CN104592337B - A kind of preparation method of 9- β-D- arabinofuranosidases glycosyl -2- fluoro adenine -5 '-phosphate - Google Patents
A kind of preparation method of 9- β-D- arabinofuranosidases glycosyl -2- fluoro adenine -5 '-phosphate Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of 5 ' phosphate of 92 fluoro adenine of β D arabinofuranosidases glycosyls, this method is using 9 β D arabinofuranosidases glycosyl, 2 fluoro adenine as starting material, by making it be reacted with the mixture of triethyl phosphate and phosphorus oxychloride and being post-processed using water, it is harsh to solve reaction temperature in other synthetic methods, reaction time is long, the problem of post-processing operation complexity, the present invention includes a kind of simple simultaneously, feasible process for purification, effectively raise the purity of 92 fluoro adenine of β D arabinofuranosidases glycosyls, 5 ' phosphate.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of 9- β-D- arabinofuranosidases glycosyl -2- fluoro adenine -
The preparation method of 5 '-phosphates.
Background technology
Fludarabine phosphate（9- β-D- arabinofuranosidase glycosyl -2- fluoro adenine -5 '-phosphate）, English name；
Fludarabine phosphate, molecular formula：C10H13FN5O7P, molecular weight：365.2117 structural formula is：
It is developed, is listed in the U.S. first by German Berlex Labs within 1991, it is thin for treating B cell chronic lymphatic
Born of the same parents' leukaemia (CLL).Through going phosphatizing to generate metabolin 9- β-fludarabine (F-Ara-A), Hou Zhe after this product intake
The intracellular phosphorylated F-Ara-ATP for becoming to have antitumor activity.The antitumor mechanism of this product is related to participating in DNA of tumor cell
Or RNA chains, make chain stop extending, to achieve the purpose that DNA or RNA is inhibited to synthesize.This product and other anticarcinogen cytarabines
(Ara-C), the combinations such as mitoxantrone can enhance the killing effect to tumour cell.
It is with 9- β-D- arabinofuranosidase glycosyl -2- fluoro adenines（Fludarabine）For prodrug, structural formula
For；
The preparation of fludarabine phosphate is found in many patent documents, all of which using fludarabine as starting material into
It is prepared by row.
US5110919 uses the method that trimethyl phosphate and phosphorus oxychloride are reacted at 0 DEG C, the method for post-processing
It is that water and dichloromethane is added, stands arrive two-phase laminated flow under stiring, removes dichloromethane with decantation, obtain lurid glue
Shape residue is dissolved in 50 DEG C of hot water and remains to precipitate.Unique characterization of obtained crude product is decomposition point（200℃-250
℃）, with thin layer chromatography, secondary output object is recycled by resin, obtained solid is recrystallized with water.
The shortcomings that this method is that decantation operation is difficult to realize in industrially scale, is advised in industry in addition, can also generate
The gelatinous residue brought a lot of trouble is stirred on mould to reactor, and is purified using chromatography, complicated for operation, yield is low.
US4357324 uses trimethyl phosphate and phosphorus oxychloride and is reacted at 0 DEG C again, is hydrolyzed with water, generates sodium salt
Then the method for the latter being converted to free acid.
The yield that the method that the patent uses obtains is general, it is hard to which commercial scale reproduces, and this method is in extraction stages
Using azanol, the chemicals that may be exploded, therefore unsuitable large-scale use have been used.
CN200480030273.5 is put into using triethyl phosphate and fludarabine in -15/-20 DEG C of reactors, by trichlorine
Oxygen phosphorus was added dropwise to about one hour ground time, was reacted 48 hours at -10/-15 DEG C, and cold toluene, which is added, makes product precipitate slightly
Product, then with purifying resin, recrystallization.
The shortcomings that this method is that reaction temperature is low, and the reaction time is long, and energy consumption is big；Phosphorus oxychloride needs to be added dropwise, dangerous
Greatly, difficult operation；It uses toluene, toxicity to increase in last handling process, in addition uses purifying resin, it is complicated for operation, it is unfavorable for work
Industry metaplasia is produced.
Invention content
Harsh for the reaction temperature of the prior art, the reaction time is long, the problem of post-processing operation complexity, the present invention one
Purpose is to provide a kind of fludarabine phosphate synthetic method.
It is a further object of the present invention to provide a kind of process for purification of fludarabine phosphate crude product, to solve process for purification
Middle to cross resin column, chromatographic column, purification step is cumbersome, and high temperature is water-soluble to cause fludarabine phosphate rotten degradation in part to generate newly miscellaneous
The problems such as matter, not high enough purity.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of synthetic method of fludarabine phosphate, synthesis step is as follows,
A. fludarabine and triethyl phosphate and phosphorus oxychloride reaction；B. water is added to mixing species obtained by the reaction, it is raw
At fludarabine phosphate.
Specially：The step a include under agitation by fludarabine, triethyl phosphate and phosphorus oxychloride less than
It is reacted at a temperature of 0 DEG C；The step b is included in, and pure water is added under stiring in gained reaction mixture less than 20 DEG C, is used
Solvent washing, gained water phase is adjusted to pH=2-3 with alkaline matter after washing, is concentrated under reduced pressure, and refrigerates crystallization, filtering, and filter cake is used a small amount of
Ethyl alcohol and water washing obtain fludarabine phosphate crude product.
It washs solvent for use in the step b to wash for dichloromethane, gained water phase is adjusted to 50%NaOH solution after washing
pH=3。
In the step b wash solvent for use washed for ethyl acetate, after washing gained water phase with potash solid be adjusted to pH=
2~3.
For every gram of fludarabine, the dosage of triethyl phosphate is 9~15mL, more preferable 11~12mL, further preferably
For 11.5mL；For every gram of fludarabine, dosage preferably 0.6~1.2mL, the more preferable 0.7~0.9mL of phosphorus oxychloride, into one
Step is preferably 0.75mL.
Reaction is being carried out less than 0 DEG C, is preferably carried out at -5 DEG C~-1 DEG C；
Reaction time is that can reflect within 12~24 hours completely；
For every gram of fludarabine, the dosage of water is preferably 5~30mL, more preferably 10~11mL.
Using synthetic method provided by the invention, effect is significant, greatly reduces operating procedure, and solvent disappears
Consumption, the reaction time is short, and purity is higher than 99%, and yield is higher than 70%, to save the energy, reduces production cost, reduces pair
In addition the load of instrument and equipment uses the solvent of environmental protection, the reaction is made to be more suitable for industrialized production.
The invention also discloses a kind of process for purification of fludarabine phosphate, include the following steps,
The fludarabine phosphate crude product that above-mentioned synthetic method is obtained, is added in pure water stirs evenly at room temperature, slowly
It is complete to dissolving that 50%NaOH solution is added dropwise, filters, in filtrate added drop-wise to dilute hydrochloric acid solution, there is white solid precipitation, filter, filter
Cake ethyl alcohol and water washing, obtain white solid, and white solid is dried in vacuo 10~12 hours at 45~50 DEG C, obtains phosphoric acid fluorine
Up to drawing shore.
Fludarabine phosphate synthetic method provided by the invention is to react in a mild condition, and the reaction time is short, after reaction
Handle simple to operation, harsh to solve in other synthetic methods reaction temperature, the reaction time is long, and energy consumption is big, post-processing behaviour
Make the problems such as complicated.
The process for purification of the present invention, refining effect is significant.Process for purification provided by the invention first, condition temperature
With energy saving, easy to operate, the used time is short, high income, does not use organic solvent, environmental pollution small；Secondly fludarabine phosphate
Stablize in this subtractive process, therefore the process for purification of the present invention has easy to operate, high income, purity is high, and stability is good
Feature, the fludarabine phosphate appearance obtained using process for purification disclosed by the invention is good, and purity is high（≥99.9%）.
Specific implementation mode
The present invention and advantage are illustrated by the following examples, and those of ordinary skill in the art make the present invention
It is obvious change and modification be also contained within the present invention.
Embodiment 1
Under agitation by fludarabine（10g）, triethyl phosphate（115mL）, phosphorus oxychloride（7.5mL）It is placed in -5
In~-10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；
When the amount of fludarabine is in HPLC area of detection, think that the reaction was complete less than 2%, then by pure water（105mL）Under stiring
It is added in gained mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3 with 50%NaOH solution, and 35-40 DEG C of decompression is dense
Contracting refrigerates crystallization, and filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum
It is 10-12 hours dry, obtain fludarabine phosphate crude product purity 99.1%, yield 74.2%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5~-10
DEG C low-temperature circulating pump in, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；When fluorine reaches
It draws the amount of shore in HPLC area of detection, thinks that the reaction was complete less than 2%, then by pure water（50mL）Institute is added under stiring
It obtains in mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3,35-40 DEG C of reduced pressure, refrigeration with 50%NaOH solution
Crystallization, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo 10- at 45-50 DEG C
12 hours, obtain fludarabine phosphate crude product purity 99.2%, yield 73.3%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（200mL）It is added under stiring
It in gained mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3 with 50%NaOH solution, and 35-40 DEG C of reduced pressure is cold
Crystallization is hidden, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo at 45 DEG C -50 DEG C
10-12 hours, obtain fludarabine phosphate crude product purity 99.1%, yield 71%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（100mL）It is added under stiring
It in gained mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3 with 50%NaOH solution, and 35-40 DEG C of reduced pressure is cold
Crystallization is hidden, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo at 45-50 DEG C
10-12 hours, obtain fludarabine phosphate crude product purity 99.2%, yield 72.3%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（110mL）It is added under stiring
It in gained mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3 with 50%NaOH solution, and 35-40 DEG C of reduced pressure is cold
Crystallization is hidden, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo at 45-50 DEG C
10-12 hours, obtain fludarabine phosphate crude product purity 99.1%, yield 73%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.4%.
Embodiment 6
Fludarabine 10g is suspended in trimethyl phosphate 100mL, ice-water bath is cooled to 0 DEG C, phosphorus oxychloride is slowly added dropwise
7.2mL.Drop finishes, and 0 DEG C is reacted 30 hours, and TLC shows that the reaction was complete；Water and dichloromethane is added, stands arrive two-phase under stiring
Separation removes dichloromethane with decantation, obtains lurid gelatinous residue, be dissolved in 50 DEG C of hot water and remain to precipitate.Institute
Obtained crude product filters, and filtrate is concentrated under reduced pressure and obtains white solid, purity 95.3%, yield 58.1%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5
In~-10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；
When the amount of fludarabine is in HPLC area of detection, think that the reaction was complete less than 2%, then by pure water（105mL）Under stiring
It is added in gained mixture, is washed with dichloromethane, gained water phase is adjusted to pH=3 with 50%NaOH solution, and 35-40 DEG C of decompression is dense
Contracting refrigerates crystallization, and filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum
It is 10-12 hours dry, obtain fludarabine phosphate crude product purity 99.1%, yield 71.1%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is suspended in the water of 25 volumes, by whole objects
Matter dissolves by heating at 65 DEG C, filters while hot, and filtrate is washed filter cake with acetone, obtained with ice-water bath cooling crystallization, filtering, filter cake
Product purity 99.2%, yield 80.3%.
Embodiment 8
Under agitation by fludarabine（10g）, triethyl phosphate（115mL）, phosphorus oxychloride（7.5mL）It is placed in -5
In~-10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；
When the amount of fludarabine is in HPLC area of detection, think that the reaction was complete less than 2%, then by pure water（170mL）Under stiring
It is added in gained mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2 with potash solid, and 35~40 DEG C of decompressions are dense
Contracting refrigerates crystallization, and filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum
It is 10~12 hours dry, obtain fludarabine phosphate crude product purity 99.2%, yield 72.9%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum forced air drying 10~
12 hours, 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）It is placed in -5~-10
DEG C low-temperature circulating pump in, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；When fluorine reaches
It draws the amount of shore in HPLC area of detection, thinks that the reaction was complete less than 2%, then by pure water（100mL）Institute is added under stiring
It obtains in mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2,35~40 DEG C of reduced pressures, refrigeration with potash solid
Crystallization, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo 10 at 45~50 DEG C
~12 hours, obtain fludarabine phosphate crude product purity 99.2%, yield 70.2%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum forced air drying 10~
12 hours, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（300mL）It is added under stiring
It in gained mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2 with potash solid, and 35~40 DEG C of reduced pressures are cold
Crystallization, filtering are hidden, filter cake a small amount of ethyl alcohol and water washing obtain white solid, and vacuum is done at 45 DEG C~50 DEG C by white solid
Dry 10~12 hours, obtain fludarabine phosphate crude product purity 99.1%, yield 71.3%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum forced air drying 10~
12 hours, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（200mL）It is added under stiring
It in gained mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2 with potash solid, and 35~40 DEG C of reduced pressures are cold
Crystallization is hidden, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo at 45~50 DEG C
10~12 hours, obtain fludarabine phosphate crude product purity 99.2%, yield 71.1%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum forced air drying 10~
12 hours, 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）It is placed in -5~-
In 10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；Work as fluorine
Think that the reaction was complete less than 2%, then by pure water in HPLC area of detection up to the amount of shore is drawn（220mL）It is added under stiring
It in gained mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2 with potash solid, and 35~40 DEG C of reduced pressures are cold
Crystallization is hidden, filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, white solid are dried in vacuo at 45~50 DEG C
10~12 hours, obtain fludarabine phosphate crude product purity 99.3%, yield 73.3%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum forced air drying 10~
12 hours, obtain fludarabine phosphate highly finished product, purity 99.9%, yield 95.5%.
Embodiment 13
Fludarabine 10g is suspended in trimethyl phosphate 100mL, ice-water bath is cooled to 0 DEG C, phosphorus oxychloride is slowly added dropwise
7.2mL.Drop finishes, and 0 DEG C is reacted 30 hours, and TLC shows that the reaction was complete；Water and dichloromethane is added, stands arrive two-phase under stiring
Separation removes dichloromethane with decantation, obtains lurid gelatinous residue, be dissolved in 50 DEG C of hot water and remain to precipitate.Institute
Obtained crude product filters, and filtrate is concentrated under reduced pressure and obtains white solid, purity 95.3%, yield 58.1%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is added in 100mL pure water and stirs evenly at room temperature,
It is complete to dissolving that 50%NaOH solution is slowly added dropwise, filtering, filtrate room temperature is added drop-wise in dilute hydrochloric acid solution, there is white solid precipitation,
Filter, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45-50 DEG C vacuum forced air drying 10-12
Hour, 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）It is placed in -5
In~-10 DEG C of low-temperature circulating pump, while to keep internal temperature -5~-1 DEG C；It is stirred to react at -5~-1 DEG C 15 hours；
When the amount of fludarabine is in HPLC area of detection, think that the reaction was complete less than 2%, then by pure water（105mL）Under stiring
It is added in gained mixture, is washed with ethyl acetate, gained water phase is adjusted to pH=2 with potash solid, and 35~40 DEG C of decompressions are dense
Contracting refrigerates crystallization, and filtering, filter cake a small amount of ethyl alcohol and water washing obtain white solid, by white solid at 45~50 DEG C vacuum
It is 10~12 hours dry, obtain fludarabine phosphate crude product purity 99.2%, yield 71.2%.
The fludarabine phosphate crude product that above-mentioned preparation method is obtained, is suspended in the water of 25 volumes, by whole objects
Matter dissolves by heating at 65 DEG C, filters while hot, and filtrate is washed filter cake with acetone, obtained with ice-water bath cooling crystallization, filtering, filter cake
Product purity 99.4%, yield 82.4%.
Comparative example 1
Fludarabine 0.25g (0.88mmol) is suspended in triethyl phosphate 2.30mL (13.5mmol), Ar protections, ice water
Bath is cooled to 0 DEG C, and phosphorus oxychloride 0.18mL (1.95mmol) is slowly added dropwise.Drop finishes, and 0 DEG C is reacted 3.5 hours.It adds
POCI30.06mL (0.65mmol), continuation are reacted 5 hours at 0 DEG C, and TLC shows that the reaction was complete.Filtering, filter residue is washed with cold water,
Merge washing lotion and filtrate, be cooled to 0 DEG C, it is 2 that 50% (w) NaOH aqueous solutions, which are added dropwise, and adjust pH value, uses CH2Cl2It extracts (10mL × 2),
Water layer is again through 50% (w/w) NaOH aqueous solution tune pH=2.Activated carbon is added, is stirred at room temperature 1 hour, filters, filtrate is concentrated under reduced pressure and obtains
White solid recrystallizes to obtain 195mg white solids, yield 59.2% with water.
Comparative example 2
By 9.5g phosphorus oxychloride add to it is pre- be cooled in 0 DEG C of trimethyl phosphate, stir 40min after again by 10g mono- be hydrated fluorine
Up to drawing shore to add system, it is stirred to react after 3h gained homogeneous phase solution being placed in refrigerator and stands overnight.10ml is added in system
1.5g is stirred after water, is subsequently poured into the dichloromethane that 500ml is cooled to 0 DEG C in advance, and stirring is until dichloromethane layer is transparent.Pour out dichloro
100ml warm water stirring and dissolvings are added in residue for methane layer.Spontaneous nucleation obtains fludarabine phosphate 8.2g after vacuum drying, receive
Rate 58.3%.
Comparative example 3
By fludarabine（19.5g;0.0683 mole）With triethyl phosphate (79.1ml;0.465 mole）Be put into be cooled to-
DEG C reactor in.By phosphorus oxychloride (15.3ml;0.164 mole）It was added dropwise with about l hours time, is wanted simultaneously
Keep internal temperature at -10/-15 DEG C.It is stirred 48 hours at -10/-15 DEG C；When the amount of fludarabine, in HPLC areas,
Then think that reaction is complete when less than 2%.Then by cold toluene（780ml, 40 volumes）It is added, maintains in about 1.5 hours
Stirring remains at filterings in 1-2 hours, filter cake at -10/-15 DEG C and is washed with 20ml toluene.By wet solid（About 35g）It is suspended to
In 40ml water, with 32% NaOH（About 20ml）By pH be adjusted to 11. solution is filled into the beaker for filling Dowex resins
Resin must be activated and wash first as follows：With water washing is softened, until washings become colourless；With about 20ml5%'s
HCL is acidified, and pH neutrality is washed to softening ］.Total material stirs 15 minutes and uses membrane filtration.Resin is resuspended in
In 500ml water.Stirring then repeats this operation in 15 minutes with membrane filtration again, until there is no fludarabine phosphorus in filtrate
Until acid esters.By the partial vacuum volatilization containing product（30-35 DEG C of temperature highest）To reduce its volume, until desirable production
Object precipitates, and final product filters and is dried under vacuum to constant weight at 60 DEG C.Obtain the white solid product that purity is higher than 97.5%
10.1g（Yield 40%).This solid can be recrystallized as follows：It is suspended in the water of 10 volumes, by total material 70
It is heated 1 hour at DEG C, filters while hot, filter cake is washed with acetone, obtain product purity 99.0%.
Claims (6)
1. a kind of preparation method of fludarabine phosphate, which is characterized in that include the following steps：
1）Fludarabine phosphate crude product synthesizes：A. fludarabine and triethyl phosphate and phosphorus oxychloride reaction；B. to being obtained by the reaction
Mixture in water is added, so that fludarabine phosphate is precipitated；
2）Fludarabine phosphate is refined；
The step a includes the temperature by fludarabine, triethyl phosphate and phosphorus oxychloride at -5 DEG C~-1 DEG C under agitation
The lower reaction of degree；The step b is included in, and pure water is added under stiring in gained reaction mixture less than 20 DEG C, is washed with solvent
Wash, after washing gained water phase be adjusted to pH=2-3 with alkaline matter, be concentrated under reduced pressure, refrigerate crystallization, filtering, a small amount of ethyl alcohol of filter cake with
Water washing obtains fludarabine phosphate crude product；
In the step b wash solvent for use be dichloromethane wash, after washing obtained by water phase with 50%NaOH solution be adjusted to pH=
3。
2. the preparation method of fludarabine phosphate according to claim 1, which is characterized in that wash institute in the step b
It is ethyl acetate with solvent, gained water phase is adjusted to pH=2~3 with potash solid after washing.
3. the preparation method of fludarabine phosphate according to claim 1, which is characterized in that for every gram of fludarabine,
The dosage of triethyl phosphate is 9~15mL.
4. the preparation method of fludarabine phosphate according to claim 1, which is characterized in that for every gram of fludarabine,
0.6~1.2mL of dosage of phosphorus oxychloride.
5. the preparation method of fludarabine phosphate according to claim 1, which is characterized in that for every gram of fludarabine,
The dosage of water is 5~30mL.
6. the preparation method of fludarabine phosphate according to claim 1, which is characterized in that described refined including following step
Suddenly：The fludarabine phosphate crude product that synthesis is obtained, is added in pure water stirs evenly at room temperature, it is molten that 50%NaOH is slowly added dropwise
Liquid is complete to dissolving, filtering, in filtrate added drop-wise to dilute hydrochloric acid solution, there is white solid precipitation, filters, filter cake ethyl alcohol and washing
It washs, obtains white solid, white solid is dried in vacuo 10-12 hours at 45~50 DEG C, obtains fludarabine phosphate.
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| WO2017036356A1 (en) * | 2015-08-28 | 2017-03-09 | 浙江海正药业股份有限公司 | Crystal form of fludarabine phosphat, preparation method therefor, and application thereof |
| CN105859812B (en) * | 2016-05-03 | 2019-07-26 | 河南师范大学 | A kind of preparation method of fludarabine phosphate |
| CN106083837B (en) * | 2016-05-27 | 2018-08-31 | 浙江普洛得邦制药有限公司 | The preparation method of Yi Zhong oxazolidinones antibacterials and its intermediate |
| CN110028538A (en) * | 2019-05-17 | 2019-07-19 | 连云港杰瑞药业有限公司 | A kind of drying means of fludarabine phosphate bulk pharmaceutical chemicals |
| CN115448966A (en) * | 2022-10-20 | 2022-12-09 | 海南锦瑞制药有限公司 | Preparation method of fludarabine phosphate and preparation method of fludarabine phosphate for injection |
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