CN102260288A - Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate - Google Patents
Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate Download PDFInfo
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Abstract
The invention relates to a synthesis method of 3-amino-propyl aminoethyl thiophosphate (amifostine) trihydrate. In the synthesis method, polyethylene glycol (PEG) is used as a reaction solvent, and has good biocompatibility and far lower irritation to a human body in comparison with dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO); the amifostine obtained by the reaction has high purity; especially when PEG400 is used as the reaction solvent, the prepared amifostine trihydrate product has higher yield and crude product purity; and in the post-treatment method, concentrated ammonia water/methanol are used to replace pure methanol, so that the product yield is significantly improved, especially the crude product purity can be up to 95% or above, and high-purity amifostine can be more easily obtained through secondary refining.
Description
Technical field
The present invention relates to a kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids.
Background technology
Amifostine (Amifostine); chemistry 3-aminopropyl amine ethyl phosphorothioic acid by name; have another name called amifostine; it is the selecting cell protective material of first wide spectrum in the world; it is used to protect the medicine of nuclear radiation the earliest, has active meta-bolites WR-1065 (H but find afterwards that it can be generated as with the alkaline phosphatase enzymic hydrolysis of cytolemma bonded in tissue
2N-(CH
2)
3-NH-(CH
2)
2-SH), because of sulfydryl has the effect of removing free radical in the tissue, so can lower the toxicity of cis-platinum, endoxan and mitomycin etc.Nineteen ninety-five FDA official approval amifostine goes on the market in the U.S.; be used for the protection of ovarian cancer cisplatin chemotherapy renal toxicity; FDA approval in 1996 is used for the protection of nonsmall-cell lung cancer cisplatin chemotherapy renal toxicity, and FDA approval in 1999 is used for the protection of head and neck cancer radiotherapy toxicity, and China also goes on the market in calendar year 2001.At present amifostine is widely used in the assisting therapy of various cancers clinically, can obviously alleviate put, kidney, marrow, heart, ear and neural toxicity that chemotherapeutics produced, do not reduce simultaneously put, the drug effect of chemotherapeutics.Because these advantageous properties of this medicine, (400-1200 unit/0.4g), this also makes the optimization of amifostine production technique seem especially important to have brought up the high price of amifostine.
According to the chemical structure characteristic of amifostine, one step of key of its preparation substantially all is with N-(2-bromotrifluoromethane)-1, and 3-propylene diamine two hydrobromates (being called for short bromine salt) form finished product with sodium thiophosphate (abbreviation sodium salt) reaction.
The preparation method of present two kinds of raw material bromine salt and sodium salt is comparatively ripe, the result of crucial final step reaction pair reaction, and especially quality and the yield influence to the amifostine finished product is very big.The processing condition of this step reaction of reporting in the document at present can be divided into 3 classes by the solvent for use difference, and promptly pure water is made solvent, water-DMF is that solvent, water-DMSO are solvent.
(1) the reaction present situation of water-DMF solvent: Piper J R (J Med Chem, 1969,12:236-243) the earliest with the sodium salt that does not contain crystal water in water-DMF with the bromine reactant salt, reaction solution is separated out crude product towards methyl alcohol, uses water-solublely again, adds methyl alcohol and separates out the amifostine finished product.This method products obtained therefrom is anhydrous amifostine, less stable, and yield also has only 30%.(medicine industry, 1982,114 (2): 10-11) also make solubility promoter with DMF, reacted crude product with refining methanol once obtains containing the amifostine finished product of a crystal water to Zhang Xuexing etc.In above method, the purpose that adds DMF mainly is in order to improve the speed that two kinds of salt generate the amifostine molecule, the volume ratio of water and DMF is generally about 1: 1 in the solvent for use, but because DMF polarity is bigger, still may be remaining micro-in the finished product amifostine through aftertreatment, and DMF itself has certain pungency to human body, causes the report to patient's irritative response behind the amifostine of the U.S.'s this kind of existing use explained hereafter, so the investigator does not adopt the preparation technology of DMF yet in exploitation.
(2) the reaction present situation of pure water solvent: the Dlaske Rainer of Germany was in (DD289449 in one piece of patent in 1991,1991-2-5) be reported in the pure water with 12 water sodium thiophosphates and bromine reactant salt, with ethanol aftertreatment, refining, obtained amifostine trihydrate again.Li Jiaming etc. (the Anhui chemical industry, 2000,2:17-18) also report adopts 12 water sodium thiophosphates and bromine salt to react in water, obtains amifostine trihydrate, yield 80% after water-ethanol is refining.These class methods adopt the solvent of pure water as reaction, the pungency of thoroughly having avoided DMF to bring, but the effect of reaction is poor than water-DMF solvent, the purity of making solvent gained crude product with pure water is lower, the difficult purity requirement that reaches highly finished product after refining, even purity can reach requirement, its yield also can significantly reduce.
(3) the reaction present situation of water-DMSO solvent: the domestic investigator of having adopts the DMSO that belongs to aprotic polar solvent with DMF to replace DMF to be carried out to the reaction of amifostine as solubility promoter.(Acta Pharmaceutica Sinica, 1981,16 (4): 302-5 such as Tong Cengshou; CN1752092,2006-3-29) the used DMSO and the ratio of water are about 3: 4 to the 20min time that proposes the earliest to replace can shortening greatly behind the DMF reaction with DMSO.What this class methods gained crude product obtained behind water and refining methanol is the amifostine product that contains a crystal water.(CN101412732,2009-4-22 such as Meng Qingwei; Qi Feifei, Dalian University of Technology's master thesis, 2009-7-1) also adopting water-DMSO is reaction solvent, methyl alcohol is poured at the reaction end in reaction solution, the yield of gained crude product is 91.2% under the optimum reaction condition, purity is 89.8%, and this crude product obtains amifostine trihydrate through twice after refining with water-ethanol again, and the ratio of used DMSO and water is also about 1: 1 in the reaction.Adopt water-DMSO to adopt the method for pure water or water-DMF on the effect of reaction, bigger improvement to be arranged as the preparation method of solvent, DMF is residual may to have certain effect to the pungency of skin also tool to reducing simultaneously, but, because also there is certain toxicity in DMSO itself, therefore, such solvent method prepares in the finished product amifostine, still may have the potential stimulus to human body.
At present, be badly in need of a kind ofly can preparing safe amifostine, can guarantee high yield and highly purified preparation method again.
Summary of the invention
Technical scheme of the present invention has provided a kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids.
A kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids, its synthetic route is:
It comprises the steps:
A, the reactant sodium thiophosphate is added in the distilled water stirring suspension, outside ice-water bath; Add N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates obtain outstanding turbid system, add poly(oxyethylene glycol) 400-800 again, remove ice-water bath after stirring, and keeping temperature of reaction is 0-35 ℃, stirs, and question response is complete, gets reaction solution;
Wherein said sodium thiophosphate, N-(2-bromotrifluoromethane)-1, the weight proportion of 3-propylene diamine two hydrobromates, water, polyoxyethylene glycol is:
10 parts of sodium thiophosphates, N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromate 8.5-13 parts, water 5-40 part, polyoxyethylene glycol 5-20 part;
Strong aqua/methyl alcohol mixed liquor of b, 1-4 times of W/V of adding reaction solution, the volume ratio of strong aqua and methyl alcohol is 1: 39-1: 9, after waiting to separate out white solid, under 4 ℃, leave standstill crystallization, filter, use methanol wash again, get the amifostine crude product.Content is more than 97%.
Further, the part by weight of described water and PEG is 4: 1-1: 3.And polyoxyethylene glycol (PEG) class phase-transfer catalyst is generally below 10% (mol ratio) of reactant at its consumption of pharmaceutical industry, polyoxyethylene glycol can reference: Zhao Linxiang chief editor as application scenario and the general consumption of phase-transfer catalyst of phase-transfer catalyst in chemical pharmacy industry, chemical pharmacy technology, Chinese Medicine science and technology press, first version in 2003, p84, p91.
Further, the part by weight of described water and PEG is 4: 1-1.6: 1, be preferably 2.5: 1.
Wherein, described sodium thiophosphate, N-(2-bromotrifluoromethane)-1, the weight proportion of 3-propylene diamine two hydrobromates, polyoxyethylene glycol, water is:
10 parts of sodium thiophosphates, N-(2-bromotrifluoromethane)-1,9.5 parts of 3-propylene diamine two hydrobromates, 25 parts in water, 10 parts of polyoxyethylene glycol.
Further, temperature of reaction is 5-30 ℃, is preferably 5-10 ℃.
Further, in the b step, add strong aqua/methyl alcohol mixed liquor of 2-3 times of W/V of reaction solution, preferred 3 times; The volume ratio of strong aqua and methyl alcohol is 1: 29-1: 39, be preferably 1: 29.
Wherein, described polyoxyethylene glycol is poly(oxyethylene glycol) 400, Polyethylene Glycol-600, is preferably poly(oxyethylene glycol) 400.
Wherein, technology of the present invention also comprises step c, refining: carry out recrystallization with ethanol.
Further, described process for purification is:
1. get the amifostine crude product, be dissolved in and contain in the alcoholic acid aqueous solution, add activated carbon and 201 * 7 type strongly-acid anionite-exchange resin then, temperature control is at 30 ℃, filter, water stirs down at 30 ℃, is added dropwise to 99.5% ethanol, gradually reduces to room temperature then, under 4 ℃, leave standstill again, treat that precipitation fully, filters, obtain highly finished product of white after the vacuum-drying;
2. secondary refining: get 1. step one time highly finished product, be dissolved in and contain in the alcoholic acid aqueous solution, add activated carbon, stir down at 30 ℃, filter, after filtrate was washed with ethyl acetate, water stirred down at 30 ℃, be added dropwise to 99.5% ethanol, gradually reduce to room temperature then, under 4 ℃, leave standstill again, treat that precipitation fully, filter, obtain the secondary refining product of white after the vacuum-drying.
Further, step 1., 2. in, described containing in the alcoholic acid aqueous solution, ethanol content is 5%V/V.
Greater than 99.0% amifostine, mercaptan impurities content is below 0.05% with the refining content that can obtain for twice of alcohol-water, and water content is suitable for suitability for industrialized production 19.2～21.2%.
The present invention is in to amifostine technical study process, it is that solvent, water-DMSO are that the technology of three kinds of solvent systems of solvent is all studied that pure water is made solvent, water-DMF, the crude product quality of finding reaction back gained is all not ideal, the also difficult content that reaches more than 99% after repeatedly making with extra care.Attempted afterwards improving reaction with phase-transfer catalyst, effect is not ideal.But in research to acyclic polyether class phase-transfer catalyst, (part by weight of water and PEG is between 4: 1 to 1: 3 under the situation that to find that its consumption increases to suitable with the amount of aqueous solvent, and the polyethylene glycols phase-transfer catalyst is generally below 10% (mol ratio) of reactant at its consumption of pharmaceutical industry), the result of reaction can improve greatly, only crude product purity just increases to more than 95%, can be under the top condition more than 97%, the purity of reporting in the document is (as Qi Feifei, Dalian University of Technology's master thesis, adding in the water as promotor gained amifostine crude product yield with DMSO among the 2009-7-1 is 91.2%, and content is 89.8%).This crude product generally just can reach more than 99% through the refining twice back content of water-ethanol again.The contriver finds that the mixing solutions with strong aqua-methyl alcohol replaces pure methyl alcohol or ethanol when aftertreatment in addition, can improve the quality of crude product.
The inventive method adopts PEG as reaction solvent, good biocompatibility, and the pungency to human body is little more than DMF and DMSO, reaction gained amifostine purity height, especially PEG400 is as reaction solvent, the yield and the crude product purity of the amifostine trihydrate product of preparation are all higher, in post-treating method, also adopt strong aqua/methyl alcohol to replace pure methyl alcohol, significantly improved product yield, particularly crude product purity can more easily obtain highly purified amifostine by secondary refining up to more than 95%.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
Following embodiment, should not be construed as is limiting the scope of the invention, all based on above-mentioned technological thought, the modification, replacement, the change that utilize ordinary skill knowledge and customary means to make all belong to scope of the present invention.
Description of drawings
Fig. 1 proton nmr spectra
Fig. 2 carbon-13 nmr spectra
Fig. 3 XRPD powder diagram
Fig. 4 high resolution mass spectrum
Fig. 5 thermogravimetric analysis, differential thermal analysis curve
Embodiment
Embodiment 1 amifostine synthesis technique of the present invention
A, in being equipped with, add in the flask of temperature thermometer 12 water sodium thiophosphates (10.0g, 25.2mmol) and 25ml distilled water, stirring suspension, outside ice-water bath.Add N-(2-bromotrifluoromethane)-1 earlier, (9.5g 27.7mmol), obtains beige outstanding turbid system to 3-propylene diamine two hydrobromates, and adding poly(oxyethylene glycol) 400 again is PEG400 (10g), removes ice-water bath after stirring, and keeps 5-10 ℃ of following stirring reaction.Reaction system becomes beige settled solution earlier in the reaction process, becomes the muddy system of off-white color subsequently again.
Behind b, the reaction 24h, in the reaction mass that stirs, add strong aqua-methyl alcohol mixed liquor (volume ratio 1/29) of 163ml under the room temperature, separate out white solid in the visible bottle.Under 4 ℃, leave standstill crystallization behind the stir about 10min.Suction filtration, the small amount of methanol washing obtains white amifostine (AF) crude product 6.1g, yield 90.2% (by amifostine trihydrate) after 30 ℃ of following vacuum-dryings, HPLC (pressing 29 editions test conditions of American Pharmacopeia) measures content: more than 95%～97% or 97%, this content is near pure product content.
Embodiment 2 amifostine synthesis techniques of the present invention
Obtain the amifostine crude product according to the technology of embodiment 1 is synthetic earlier, carry out following operation again and make with extra care:
Once refining: as to get above-mentioned crude product 1g, add the aqueous solution dissolving that 10ml contains 5% volume ethanol, add 0.02g activated carbon and 1.0g201 * 7 type strongly-acid anionite-exchange resin, in 30 ℃ of oil baths, stir 10min, normal pressure filters, water is insulated and stirred in 30 ℃ of oil baths, is added dropwise to the ethanol of 4ml 99.5%, will bathe temperature then and gradually reduce to room temperature by 30 ℃.This moment, existing a large amount of white solids were separated out, and left standstill 2h again under 4 ℃, and suction filtration obtains a white highly finished product 0.78g after 30 ℃ of following vacuum-dryings, yield 78%, and HPLC measures content about 98%.
Secondary refining: get an above-mentioned highly finished product 1g, add the aqueous solution dissolving that 10ml contains 5% volume ethanol, add the 0.02g activated carbon, in 30 ℃ of oil baths, stir 10min, normal pressure filters, and filtrate is washed with the 3.5ml ethyl acetate, and the water of telling is insulated and stirred in 30 ℃ of oil baths again, be added dropwise to the ethanol of 2.5ml 99.5%, will bathe temperature then and gradually reduce to room temperature by 30 ℃.Leave standstill 2h again under 4 ℃, suction filtration obtains white secondary refining product 0.68g after 30 ℃ of following vacuum-dryings, and yield 68%, HPLC are measured content more than 99.0%.Ultimate analysis: calculated value %C22.39, H7.89, N10.44, P11.55; Measured value %C22.31, H7.80, N10.37, P10.96 is with the molecular formula C of amifostine trihydrate
5H
21N
2O
6PS conforms to.The spectrogram of all the other structural confirmations is seen accompanying drawing.(proton nmr spectra, carbon spectrum; High resolution mass spectrum; Thermogravimetric analysis, differential thermal analysis curve; The XRPD powder diagram)
Embodiment 3 amifostine synthesis technique different condition shaker tests of the present invention
Following form is the operating process according to step a among the embodiment 1, the experimental result (method of step b is identical) of gained when adopting different batchings when temperature of reaction preparing the amifostine crude product
Table 1
As shown in Table 1, the consumption proportion of water and PEG plays significant effects to the yield and the purity of reaction: when the weight ratio of sodium salt and bromine salt 1: during 0.8-1.3, the weight ratio of water and PEG was at 4: 1～1: 3 o'clock, and all more than 54%, purity is higher than 73% to the yield of product; When the weight ratio of water and PEG during at 4: 1～1.6: 1, the yield of product is all more than 83%, and purity is higher than 87%, show this condition be better than existing pure water reactive system (Ru Lijia is bright etc., the Anhui chemical industry, 2000,2:17-18); When the weight ratio of water and PEG during at 2.5: 1, product yield is more than 86%, and purity is higher than 87%, shows that this condition significantly is better than existing pure water reactive system; When temperature of reaction was lower than 10 ℃, the weight ratio of water and PEG was at 2.5: 1 o'clock, and product yield is more than 88%, and purity is higher than 90%; And in this shaker test, optimum condition is: the weight ratio of sodium salt and bromine salt 10: 9.5, the weight ratio of water and PEG 2.5: 1, temperature of reaction 5-10 ℃, the crude product yield that obtains under this condition is up to 90.2%, and purity is up to 95.8%, its yield can also reach the respective horizontal of water-DMSO reactive system, and purity be significantly higher than water-DMSO reactive system (Qi Feifei, Dalian University of Technology's master thesis, 2009-7-1).
The selection of solvent PEG test in the embodiment 4 amifostine synthesis techniques of the present invention
(1) PEG 400 does under the outside ice-water bath condition of reaction solvent, and 12 water sodium thiophosphates (10g, 0.025mol) stirring suspension is in 25ml water, and (9.1g 0.026mol), and then is added dropwise to 15g PEG 400 to add bromine salt.Naturally keep stirring reaction 24h after rising to room temperature.Slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29) in the room temperature downhill reaction liquid, leave standstill 2h at 4 ℃, suction filtration obtains white solid 5.7g (yield 84.4%, purity 97.1%).
(2) PEG 600 does under the outside ice-water bath condition of reaction solvent, and 12 water sodium thiophosphates (10g, 0.025mol) stirring suspension is in 25ml water, and (9.1g 0.026mol), and then is added dropwise to 15g PEG 600 to add bromine salt.Naturally keep stirring reaction 24h after rising to room temperature.Slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29) in the room temperature downhill reaction liquid, leave standstill 2h at 4 ℃, suction filtration obtains white solid 5.49g (yield 81.1%, purity 95.5%).
(3) PEG 800 does under the outside ice-water bath condition of reaction solvent, and 12 water sodium thiophosphates (10g, 0.025mol) stirring suspension is in 25ml water, and (9.1g 0.026mol), and then is added dropwise to 15g PEG 800 to add bromine salt.Naturally keep stirring reaction 24h after rising to room temperature.Slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29) in the room temperature downhill reaction liquid, leave standstill 2h at 4 ℃, suction filtration obtains white solid 5.10g (yield 75.4%, purity 93.2%).
From above-mentioned test, PEG400 is the most remarkable to the promoter action of reaction, and PEG600 is also basic identical, and PEG800 is poor slightly.
Polyoxyethylene glycol (PEG) class phase-transfer catalyst also has application in pharmaceutical industry, but its consumption is generally below 10% (mol ratio) of reactant, and these are different fully with consumption of the present invention.
The amount of strong aqua/methyl alcohol and the shaker test of ratio in the embodiment 5 amifostine synthesis techniques of the present invention
To same batch of reaction solution according to the optimum reaction condition gained of step a among the embodiment 1, add the different solvent of 30ml after respectively getting 10g, separate out yield and the content situation such as the following table of crude product:
The different sedimentation solvent ratios of table 2 are to the influence of crude product yield and purity
As seen from the above table, strong aqua/methyl alcohol volume ratio is 1: 9-1: 39 o'clock, the crude product yield was all more than 81%, and purity is higher than 94%; And when strong aqua/methyl alcohol volume ratio be 1: 29-1: in the time of 39, the crude product yield is all more than 88%, is significantly improved during than independent use methyl alcohol, and this yield is near water-DMSO reactive system gained yield, and purity more is better than water-DMSO reactive system.To same batch of reaction solution according to the optimum reaction condition gained among the embodiment 1, respectively get strong aqua/methyl alcohol of 1: 29 that 10g adds different volumes after, separate out yield and the content situation such as the following table of crude product:
The sedimentation solvent of the different amounts of table 3 is to the influence of crude product yield and purity
In sum, the inventive method adopts PEG as reaction solvent, good biocompatibility, and the pungency to human body is little more than DMF and DMSO, reaction gained amifostine purity height, especially PEG400 is as reaction solvent, the yield and the crude product purity of the amifostine trihydrate product of preparation are all higher, in post-treating method, also adopt strong aqua/methyl alcohol to replace pure methyl alcohol, significantly improved product yield, particularly crude product purity can more easily obtain highly purified amifostine by secondary refining up to more than 95%.
Claims (10)
1. the synthetic method of a hydration 3-aminopropyl amine ethyl phosphorothioic acid, its synthetic route is:
It is characterized in that: it comprises the steps:
A, the reactant sodium thiophosphate is added in the distilled water stirring suspension, outside ice-water bath; Add N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates obtain outstanding turbid system, add poly(oxyethylene glycol) 400-800 again, remove ice-water bath after stirring, and keeping temperature of reaction is 0-35 ℃, stirs, and question response is complete, gets reaction solution;
Wherein said sodium thiophosphate, N-(2-bromotrifluoromethane)-1, the weight proportion of 3-propylene diamine two hydrobromates, water, polyoxyethylene glycol is:
10 parts of sodium thiophosphates, N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromate 8.5-13 parts, water 5-40 part, polyoxyethylene glycol 5-20 part;
Strong aqua/methyl alcohol mixed liquor of b, 1-4 times of W/V of adding reaction solution, the volume ratio of strong aqua and methyl alcohol is 1: 39-1: 9, after waiting to separate out white solid, under 4 ℃, leave standstill crystallization, filter, use methanol wash again, get the amifostine crude product.
2. synthetic method according to claim 1 is characterized in that: the part by weight of described water and polyoxyethylene glycol is 4: 1-1: 3.
3. synthetic method according to claim 2 is characterized in that: the part by weight of described water and polyoxyethylene glycol is 4: 1-1.6: 1, be preferably 2.5: 1.
4. synthetic method according to claim 3 is characterized in that: described sodium thiophosphate, N-(2-bromotrifluoromethane)-1, and the weight proportion of 3-propylene diamine two hydrobromates, polyoxyethylene glycol, water is:
10 parts of sodium thiophosphates, N-(2-bromotrifluoromethane)-1,9.5 parts of 3-propylene diamine two hydrobromates, 25 parts in water, 10 parts of polyoxyethylene glycol.
5. according to any described synthetic method of claim 1-4, it is characterized in that: temperature of reaction is 5-30 ℃, is preferably 5-10 ℃.
6. synthetic method according to claim 1 is characterized in that: in the b step, add strong aqua/methyl alcohol mixed liquor of 2-3 times of W/V of reaction solution, preferred 3 times; The volume ratio of strong aqua and methyl alcohol is 1: 29-1: 39, be preferably 1: 29.
7. according to any described synthetic method of claim 1-4, it is characterized in that: described polyoxyethylene glycol is poly(oxyethylene glycol) 400, Polyethylene Glycol-600, is preferably poly(oxyethylene glycol) 400.
8. according to any described synthetic method of claim 1-7, it is characterized in that: also comprise step c, refining: carry out recrystallization with ethanol.
9. synthetic method according to claim 8 is characterized in that: described process for purification is:
1. get the amifostine crude product, be dissolved in and contain in the alcoholic acid aqueous solution, add activated carbon and 201 * 7 type strongly-acid anionite-exchange resin then, temperature control is at 30 ℃, filter, water stirs down at 30 ℃, drips ethanol, gradually reduces to room temperature then, under 4 ℃, leave standstill again, treat that precipitation fully, filters, obtain highly finished product of white after the vacuum-drying;
2. secondary refining: get 1. step one time highly finished product, be dissolved in and contain in the alcoholic acid aqueous solution, add activated carbon, stir down at 30 ℃, filter, after filtrate was washed with ethyl acetate, water stirred down at 30 ℃, drip ethanol, gradually reduce to room temperature then, under 4 ℃, leave standstill again, treat that precipitation fully, filter, obtain the secondary refining product of white after the vacuum-drying.
10. synthetic method according to claim 9 is characterized in that: step 1., 2. in, described containing in the alcoholic acid aqueous solution, ethanol content is 5%V/V.
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Cited By (7)
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| CN103396439A (en) * | 2013-08-01 | 2013-11-20 | 沈阳药科大学 | Synthetic method for thiophosphate cell protective agent-amifostine |
| CN103509049A (en) * | 2013-10-15 | 2014-01-15 | 美罗药业股份有限公司 | Method for preparing medicinal amifostine |
| CN103509048A (en) * | 2013-10-15 | 2014-01-15 | 大连理工大学 | Environment-friendly preparation method of amifostine |
| CN104230984A (en) * | 2013-06-08 | 2014-12-24 | 上海医药工业研究院 | Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid |
| CN106674272A (en) * | 2016-12-27 | 2017-05-17 | 张家港市华天药业有限公司 | Processing method for amifostine |
| CN109942623A (en) * | 2019-04-15 | 2019-06-28 | 张家港市华天药业有限公司 | A kind of synthetic method of Amifostine |
| CN112745347A (en) * | 2021-02-08 | 2021-05-04 | 青岛联吉生物医疗科技有限公司 | Preparation method of amifostine trihydrate |
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