CN102260288B - 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, but finds afterwards that it can be generated as the activated meta-bolites WR-1065 of tool (H with the membrane-bound alkaline phosphatase enzymic hydrolysis of cell in tissue
2n-(CH
2)
3-NH-(CH
2)
2-SH), because sulfydryl has the effect of removing free radical in tissue, therefore 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.; for the protection of ovarian cancer cisplatin chemotherapy renal toxicity; FDA approval in 1996 is for the protection of nonsmall-cell lung cancer cisplatin chemotherapy renal toxicity, and FDA approval in 1999 is for the protection of head and neck cancer radiotherapy toxicity, and China also goes on the market in calendar year 2001.Amifostine is widely used in the assisting therapy of various cancers clinically at present, can obviously alleviate kidney, marrow, heart, ear and neural toxicity that Radiotherapy chemotherapy medicine produces, does not reduce the drug effect of Radiotherapy chemotherapy medicine simultaneously.Due to these advantageous properties of this medicine, brought up the high price (400-1200 unit/0.4g) of amifostine, this also makes the optimization of amifostine production technique seem especially important.
According to the chemical structure characteristic of amifostine, its key of preparing one step is substantially all with N-(2-bromotrifluoromethane)-1, and 3-propylene diamine two hydrobromates (being called for short bromine salt) react with sodium thiophosphate (abbreviation sodium salt) and form finished product.
The preparation method of order first two raw material bromine salt and sodium salt is comparatively ripe, and the result of crucial final step reaction to reaction is especially very large on the quality of amifostine finished product and yield impact.The processing condition of this step reaction of reporting in document at present can be divided into 3 classes by solvent for use difference, and pure water as solvent, water-DMF are 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 containing the sodium salt of crystal water in water-DMF with bromine reactant salt, reaction solution rushes methyl alcohol and separates out crude product, use again water-solublely, add methyl alcohol and separate out amifostine finished product.The method products obtained therefrom is anhydrous amifostine, less stable, and yield also only has 30%.(medicine industry, 1982,114 (2): 10-11) also with DMF, make solubility promoter, reacted crude product with refining methanol once, obtains the amifostine finished product containing a crystal water such as Zhang Xuexing.In above method, the object that adds DMF is mainly the speed of amifostine molecule that generates in order to improve two kinds of salt, in solvent for use, the volume ratio of water and DMF is generally 1: 1 left and right, but because DMF polarity is larger, still may be remaining micro-in finished product amifostine through aftertreatment, and DMF itself causes the report to patient's irritative response after human body is had to the existing amifostine that uses this kind of explained hereafter of certain pungency ， U.S., so 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 pure water with 12 water sodium thiophosphates and bromine reactant salt, with ethanol aftertreatment, refining, obtained amifostine trihydrate again.Li Jiaming etc. (Anhui chemical industry, 2000,2:17-18) also report adopts 12 water sodium thiophosphates and bromine salt to react in water, after water-ethanol is refining, obtains amifostine trihydrate, yield 80%.These class methods adopt pure water as the solvent of reaction, the pungency of thoroughly having avoided DMF to bring, but the effect of reaction is poor compared with water-DMF solvent, lower by the purity of pure water as solvent gained crude product, the more difficult purity requirement that reaches highly finished product after refining, even if 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 become the reaction of amifostine as solubility promoter.(Acta Pharmaceutica Sinica, 1981,16 (4): 302-5 such as Tong Zengshou; CN1752092,2006-3-29) propose the earliest to replace the time that can greatly shorten reaction after DMF to 20min left and right with DMSO, DMSO used and the ratio of water are about 3: 4.What this class methods gained crude product obtained after water and refining methanol is the amifostine product containing a crystal water.(CN101412732, the 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 in reaction end in reaction solution, under optimum reaction condition, the yield of gained crude product is 91.2%, purity is 89.8%, after this crude product is refining through twice with water-ethanol again, obtains amifostine trihydrate, and in reaction, the ratio of DMSO used and water is also 1: 1 left and right.Adopt water-DMSO to adopt the method for pure water or water-DMF to have larger improvement in the effect of reaction as the preparation method of solvent, to reducing, DMF is residual may have certain effect to the pungency of skin also tool simultaneously, but, because DMSO itself also exists certain toxicity, therefore, such solvent method prepares in 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 again high yield and highly purified preparation method.
Summary of the invention
Technical scheme of the present invention has been to provide a kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids.
A synthetic method for three hydration 3-aminopropyl amine ethyl phosphorothioic acids, its synthetic route is:
It comprises the steps:
A, reactant sodium thiophosphate is added in distilled water to stirring suspension, outside ice-water bath; Add N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates, obtain being suspended system, then add poly(oxyethylene glycol) 400-800, after stirring, remove ice-water bath, and maintenance temperature of reaction is 0-35 ℃, stir, and question response is complete, obtains 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;
B, add strong aqua/methyl alcohol mixed liquor of reaction solution 1-4 times W/V, the volume ratio of strong aqua and methyl alcohol is 1: 39-1: 9, and after separating out white solid, standing crystallization at 4 ℃, filters, then uses methanol wash, obtains 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, the general consumption of the polyoxyethylene glycol application scenario in chemical pharmacy industry and phase-transfer catalyst as phase-transfer catalyst can reference: Zhao Linxiang chief editor, chemical pharmacy technology, Chinese Medicine science and technology press, first version in 2003, p84, p91.
Further, described water and the part by weight of PEG are 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, water, 10 parts of polyoxyethylene glycol.
Further, temperature of reaction is 5-30 ℃, is preferably 5-10 ℃.
Further, in b step, add strong aqua/methyl alcohol mixed liquor of reaction solution 2-3 times W/V, preferably 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, technique of the present invention also comprises step c, refining: with ethanol, carry out recrystallization.
Further, described process for purification is:
1. get amifostine crude product, be dissolved in the aqueous solution that contains ethanol, then add activated carbon and 201 * 7 type strongly-acid anionite-exchange resin, temperature control is at 30 ℃, filter, water stirs at 30 ℃, is added dropwise to 99.5% ethanol, is then gradually down to room temperature, standing at 4 ℃ again, treat that precipitation completely, filters, after vacuum-drying, obtain white primary purification product;
2. secondary refining: get 1. step one time highly finished product, be dissolved in the aqueous solution that contains ethanol, add activated carbon, at 30 ℃, stir, filter, filtrate is with after ethyl acetate washing, and water stirs at 30 ℃, be added dropwise to 99.5% ethanol, then be gradually down to room temperature, more standing at 4 ℃, treat that precipitation is completely, filter, after vacuum-drying, obtain white secondary fine goods.
Further, step 1., 2. in, described in contain ethanol the aqueous solution in, ethanol content is 5%V/V.
With alcohol-water is refining, can obtain the amifostine that content is greater than 99.0% twice, mercaptan impurities content is below 0.05%, and water content, 19.2～21.2%, is suitable for suitability for industrialized production.
The present invention is in to amifostine technical study process, to pure water as solvent, water-DMF, be that solvent, water-DMSO are that the technique of three kinds of solvent systems of solvent is all studied, find that the crude product quality of gained is all not ideal after reaction, the also more difficult content reaching more than 99% after repeatedly refining.Attempted afterwards improving reaction with phase-transfer catalyst, effect is not ideal.But in to the research of noncyclic polyether class phase-transfer catalyst, in the situation that to find that its consumption increases to suitable with the amount of aqueous solvent, (part by weight of water and PEG is between 4: 1 to 1: 3, and polyethylene glycols phase-transfer catalyst is generally below 10% (mol ratio) of reactant at its consumption of pharmaceutical industry), the result of reaction can be improved greatly, only crude product purity just increases to more than 95%, can be more than 97% under top condition, apparently higher than the purity of reporting in document (as Qi Feifei, Dalian University of Technology's master thesis, it is 91.2% as promotor gained amifostine crude product yield that the DMSO of take in 2009-7-1 adds in water, content is 89.8%).This crude product generally just can reach more than 99% through content after refining twice of water-ethanol again.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 little more than DMF and DMSO to the pungency of human body, reaction gained amifostine purity is high, especially PEG400 is as reaction solvent, 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, up to more than 95%, can more easily obtain highly purified amifostine by secondary refining.
Obviously, according to foregoing of the present invention, according to ordinary skill knowledge and the customary means of this area, not departing under the above-mentioned basic fundamental thought of the present invention prerequisite, can also make modification, replacement or the change of other various ways.
Following embodiment, should not be understood as limiting the scope of the invention, all based on above-mentioned technological thought, utilizes modification, replacement, the change that ordinary skill knowledge and customary means are made all to belong to scope of the present invention.
Accompanying drawing explanation
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, to being equipped with in the flask of interior temperature thermometer, add 12 water sodium thiophosphates (10.0g, 25.2mmol) and 25ml distilled water, stirring suspension, outside ice-water bath.First add N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates (9.5g, 27.7mmol), obtain the beige system that is suspended, adding poly(oxyethylene glycol) 400 is PEG400 (10g) again, after stirring, removes ice-water bath, keep 5-10 ℃ at stirring reaction.In reaction process, reaction system first becomes beige settled solution, becomes again subsequently the muddy system of off-white color.
After b, reaction 24h, under room temperature, to the strong aqua-methyl alcohol mixed liquor (volume ratio 1/29) that adds 163ml in the reaction mass stirring, in visible bottle, separate out white solid.After stir about 10min at 4 ℃ standing crystallization.Suction filtration, a small amount of methanol wash, at 30 ℃, after vacuum-drying, obtain white amifostine (AF) crude product 6.1g, yield 90.2% (by amifostine trihydrate), HPLC (pressing 29 editions test conditions of American Pharmacopeia) measures content: more than 95%～97% or 97%, this content has approached sterling content.
Embodiment 2 amifostine synthesis technique of the present invention
First according to the technique of embodiment 1 is synthetic, obtain amifostine crude product, then proceed as follows and refine:
Primary purification: get above-mentioned crude product 1g, add 10ml containing the aqueous solution dissolving of 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%, then bath temperature is gradually down to room temperature by 30 ℃.Now existing a large amount of white solids are separated out, then at 4 ℃ standing 2h, suction filtration, obtains white primary purification product 0.78g after vacuum-drying at 30 ℃, yield 78%, HPLC measures content approximately 98%.
Secondary refining: get above-mentioned primary purification product 1g, add 10ml containing the aqueous solution dissolving of 5% volume ethanol, add 0.02g activated carbon, in 30 ℃ of oil baths, stir 10min, normal pressure filters, and filtrate is washed by 3.5ml ethyl acetate, and the water separating is insulated and stirred in 30 ℃ of oil baths again, be added dropwise to the ethanol of 2.5ml 99.5%, then bath temperature be gradually down to room temperature by 30 ℃.Standing 2h at 4 ℃ again, suction filtration, obtains white secondary fine goods 0.68g after vacuum-drying at 30 ℃, yield 68%, HPLC measures 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, with the molecular formula C of amifostine trihydrate
5h
21n
2o
6pS conforms to.The spectrogram of all the other structural confirmations is shown in accompanying drawing.(proton nmr spectra, carbon spectrum; High resolution mass spectrum; Thermogravimetric analysis, differential thermal analysis curve; XRPD powder diagram)
Embodiment 3 amifostine synthesis technique of the present invention different condition shaker test
Following form is according to the operating process of step a in embodiment 1, the experimental result (method of step b is identical) of gained when adopting different batchings when temperature of reaction being prepared amifostine crude product
Table 1
As shown in Table 1, the consumption proportion of water and PEG plays important impact to yield and the purity of reaction: when the weight ratio of sodium salt and bromine salt is 1: during 0.8-1.3, the weight ratio of water and PEG was at 4: 1～1: 3 o'clock, and the yield of product is all more than 54%, and purity is higher than 73%; When the weight ratio of water and PEG is 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., Anhui chemical industry, 2000,2:17-18); When the weight ratio of water and PEG is during at 2.5: 1, product yield is more than 86%, and purity, higher than 87%, shows that this condition is significantly better than existing pure water reactive system; When temperature of reaction is during 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 obtaining 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 embodiment 4 amifostine synthesis technique of the present invention
(1) PEG 400 does under the outside ice-water bath condition of reaction solvent, and 12 water sodium thiophosphate (10g, 0.025mol) stirring suspensions, in 25ml water, add bromine salt (9.1g, 0.026mol), and then are added dropwise to 15g PEG 400.Naturally after rising to room temperature, maintain stirring reaction 24h.In room temperature downhill reaction liquid, slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29), at 4 ℃ of standing 2h, 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 thiophosphate (10g, 0.025mol) stirring suspensions, in 25ml water, add bromine salt (9.1g, 0.026mol), and then are added dropwise to 15g PEG 600.Naturally after rising to room temperature, maintain stirring reaction 24h.In room temperature downhill reaction liquid, slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29), at 4 ℃ of standing 2h, 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 thiophosphate (10g, 0.025mol) stirring suspensions, in 25ml water, add bromine salt (9.1g, 0.026mol), and then are added dropwise to 15g PEG 800.Naturally after rising to room temperature, maintain stirring reaction 24h.In room temperature downhill reaction liquid, slowly drip 162ml strong aqua-methyl alcohol mixed liquor (volume ratio 1/29), at 4 ℃ of standing 2h, 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 slightly poor.
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 completely different from consumption of the present invention.
The amount of strong aqua/methyl alcohol and the shaker test of ratio in embodiment 5 amifostine synthesis technique of the present invention
To according to same batch of reaction solution of the optimum reaction condition gained of step a in embodiment 1, add the solvent that 30ml is different after respectively getting 10g, separate out the yield of crude product and content situation as following table:
The impact of the different sedimentation solvent ratios of table 2 on crude product yield and purity
As seen from the above table, strong aqua/methyl alcohol volume ratio is 1: 9-1: 39 o'clock, 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, crude product yield, all more than 88%, is significantly improved during than independent use methyl alcohol, this yield approaches water-DMSO reactive system gained yield, purity is more better than water-DMSO reactive system.The same batch of reaction solution to the optimum reaction condition gained according in embodiment 1, respectively gets after the strong aqua/methyl alcohol of 1: 29 that 10g adds different volumes, separates out the yield of crude product and content situation as following table:
The impact of the sedimentation solvent of the different amounts of table 3 on crude product yield and purity
In sum, the inventive method adopts PEG as reaction solvent, good biocompatibility, and little more than DMF and DMSO to the pungency of human body, reaction gained amifostine purity is high, especially PEG400 is as reaction solvent, 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, up to more than 95%, can more easily obtain highly purified amifostine by secondary refining.
Claims (13)
1. a synthetic method for three hydration 3-aminopropyl amine ethyl phosphorothioic acids, its synthetic route is:
It is characterized in that: it comprises the steps:
A, reactant sodium thiophosphate is added in distilled water to stirring suspension, outside ice-water bath; Add N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates, obtain being suspended system, then add poly(oxyethylene glycol) 400-800, after stirring, remove ice-water bath, keep temperature of reaction to be 0-35 ℃, stir, and question response is complete, obtains reaction solution; Described water and the part by weight of polyoxyethylene glycol are 4:1-1:3;
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;
B, add strong aqua/methyl alcohol mixed liquor of reaction solution 1-4 times W/V, the volume ratio of strong aqua and methyl alcohol is 1:39-1:9, after separating out white solid, standing crystallization at 4 ℃, filter, then use methanol wash, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products.
2. synthetic method according to claim 1, is characterized in that: described water and the part by weight of polyoxyethylene glycol are 4:1-1.6:1.
3. synthetic method according to claim 2, it is levied and is: described water and the part by weight of polyoxyethylene glycol are 2.5:1.
4. synthetic method according to claim 1, is characterized in that: 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, water, 10 parts of polyoxyethylene glycol.
5. synthetic method according to claim 1, is characterized in that: temperature of reaction is 5-30 ℃.
6. synthetic method according to claim 5, is characterized in that: described temperature of reaction is 5-10 ℃.
7. synthetic method according to claim 1, is characterized in that: in b step, add strong aqua/methyl alcohol mixed liquor of reaction solution 2-3 times W/V; The volume ratio of strong aqua and methyl alcohol is 1 ︰ 29-1:39.
8. synthetic method according to claim 7, is characterized in that: in b step, add strong aqua/methyl alcohol mixed liquor of 3 times of W/V of reaction solution; The volume ratio of strong aqua and methyl alcohol is 1 ︰ 29.
9. according to the synthetic method described in claim 1-3 any one, it is characterized in that: described polyoxyethylene glycol is poly(oxyethylene glycol) 400, Polyethylene Glycol-600.
10. synthetic method according to claim 9, is characterized in that: described polyoxyethylene glycol is poly(oxyethylene glycol) 400.
11. synthetic methods according to claim 1, is characterized in that: also comprise step c, refining: with ethanol, carry out recrystallization.
12. synthetic methods according to claim 11, is characterized in that: described process for purification is:
1. get three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products, be dissolved in the aqueous solution that contains ethanol, then add activated carbon and 201 ╳ 7 type strongly-acid anionite-exchange resin, temperature control is at 30 ℃, filter, water stirs at 30 ℃, drips ethanol, is then gradually down to room temperature, standing at 4 ℃ again, treat that precipitation completely, filters, after vacuum-drying, obtain white primary purification product;
2. secondary refining: get 1. step one time highly finished product, be dissolved in the aqueous solution that contains ethanol, add activated carbon, at 30 ℃, stir, filter, filtrate is with after ethyl acetate washing, and water stirs at 30 ℃, drip ethanol, then be gradually down to room temperature, more standing at 4 ℃, treat that precipitation is completely, filter, after vacuum-drying, obtain white secondary fine goods.
13. synthetic methods according to claim 12, is characterized in that: step 1., 2. in, described in contain ethanol the aqueous solution in, ethanol content is 5%V/V.
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| CN104230984B (en) * | 2013-06-08 | 2017-02-08 | 国药集团国瑞药业有限公司 | Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid |
| CN103396439B (en) * | 2013-08-01 | 2016-04-27 | 沈阳药科大学 | The synthetic method of thiophosphate cell protective agent-amifostine |
| CN103509048B (en) * | 2013-10-15 | 2016-04-20 | 大连理工大学 | A kind of preparation method of green amifostine |
| CN103509049B (en) * | 2013-10-15 | 2016-05-25 | 美罗药业股份有限公司 | A kind of method of preparing medicinal Amifostine |
| 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 |
| CN112745347B (en) * | 2021-02-08 | 2021-11-23 | 重庆大学附属肿瘤医院 | Preparation method of amifostine trihydrate |
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