ketone is dissolved in the 2.5L acetonitrile, is cooled to 5 ℃, splashes into the 1.3kg trifluoroacetic anhydride, keeps temperature of reaction lower than 35 ℃, drips off and continues to stir 1h.
(2) 1.2kg (R)-1-(3,5-two (trifluoromethyl) phenyl) ethyl-1-alcohol is dissolved in the 1.5kg acetonitrile, adds in above-mentioned system, then adds 310mL boron trifluoride ether solution, stirring at room 2h.
(3) reaction solution splashes into the aqueous sodium hydroxide solution that 4L concentration is 5mol/L, keeps temperature of reaction lower than 25 ℃, then adds 1.5L water, the 1.5kg tetrahydrolinalool.
(4) air distillation to gas phase temperature to 92 ℃, is cooled to 50 ℃, adds the 10L normal hexane, extraction, separatory.
(5) organic layer with anhydrous sodium sulfate drying after, remove the part normal hexane under reduced pressure, be cooled to room temperature, add a small amount of (2R, 2 α R)-4-benzyl-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-1,4-oxazine-3-ketone is as crystal seed, continues to be cooled to t＜-10 ℃.
(6) form brilliant bed after, add 300g tetrahydrolinalool potassium, mix, keep system temperature-5-12 ℃, stirring is spent the night.
(7) add the 200mL Glacial acetic acid, stir 0.5h, splash into the sodium bicarbonate aqueous solution of 2.5L5%, be stirred to without bubble and overflow, add the 10L normal hexane, be heated to 50 ℃, extraction.
(8) organic layer with anhydrous sodium sulfate drying after, remove the part normal hexane under reduced pressure, add a small amount of (2R, 2 α R)-4-benzyl-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-Isosorbide-5-Nitrae-oxazines-3-ketone is as crystal seed, keep temperature 2h under 0-5 ℃, suction filtration, the cooling normal hexane washing of 50mL solid, 50 ℃ of vacuum-dryings, get white crystal 1.1g, productive rate is that 50.2%, Mp is 92-93 ℃, [α] D25=+47.6 ° (c=1, MeOH).
4, [2R-2 α (R*), 3 α]]-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-3-morpholine hydrochloride synthetic, operation steps comprises:
(1) 800g (2R, 2 α R)-4-benzyl-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-Isosorbide-5-Nitrae-oxazines-3-ketone is dissolved in the 800mL tetrahydrofuran (THF), is cooled to 15 ℃.
(2) splash into the tetrahydrofuran solution to the fluorophenyl magnesium bromide of 3L0.8M, keep temperature of reaction lower than 25 ℃, drip off and continue to stir 1h.
(3) freezingly be cooled to 0 ℃, splash into the freezing methyl alcohol of 1.5L, keep temperature of reaction lower than 10 ℃.
(4) the 680g tosic acid is dissolved in 1.5L methyl alcohol, adds reaction system.
(5) add the palladium carbon of 80g5%, and change reaction solution over to hydriding reactor.
(6) react 10h under the 0.4MPa hydrogen pressure.
(7) reaction finishes, and elimination palladium carbon removes solvent under reduced pressure, adds the 4-methyl-2 pentanone of Trisodium Citrate, 8L water and 5L of sodium bicarbonate, the 670g of 560g, stirs 0.5h.
(8) the remaining palladium carbon of elimination, separatory adds the 200g concentrated hydrochloric acid in organic layer, stir 1h.
(9) remove solvent under reduced pressure, add the 4-methyl-2 pentanone of 2L, stir, be cooled to room temperature.
(10) suction filtration, 40 ℃ of oven dry of solid get white solid 650g, and yield is that 77%, Mp is 249-250 ℃, [α] D25=+77.2 ° (c=1, MeOH).
5, Aprepitant is synthetic, and operation steps comprises:
(1) 1.1kg[2R-2 α (R*), 3 α]]-2-[1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-3-morpholine hydrochloride is dissolved in the DMF of 4L, is cooled to 0 ℃, adds the salt of wormwood of 1.2kg.
(2) the 3-chloromethyl-1,2 of 400g, 4-triazine-ketone is dissolved in the DMF of 3L, splashes in reaction system.
Observe with TLC after (3) two hours, raw material disappears, and rises to room temperature, add 40L water, stir suction filtration, dehydrated alcohol (10L) and water (7L) recrystallization, suction filtration are used in washing after solid drying, 50 ℃ of vacuum-dryings of solid get white crystal 900g, are Aprepitant, productive rate is 70%, Mp is 254-255 ℃, [α] D25=+67.9 ° (c=1, MeOH).
Second step: intermediate [3-[[(2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-2,5-dihydro-5-oxo-1H-1,2, the 4-triazol-1-yl] preparation of mono phosphoric acid ester benzyl ester, this intermediate replaces with the S100902 numbering, and operation steps comprises:
be full of nitrogen in the 50L reactor, with the 1.6kg Aprepitant, 2.2kg the tetrahydrofuran (THF) of tetra-sodium four benzyl esters (TBPP) and 16L drying drops in still, cooling-5 ℃, splash into the tetrahydrofuran solution (NaHMDS) of the 2M hexamethyl two silica-based sodium amides of 4.8L, keep temperature of reaction-5-0 ℃, maintenance-5-0 ℃ is stirred 2h, the TLC detection (methylene dichloride: methyl alcohol=20:1), treat that raw material (SM001) disappears, reaction solution is poured in the mixing solutions of cooling in advance methyl tertiary butyl ether and each 32L of saturated sodium bicarbonate, stir, standing separatory, organic layer is used saturated sodium bicarbonate aqueous solution successively, each 20L washing of 8% the sodium pyrosulfate aqueous solution and water, organic layer is done at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, slightly cold, the methyl alcohol that adds 3L, stirring and dissolving, continuation is at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, namely get the first intermediate, replace with the S100901 numbering.
Intermediate S100901 and 16L anhydrous methanol are dropped into be full of in the 50L reactor of nitrogen, heating is reacted 20h under 45 ℃.Reaction finishes, and after reaction solution is chilled to room temperature, stirs 1h under 0-5 ℃, suction filtration, and solid at 25 ℃ of lower vacuum-drying 12h, gets 1.56kg intermediate S100902, yield 73% after using the 2.5L methanol wash.
The 3rd step: synthesizing of fosaprepitant dimeglumine crude product comprises the following steps:
1.55kg intermediate S100902,0.84kg meglumine and 85g5%Pd/C are dropped in hydriding reactor, add 33L methyl alcohol and 0.83L water, keep, hydrogenation spend the night (approximately 10-12h) under 2.0MPa.After reaction finishes, filtering Pd/C, filtrate is removed approximately 28L solvent at 20 ℃ of lower concentrating under reduced pressure, adds the 4.5g triphenyl phosphorus in resistates, stirring at room 12h.Nitrogen protection splashes in the mixed solvent of the 15L dehydrated alcohol of 0-10 ℃ and 15L anhydrous acetonitrile, and 1-2h drips off; continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation; discard supernatant liquid, fill into the dehydrated alcohol of preparation in advance and the mixing solutions of anhydrous acetonitrile (6L:6L), stir 30min; the nitrogen press filtration; solid 2L absolute ethanol washing, 25 ℃ of lower vacuum-drying 20h get 1.8kg off-white color solid; be the fosaprepitant dimeglumine crude product, yield is 81%.
The 4th step: refining of fosaprepitant dimeglumine comprises the following steps:
under nitrogen protection, 1.8kg fosaprepitant dimeglumine crude product is dissolved in the anhydrous methanol of 9L, the elimination insolubles, splash in the mixed solvent of the 28L dehydrated alcohol of 0-10 ℃ and 28L anhydrous acetonitrile, 1-2h drips off, continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation, discard supernatant liquid, fill into the dehydrated alcohol of preparation in advance and the mixing solutions of anhydrous acetonitrile (7L:7L), stir 30min, the nitrogen press filtration, after solid is used the 2L absolute ethanol washing, at 25 ℃ of lower vacuum-drying 20h, get white solid, pulverize, dry 20h again, get the 1.58kg fosaprepitant dimeglumine, yield 87%.
In above synthetic fosaprepitant dimeglumine crude product, the quality control standard of each material is as follows:
The first material: the internal control quality standard of raw material Aprepitant (SM001):
1, proterties: this product is that white is to the off-white color crystalline powder.
2, specific optical rotation: get this product, accurately weighed, add dissolve with methanol and quantitatively dilution make the solution that approximately contains 10mg in every 1ml, measure according to Polarimetry (appendix VI E) in accordance with the law, specific optical rotation should be+62.0 to+69.0 °
。
3, check:
(1) moisture: get this product, measure according to aquametry (appendix VIII M first method), moisture content should cross 0.5%.
(2) related substance: it is appropriate, accurately weighed to get this product, adds assay item current downflow phased soln and the solution that every 1ml approximately contains 0.5mg is made in dilution, as need testing solution; Precision measures 1ml, puts in the 100ml measuring bottle, is diluted to scale with thinner, shakes up, as own control solution; Test according to high performance liquid chromatography (appendix V D).Take octadecylsilane chemically bonded silica as weighting agent; Mobile phase A is 0.2% phosphoric acid (with NaOH test solution adjust pH to 2.5), and Mobile phase B is acetonitrile, carries out linear gradient elution by table 1, and the detection wavelength is 215nm.Get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10%～25% of full range; Precision measures need testing solution and each 20 μ l of contrast solution, and the injection liquid chromatography, record color atlas respectively.In the need testing solution color atlas, if any impurity peaks, single impurity peak area must not be greater than 0.15 times (0.15%) of contrast solution main peak area; Each impurity peak area and must not be greater than 0.5 times (0.5%) of contrast solution main peak area.
The relation table of table 1 mobile phase A and Mobile phase B and time
4, enantiomer: measure according to high performance liquid chromatography (appendix V D).
5, chromatographic condition and system suitability: use the ChiralpakAD-H chiral column; Take normal hexane-Virahol (90:10) as moving phase, flow velocity is 0.8ml/min, and the detection wavelength is 220nm.Get the aprepitant raceme appropriate, add moving phase and dissolve and dilute and make the solution that every 1ml approximately contains 10 μ g, shake up, as system suitability solution.Precision measures system suitability solution 10 μ l, and the injection liquid chromatography records color atlas, and peak sequence is followed successively by enantiomer peak and aprepitant peak, and the peak-to-peak resolution of aprepitant peak and enantiomer should be not less than 2.5.
Assay method: this product is appropriate, adds the moving phase dissolving and quantitatively dilutes and make the solution that approximately contains 0.5mg in every 1ml, and as need testing solution, precision measures in right amount, makes the solution that every 1ml approximately contains 5 μ g, solution in contrast with the quantitative dilution of moving phase.Get contrast solution 10 μ l injection liquid chromatographies, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10%～20% of full range; Precision measures test solution and each 10 μ l of contrast solution again, and the injection liquid chromatography, record color atlas respectively.In the need testing solution color atlas, the enantiomer peak area must not surpass 0.5 times (0.5%) of contrast solution main peak area.
6, sealing: preserve at shady and cool dry place
The second material: the internal control quality standard of raw material SM002:
1, proterties: this product is the white granular solid.
2, fusing point: the fusing point of this product (appendix VI C) is 63-66 ℃.
3, moisture: get this product, measure according to aquametry (appendix VIII M first method), moisture content should cross 0.5%.
4, assay: measure according to high performance liquid chromatography (appendix V D).Take octadecylsilane chemically bonded silica as weighting agent; Mobile phase A is 0.2% phosphoric acid (with NaOH test solution adjust pH to 2.5), and Mobile phase B is acetonitrile, carries out linear gradient elution by table 2, and the detection wavelength is 215nm.
The relation table of table 2 mobile phase A and Mobile phase B and time
Get this product appropriate, accurately weighed, add acetonitrile-0.2% phosphoric acid (with NaOH test solution adjust pH to 2.5) (40:60) quantitatively dilution make the solution that approximately contains 0.2mg in every 1ml, precision measures 20 μ l, injecting chromatograph records color atlas; Calculating content by area normalization method must not be lower than 98.0%.
The third material: the internal control quality standard of raw material SM003:
1, proterties: this product is white crystalline powder; Almost odorless, distinguish the flavor of little sweet, is with salty and bitter; This product is easily molten in water, and is slightly molten in ethanol, almost insoluble in trichloromethane.
2, fusing point: the fusing point of this product (appendix VI C) is 128-132 ℃.
3, specific optical rotation: get this product, accurately weighed, be dissolved in water and quantitatively dilute and make the solution that approximately contains 0.10g in every 1ml, in the time of 25 ℃, to measure (appendix VI E) in accordance with the law, specific optical rotation is-15.5 ° to-17.5 °.
4, differentiate: (1) gets approximately 20mg of this product, puts in clean test tube. and after adding water 2ml dissolving, ammonification Silver Nitrate test solution processed 1ml shakes up, and puts in water-bath and heats. and the silver-colored inwall that namely dissociates and be attached to pipe becomes silver mirror.
(2) get approximately 10mg of this product, add iron trichloride test solution 1ml, drip 20% sodium hydroxide solution 2ml, just aobvious reddish brown precipitation, be dissolved into brown-red solution immediately.
(3) get approximately 50mg of this product, after adding the saturated aqueous solution 1ml dissolving of dithiocarbonic anhydride, add 4% nickel sulfate solution number droplet, i.e. aobvious yellow-green colour, and generate yellow-green precipitate.
(4) the infrared Absorption collection of illustrative plates of this product should be consistent with the collection of illustrative plates (spectra collection 463 figure) of contrast.
5, check:
(1) Clarity and colour of solution: get this product 1.0g, after adding water 10ml dissolving, solution should be clarified colourless; Readily carbonizable substance is got this product 0.25g, checks (appendix VIII O) in accordance with the law, compares with orange red No. 2 standard color solutions, must not be darker.
(2) weight loss on drying: get this product, be dried to constant weight at 105 ℃, less loss weight must not be crossed 0.5%(appendix VIII L).
(3) nickel salt: get this product 1.0g, after blazing ashing, after adding nitric acid 0.5ml. evaporate to dryness to Nitrous Oxide steam in residue and eliminating, let cool, add hydrochloric acid 2ml, put evaporate to dryness in water-bath, adding water 5ml makes and dissolves and move in nessler colorimetric tube, add 1 of bromine test solution. jolting 1 minute, add ammonia solution and make alkalize, test solution 1ml when adding dimethyl diketone, shake up, placed 5 minutes. add colour developing, (get the single nickel salt that contains crystal water appropriate with standard nickel solution, pressing dry product calculates, add water make contain the solution that Ni is 1.0 μ g in every 1ml) 5ml, from above-mentioned " adding 1 of bromine test solution ", color after processing with Same Way relatively, must not darker (0.0005%).
(4) residue on ignition: get this product 1.0g, check in accordance with the law and leave over (appendix VIII N) residue and must not cross 0.1%.
(5) heavy metal: get the residue of leaving under the residue on ignition item, check to contain (appendix VIII H the second method) heavy metal and must not cross 10/1000000ths in accordance with the law.
6, assay: get approximately 0.4g of this product, accurately weighed, after adding water 20ml dissolving, 2 of the red indicating liquids of methylate are with hydrochloric acid titrating solution (0.1mol/L) titration.Every 1ml hydrochloric acid titrating solution (0.1mol/L) is equivalent to the C of 19.52mg
7H
17NO
5, should be not less than 98.5%.
7, storage: shading, sealing is preserved.
The 4th kind of material: the internal control quality standard of intermediate S100902:
1, proterties: this product should be white to off-white powder.
2, check moisture: get this product, measure according to aquametry (appendix VIII M first method), moisture content should cross 0.5%.
3, assay: measure according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010).
(1) chromatographic condition and system flexibility: be weighting agent with octadecylsilane chemically bonded silica; (with NaOH test solution adjust pH to 2.5)-acetonitrile (50:50) is as moving phase take 0.2% phosphoric acid, and the detection wavelength is 215nm.
(2) assay method: it is appropriate to get this product, accurately weighed, add acetonitrile-0.2% phosphoric acid (with NaOH test solution adjust pH to 7.0) and (50:50) dissolve and quantitatively dilute and make the solution that approximately contains 200 μ g in every 1ml, precision measures 20 μ l, injecting chromatograph records color atlas; Press area normalization method and calculate content, content must not be less than 98.5%.
4, storage sealing: preserve at shady and cool dry place.
" three wastes " that produce in this process of producing product are mainly waste liquids, get final product qualified discharge after the comprehensive regulation, and concrete disposition sees Table 3:
The disposition of recycled solvent situation and " three wastes " in table 3 reaction process
Adopt the synthetic method of fosaprepitant dimeglumine of the present invention, intermediate double benzyl ester is not treated, directly change into single benzyl ester in methyl alcohol, single benzyl ester is solid, stable in properties can guarantee the quality of finished product, simplifies simultaneously production operation, therefore, can reach that raw material is easy to get, the reaction conditions gentleness is controlled, technological process is simple, yield is high and suitable suitability for industrialized production.
The proof procedure of the synthetic method of fosaprepitant dimeglumine of the present invention and result and evaluation:
Carried out continuous multiple batches of pilot process checking on the basis of lab scale craft, processing parameter and physicochemical data see the following form 4:
Table 4 processing parameter and physicochemical data table
| Lot identification mark | W101014 | W101025 | W101106 |
| (kg) in batches | 1.58 | 1.52 | 1.53 |
| Total recovery (%) | 51.4 | 49.4 | 49.7 |
| Outward appearance | White powder | White powder | White powder |
| Total assorted (%) | 0.57 | 0.52 | 0.51 |
| Maximum is notice of invitation assorted (%) not | 0.05 | 0.04 | 0.03 |
| Aprepitant (impurity A) | 0.33 | 0.33 | 0.33 |
| Monoesters (impurity B) | 0.1 | 0.09 | 0.09 |
| Isomer (%) | Do not detect | Do not detect | Do not detect |
| Content (%) | 99.3 | 99.5 | 99.3 |
| Moisture (%) | 1.51 | 1.58 | 1.25 |
| Dissolvent residual | Up to specification | Up to specification | Up to specification |
The above is the preferred embodiment of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also are considered as protection scope of the present invention.
Claims (6)
1. a fosaprepitant dimeglumine crystal formation compound, is characterized in that, molecular formula is as follows:
C23H22F7N4O6P·?2?C7H17NO5；
The preparation technology of described fosaprepitant dimeglumine crystal formation compound comprises the steps:
(1) preparation intermediate: use Aprepitant as starting raw material, in anhydrous tetrahydro furan, take the silica-based sodium amide of hexamethyl two as alkali, with tetra-sodium four benzyl ester reactions, make two benzyl ester intermediates, slough a benzyl in anhydrous methanol, generate single benzyl ester intermediate;
(2) preparation fosaprepitant dimeglumine crude product: a remaining benzyl ester is sloughed in the hydrogenation of single benzyl ester intermediate, with the meglumine salify, made the smooth two meglumine crude products of the husky pyrrole of good fortune;
(3) preparation fosaprepitant dimeglumine elaboration: the smooth two meglumine crude products of the husky pyrrole of good fortune are dissolved in anhydrous methanol, the elimination insolubles, more refining with the mixed solvent of dehydrated alcohol and anhydrous acetonitrile, obtain at last the smooth two meglumine elaboration of the husky pyrrole of white solid good fortune.
2. fosaprepitant dimeglumine crystal formation compound according to claim 1, it is characterized in that, in described preparation process, the preparation intermediate is: prepare the Aprepitant of 1.6 weight parts and the tetra-sodium four benzyl esters of 2.2 weight parts, in kg/L, add the anhydrous tetrahydro furan of 16 times of volumes, be cooled to-5 ℃, splash into the silica-based sodium amide of hexamethyl two of 4.8 times of volumes, maintenance-5-0 ℃ is stirred 2h, reaction solution is extracted with methyl tertiary butyl ether, i.e. intermediate double benzyl ester; The anhydrous methanol of two benzyl ester intermediates and 16 times of volumes is heated, react 20h under 45 ℃, after cooling, suction filtration and drying process, get single benzyl ester intermediate.
3. fosaprepitant dimeglumine crystal formation compound according to claim 1, it is characterized in that, preparation fosaprepitant dimeglumine crude product: in kg/L, intermediate S100902 with 1.55 weight parts, 0.84 the 5%Pd/C of the meglumine of weight part and 0.085 weight part drops in hydriding reactor, add the methyl alcohol of 33 times of volumes and the water of 0.83 times of volume, remain on hydrogenation 10-12h under 2.0MPa, filtering Pd/C, filtrate is at 20 ℃ of lower concentrating under reduced pressure, remove the solvent of 28 times of volumes, the triphenyl phosphorus that adds 4.5 weight parts in resistates, stirring at room 12h, nitrogen protection, splash in the mixed solvent of anhydrous acetonitrile of the dehydrated alcohol of 15 times of volumes of 0-10 ℃ and 15 times of volumes, 1-2h drips off, continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation, discard supernatant liquid, fill into dehydrated alcohol and anhydrous acetonitrile (6 times of volumes: mixing solutions 6 times of volumes) of preparation in advance, stir 30min, the nitrogen press filtration, solid 2L absolute ethanol washing, 25 ℃ of lower vacuum-drying 20h, get the fosaprepitant dimeglumine crude product.
4. fosaprepitant dimeglumine crystal formation compound according to claim 1, it is characterized in that, making with extra care of fosaprepitant dimeglumine crude product: in kg/L, under nitrogen protection, the fosaprepitant dimeglumine crude product of 1.8 weight parts is dissolved in the anhydrous methanol of 9 times of volumes, the elimination insolubles, splash in the mixed solvent of anhydrous acetonitrile of the dehydrated alcohol of 28 times of volumes of 0-10 ℃ and 28 times of volumes, 1-2h drips off, continue to stir 1h, be warming up to 20-30 ℃, standing sedimentation, discard supernatant liquid, fill into dehydrated alcohol and anhydrous acetonitrile (7 times of volumes: mixing solutions 7 times of volumes) of preparation in advance, stir 30min, the nitrogen press filtration, after the absolute ethanol washing of solid with 2 times of volumes, at 25 ℃ of lower vacuum-drying 20h, get white solid, pulverize, dry 20h again, get the fosaprepitant dimeglumine product.
5. the fosaprepitant dimeglumine crystal formation compound of stating according to claim 2, it is characterized in that, methyl tertiary butyl ether extraction in described step (1) refers to reaction solution is poured in the mixing solutions of cooling in advance methyl tertiary butyl ether and each 32 times of volumes of saturated sodium bicarbonate, stir, standing separatory, it is respectively the saturated sodium bicarbonate aqueous solution of 20 times of volumes that organic layer is used successively, 8% the sodium pyrosulfate aqueous solution and water wash, organic layer is done at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, the methyl alcohol that adds 3 times of volumes, stirring and dissolving, continuation is at 20 ℃ of lower concentrating under reduced pressure, get orange viscous liquid, be two benzyl ester intermediates.
6. the fosaprepitant dimeglumine crystal formation compound of stating according to claim 2, it is characterized in that, after cooling, suction filtration in described step (1) and drying process refer to reaction solution is chilled to room temperature, stir 1h under 0-5 ℃, suction filtration obtains solid, after the methanol wash of solid with 2.5 times of volumes, at 25 ℃ of lower vacuum-drying 12h, namely obtain single benzyl ester intermediate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447607A (en) * | 2014-12-12 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of aprepitant intermediate |
| CN104557760A (en) * | 2015-01-28 | 2015-04-29 | 武汉励合生物医药科技有限公司 | Preparation method of aprepitant intermediate |
| CN104650143A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Method for preparing fosaprepitant dimeglumine intermediates |
| CN106565783A (en) * | 2016-11-08 | 2017-04-19 | 山东裕欣药业有限公司 | Fosaprepitant-meglumine crystal compound, preparation method thereof, and pharmaceutical composition |
| CN106588989A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Novel crystal form of fosaprepitant dual-meglumine compound and preparing method thereof |
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| CN109516964A (en) * | 2017-09-19 | 2019-03-26 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aprepitant intermediate |
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| CN104650143A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Method for preparing fosaprepitant dimeglumine intermediates |
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| CN104447607A (en) * | 2014-12-12 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of aprepitant intermediate |
| CN104557760A (en) * | 2015-01-28 | 2015-04-29 | 武汉励合生物医药科技有限公司 | Preparation method of aprepitant intermediate |
| CN107176964B (en) * | 2016-03-09 | 2019-09-20 | 杭州九源基因工程有限公司 | A kind of purification palladium removing technique of Fosaprepitant |
| CN107176964A (en) * | 2016-03-09 | 2017-09-19 | 杭州九源基因工程有限公司 | A kind of refined palladium removing technique of Fosaprepitant |
| CN106565783A (en) * | 2016-11-08 | 2017-04-19 | 山东裕欣药业有限公司 | Fosaprepitant-meglumine crystal compound, preparation method thereof, and pharmaceutical composition |
| CN106588989A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Novel crystal form of fosaprepitant dual-meglumine compound and preparing method thereof |
| CN108948080B (en) * | 2017-05-22 | 2022-03-04 | 齐鲁制药有限公司 | Preparation method of fosaprepitant pharmaceutical salt |
| CN108948080A (en) * | 2017-05-22 | 2018-12-07 | 齐鲁制药有限公司 | A kind of preparation method of Fosaprepitant pharmaceutical salts |
| CN109516964A (en) * | 2017-09-19 | 2019-03-26 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aprepitant intermediate |
| CN109516964B (en) * | 2017-09-19 | 2022-05-31 | 鲁南制药集团股份有限公司 | Preparation method of aprepitant intermediate |
| CN107739391A (en) * | 2017-11-16 | 2018-02-27 | 浙江普洛得邦制药有限公司 | Oxazolidone medicine list debenzylation impurity and its preparation method and application |
| CN110655515A (en) * | 2018-06-29 | 2020-01-07 | 江苏海悦康医药科技有限公司 | Preparation method of high-purity aprepitant |
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