CN104592337A - Preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate - Google Patents
Preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate Download PDFInfo
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Abstract
The invention discloses a preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate. The method employs 9-beta-D-arabinofuranosyl-2-fluoroadenine as an initial raw material, enables the raw material to be reacted with a mixture of triethyl phosphate and phosphorus oxychloride and employs water for post-processing, thereby solving the problems in other synthetic methods that reaction temperature is sever, reaction time is long and post-processing operation is complex. Also, the invention discloses a simple practicable refining method, and helps to effectively improve the purity of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of 9-β-D-arabinofuranosidase glycosyl-2-fluoro VITAMIN B4-5 ' preparation method of-phosphoric acid ester.
Background technology
Fludarabine phosphate (9-β-D-arabinofuranosidase glycosyl-2-fluoro VITAMIN B4-5 '-phosphoric acid ester), English name; Fludarabine phosphate, molecular formula: C
10h
13fN
5o
7p, molecular weight: 365.2117, its structural formula is:
Developed by German Berlex Labs, within 1991, first in U.S.'s listing, be used for the treatment of B cell chronic lymphocytic leukemia (CLL).Through going phosphatizing to generate metabolite 9-β-fludarabine (F-Ara-A) after this product absorption, the latter becomes the F-Ara-ATP of tool anti-tumor activity in cell through phosphorylation.The antitumor mechanism of this product relates to and participates in DNA of tumor cell or RNA chain, makes chain stop extending, to reach the object suppressing DNA or RNA synthesis.The couplings such as this product and other anticarcinogen cytosine arabinoside (Ara-C), mitoxantrone, can strengthen the killing effect to tumour cell.
It is that its structural formula is with 9-β-D-arabinofuranosidase glycosyl-2-fluoro VITAMIN B4 (fludarabine) for prodrug;
The preparation of fludarabine phosphate is found in many patent documentations, and they are all that starting raw material is prepared with fludarabine.
US5110919 have employed the method that trimethyl phosphite 99 and phosphorus oxychloride carry out reacting at 0 DEG C, the method of aftertreatment adds water and methylene dichloride, under agitation leave standstill two-phase laminated flow, methylene dichloride is removed with decantation, obtain lurid gelatinous residue, be dissolved in 50 DEG C of hot water and wait until precipitation.Unique sign of the crude product obtained is decomposition point (200 DEG C-250 DEG C), with thin layer chromatography, reclaims secondary output object, by the solid water recrystallization obtained by resin.
The shortcoming of this method is that decant operation is difficult to industrially scale realize, and in addition, also can generate and stir the gelatinous residue bringing very burden to reactor at industrial scale, and adopt chromatography purification, complicated operation, yield is low.
US4357324 have employed trimethyl phosphite 99 and phosphorus oxychloride and reacts at 0 DEG C, with water hydrolysis, generates the method that the latter is then changed into free acid by sodium salt.
The output that the method that this patent adopts obtains is general, be difficult to technical scale and reproduce, and the method uses azanol in extraction stages, employs the chemicals that may explode, and therefore should not use on a large scale.
CN200480030273.5 adopts triethyl phosphate and fludarabine to put into-15/-20 DEG C of reactor, by phosphorus oxychloride with about one hour ground the time be added dropwise to, at-10/-15 DEG C react 48 hours, add cold toluene product is precipitated crude product, use resin purification again, recrystallization.
The shortcoming of this method is that temperature of reaction is low, long reaction time, and energy consumption is large; Phosphorus oxychloride needs to drip, dangerous large, difficult operation; In last handling process, use toluene, toxicity strengthens, and uses resin purification in addition, complicated operation, is unfavorable for suitability for industrialized production.
Summary of the invention
Temperature of reaction for prior art is harsh, and long reaction time, the problem of post-processing operation complexity, the present invention's object is to provide a kind of fludarabine phosphate synthetic method.
Another object of the present invention is to provide a kind of process for purification of fludarabine phosphate crude product, thus cross resin column in solution process for purification, chromatographic column, purification step is loaded down with trivial details, and high temperature is water-soluble causes the degraded of going bad of part fludarabine phosphate to generate the problems such as new impurity, purity are high not.
The object of the invention is to be achieved through the following technical solutions:
A synthetic method for fludarabine phosphate, synthesis step is as follows,
A. fludarabine and triethyl phosphate and phosphorus oxychloride reaction; B. add water to the mixing species be obtained by reacting, generate fludarabine phosphate.
Be specially: described step a comprises under agitation by fludarabine, triethyl phosphate and phosphorus oxychloride are reacted at lower than the temperature of 0 DEG C; Described step b is included in and under agitation adds in gained reaction mixture lower than 20 DEG C by pure water, and with solvent wash, after washing, gained aqueous phase alkaline matter is adjusted to pH=2-3, concentrating under reduced pressure, refrigeration crystallization, filters, filter cake a small amount of ethanol and water washing, obtain fludarabine phosphate crude product.
Washing solvent for use in described step b is washed with dichloromethane, and after washing, gained aqueous phase 50%NaOH solution is adjusted to pH=3.
Washing solvent for use in described step b is that ethyl acetate is washed, and after washing, gained aqueous phase potash solid is adjusted to pH=2 ~ 3.
For every gram of fludarabine, the consumption of triethyl phosphate is 9 ~ 15mL, more preferably 11 ~ 12mL, more preferably 11.5mL; For every gram of fludarabine, the consumption preferably 0.6 ~ 1.2mL of phosphorus oxychloride, more preferably 0.7 ~ 0.9mL, more preferably 0.75mL.
Reaction is being carried out lower than 0 DEG C, preferably carries out at-5 DEG C ~-1 DEG C;
Reaction times is within 12 ~ 24 hours, to reflect completely;
For every gram of fludarabine, the consumption of water is preferably 5 ~ 30mL, is more preferably 10 ~ 11mL.
Adopt synthetic method provided by the invention, its effect is significant, greatly reduces operation steps, the consumption of solvent, reaction times is short, purity is higher than 99%, and yield higher than 70%, thus has saved the energy, reduce production cost, decrease the load to plant and instrument, adopt the solvent of environmental protection in addition, make this reaction be more suitable for suitability for industrialized production.
The invention also discloses a kind of process for purification of fludarabine phosphate, comprise the following steps,
The fludarabine phosphate crude product that above-mentioned synthetic method is obtained, join in pure water under room temperature and stir, slow dropping 50%NaOH solution is to dissolving completely, and filter, filtrate added drop-wise is in dilute hydrochloric acid solution, adularescent solid is separated out, suction filtration, filter cake ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate.
Fludarabine phosphate synthetic method provided by the invention, be react in a mild condition, the reaction times is short, and post-reaction treatment is simple to operation, thus it is harsh to solve temperature of reaction in other synthetic methods, long reaction time, the problems such as energy consumption is large, and post-processing operation is complicated.
Process for purification of the present invention, its refining effect is significant.First process for purification provided by the invention, mild condition, save energy, easy and simple to handle, the used time is short, and yield is high, does not adopt organic solvent, and environmental pollution is little; Secondly fludarabine phosphate is stable in this treating process, and therefore process for purification of the present invention has easy to operate, and yield is high, purity is high, the feature of good stability, the fludarabine phosphate outward appearance adopting process for purification disclosed by the invention to obtain is good, purity high (>=99.9%).
Embodiment
Illustrate the present invention and beneficial effect thereof by the following examples, the apparent change that those of ordinary skill in the art do the present invention and modification are also contained within the present invention.
Embodiment 1
Under agitation by fludarabine (10g), triethyl phosphate (115mL), phosphorus oxychloride (7.5mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (105mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate crude product purity 99.1%, yield 74.2%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 96.2%.
Embodiment 2
Under agitation by fludarabine (10g), triethyl phosphate (90mL), phosphorus oxychloride (6mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (50mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 73.3%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 96.5%.
Embodiment 3
Under agitation by fludarabine (10g), triethyl phosphate (150mL), phosphorus oxychloride (12mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (200mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45 DEG C-50 DEG C, obtain fludarabine phosphate crude product purity 99.1%, yield 71%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 96.2%.
Embodiment 4
Under agitation by fludarabine (10g), triethyl phosphate (110mL), phosphorus oxychloride (7mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (100mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 72.3%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.1%.
Embodiment 5
Under agitation by fludarabine (10g), triethyl phosphate (120mL), phosphorus oxychloride (9mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (110mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate crude product purity 99.1%, yield 73%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.4%.
Embodiment 6
Fludarabine 10g is suspended in trimethyl phosphite 99 100mL, and ice-water bath is chilled to 0 DEG C, slowly drips phosphorus oxychloride 7.2mL.Drip and finish, 0 DEG C is reacted 30 hours, and TLC display reacts completely; Add water and methylene dichloride, under agitation leave standstill two-phase laminated flow, remove methylene dichloride with decantation, obtain lurid gelatinous residue, be dissolved in 50 DEG C of hot water and wait until precipitation.The crude product obtained, suction filtration, concentrating under reduced pressure filtrate obtains white solid, purity 95.3%, yield 58.1%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.2%.
Embodiment 7
Under agitation by fludarabine (10g), triethyl phosphate (115mL), phosphorus oxychloride (7.5mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (105mL) is under agitation added in gained mixture, by washed with dichloromethane, gained aqueous phase 50%NaOH solution is adjusted to pH=3,35-40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate crude product purity 99.1%, yield 71.1%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, is suspended in the water of 25 volumes, by total material heating for dissolving at 65 DEG C, filtered while hot, filtrate to be lowered the temperature crystallization with ice-water bath, filters, filter cake washing with acetone filter cake, obtains product purity 99.2%, yield 80.3%.
Embodiment 8
Under agitation by fludarabine (10g), triethyl phosphate (115mL), phosphorus oxychloride (7.5mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (170mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 72.9%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, white solid, by white solid vacuum forced air drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 94.6%.
Embodiment 9
Under agitation by fludarabine (10g), triethyl phosphate (90mL), phosphorus oxychloride (6mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (100mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 70.2%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, white solid, by white solid vacuum forced air drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.2%.
Embodiment 10
Under agitation by fludarabine (10g), triethyl phosphate (150mL), phosphorus oxychloride (12mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (300mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 DEG C ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.1%, yield 71.3%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, white solid, by white solid vacuum forced air drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.1%.
Embodiment 11
Under agitation by fludarabine (10g), triethyl phosphate (110mL), phosphorus oxychloride (7mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (200mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 71.1%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, white solid, by white solid vacuum forced air drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.3%.
Embodiment 12
Under agitation by fludarabine (10g), triethyl phosphate (120mL), phosphorus oxychloride (9mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (220mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.3%, yield 73.3%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, white solid, by white solid vacuum forced air drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.5%.
Embodiment 13
Fludarabine 10g is suspended in trimethyl phosphite 99 100mL, and ice-water bath is chilled to 0 DEG C, slowly drips phosphorus oxychloride 7.2mL.Drip and finish, 0 DEG C is reacted 30 hours, and TLC display reacts completely; Add water and methylene dichloride, under agitation leave standstill two-phase laminated flow, remove methylene dichloride with decantation, obtain lurid gelatinous residue, be dissolved in 50 DEG C of hot water and wait until precipitation.The crude product obtained, suction filtration, concentrating under reduced pressure filtrate obtains white solid, purity 95.3%, yield 58.1%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, joins under room temperature in 100mL pure water and stirs, and slowly drips 50%NaOH solution to dissolving completely, filter, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, and adularescent solid is separated out, suction filtration, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum forced air drying 10-12 hour at 45-50 DEG C, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.2%.
Embodiment 14
Under agitation by fludarabine (10g), triethyl phosphate (115mL), phosphorus oxychloride (7.5mL) is placed in the cold cycle pump of-5 ~-10 DEG C, will keep internal temperature-5 ~-1 DEG C simultaneously; Stirring reaction 15 hours at-5 ~-1 DEG C; When the amount of fludarabine is in HPLC area of detection, be less than 2% and think and react completely, then pure water (105mL) is under agitation added in gained mixture, wash by ethyl acetate, gained aqueous phase potash solid is adjusted to pH=2,35 ~ 40 DEG C of concentrating under reduced pressure, refrigeration crystallization, filter, filter cake a small amount of ethanol and water washing, obtain white solid, by white solid vacuum-drying 10 ~ 12 hours at 45 ~ 50 DEG C, obtain fludarabine phosphate crude product purity 99.2%, yield 71.2%.
The fludarabine phosphate crude product above-mentioned preparation method obtained, is suspended in the water of 25 volumes, by total material heating for dissolving at 65 DEG C, filtered while hot, filtrate to be lowered the temperature crystallization with ice-water bath, filters, filter cake washing with acetone filter cake, obtains product purity 99.4%, yield 82.4%.
Comparative example 1
Fludarabine 0.25g (0.88mmol) is suspended in triethyl phosphate 2.30mL (13.5mmol), and Ar protects, and ice-water bath is chilled to 0 DEG C, slowly drips phosphorus oxychloride 0.18mL (1.95mmol).Drip and finish, 0 DEG C is reacted 3.5 hours.Add POCI
30.06mL (0.65mmol), continue 0 DEG C of reaction 5 hours, TLC display reacts completely.Filter, use cold water washing filter residue, merge washing lotion and filtrate, be chilled to 0 DEG C, dripping 50% (w) NaOH aqueous solution adjust ph is 2, uses CH
2cl
2extraction (10mL × 2), water layer adjusts pH=2 through 50% (w/w) NaOH aqueous solution again.Add gac, stirring at room temperature 1 hour, suction filtration, concentrating under reduced pressure filtrate obtains white solid, obtains 195mg white solid with water recrystallization, yield 59.2%.
Comparative example 2
9.5g phosphorus oxychloride is added in the trimethyl phosphite 99 being chilled to 0 DEG C in advance, after stirring 40min, again 10g mono-hydration fludarabine is added system, after stirring reaction 3h, gained homogeneous phase solution is placed in refrigerator placement and spends the night.Stir 1.5g after adding 10ml water again in system, then pour the methylene dichloride that 500ml is chilled to 0 DEG C in advance into, stir until dichloromethane layer is transparent.Pour out dichloromethane layer, in residuum, add 100ml warm water stirring and dissolving.Spontaneous nucleation, obtains fludarabine phosphate 8.2g after vacuum-drying, yield 58.3%.
Comparative example 3
By fludarabine (19.5g; 0.0683 mole) and triethyl phosphate (79.1ml; 0.465 mole) put into the reactor being cooled to-15/-20 DEG C.By phosphorus oxychloride (15.3ml; 0.164 mole) dropwise add with the time of about l hour, internal temperature will be kept at-10/-15 DEG C simultaneously.Stir 48 hours at-10/-15 DEG C; When the amount of fludarabine, in HPLC area, when being less than 2%, then think that reaction is complete.Then cold toluene (780ml, 40 volumes) was added in about 1.5 hours, maintain and stir, 1-2 hour at still remaining on-10/-15 DEG C. filter, filter cake 20ml toluene wash.The solid (about 35g) that will wet is suspended in 40ml water, 20ml is about with the NaOH(of 32%) pH is adjusted to 11. and solution is filled in the beaker filling Dowex resin. ［ first resin must be activated and be washed as follows: with demineralized water, until washing water become colourless; With the HCL acidifying of about 20ml5%, be washed till pH neutrality with softening water ］.Total material stirs 15 minutes and uses membrane filtration.Resin is resuspended in 500ml water.Stir and then use membrane filtration again in 15 minutes. repeat this operation, no longer include fludarabine phosphate in filtrate till.Partial vacuum containing product is volatilized (the highest 30-35 DEG C of temperature) to reduce its volume, until desired product precipitation, final product filters and 60 DEG C of vacuum-dryings to constant weight.Obtain purity higher than 97.5% white solid product 10.1g(productive rate 40%).Can by as follows for this solid recrystallization: be suspended in the water of 10 volumes, total material heated 1 hour at 70 DEG C, filtered while hot, use washing with acetone filter cake, obtain product purity 99.0%.
Claims (10)
1. a preparation method for fludarabine phosphate, is characterized in that, comprises the steps:
1). fludarabine phosphate crude product synthesizes: a. fludarabine and triethyl phosphate and phosphorus oxychloride reaction; B. add water to the mixing species be obtained by reacting, fludarabine phosphate is precipitated;
2) fludarabine phosphate is refined.
2. the preparation method of fludarabine phosphate according to claim 1, is characterized in that, described step a comprises under agitation by fludarabine, and triethyl phosphate and phosphorus oxychloride are reacted at lower than the temperature of 0 DEG C; Described step b is included in and under agitation adds in gained reaction mixture lower than 20 DEG C by pure water, and with solvent wash, after washing, gained aqueous phase alkaline matter is adjusted to pH=2-3, concentrating under reduced pressure, refrigeration crystallization, filters, filter cake a small amount of ethanol and water washing, obtain fludarabine phosphate crude product.
3. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, washing solvent for use in described step b is washed with dichloromethane, and after washing, gained aqueous phase 50%NaOH solution is adjusted to pH=3.
4. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, washing solvent for use in described step b is that ethyl acetate is washed, and after washing, gained aqueous phase potash solid is adjusted to pH=2 ~ 3.
5. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, for every gram of fludarabine, the consumption of triethyl phosphate is 9 ~ 15mL.
6. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, for every gram of fludarabine, and the consumption 0.6 ~ 1.2mL of phosphorus oxychloride.
7. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, for every gram of fludarabine, the consumption of water is 5 ~ 30mL.
8. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, the temperature of reaction of step a is-5 DEG C ~-1 DEG C.
9. the preparation method of fludarabine phosphate according to claim 2, is characterized in that, described refining comprising the steps: will synthesize the fludarabine phosphate crude product obtained, join in pure water under room temperature and stir, slow dropping 50%NaOH solution is to dissolving completely, and filter, filtrate added drop-wise is in dilute hydrochloric acid solution, adularescent solid is separated out, suction filtration, filter cake ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45 ~ 50 DEG C, obtain fludarabine phosphate.
10. a process for purification for fludarabine phosphate, is characterized in that, it comprises the steps: to synthesize the fludarabine phosphate crude product obtained, join in pure water under room temperature and stir, slow dropping 50%NaOH solution is to dissolving completely, and filter, filtrate added drop-wise is in dilute hydrochloric acid solution, adularescent solid is separated out, suction filtration, filter cake ethanol and water washing, obtain white solid, by white solid vacuum-drying 10-12 hour at 45 ~ 50 DEG C, obtain fludarabine phosphate.
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