CN103694272A - Synthesis method of 3-aminopropyl aminoethyl phosphorothioate trihydrate - Google Patents
Synthesis method of 3-aminopropyl aminoethyl phosphorothioate trihydrate Download PDFInfo
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Abstract
The invention discloses a synthesis method of 3-aminopropyl aminoethyl phosphorothioate trihydrate. The synthesis method comprises the steps: firstly, enabling N-(2-ethoxyl)-1,3-propanediamine to primarily react with hydrobromic acid; secondly, adding the hydrobromic acid for reaction, processing after reacting to obtain N-(2-bromoethyl)-1,3-propanediamine dihydrobromide; then reacting sodium thiophosphate dodecahydrate, water and the N-(2-bromoethyl)-1,3-propanediamine dihydrobromide, decoloring, filtering and devitrifying after reacting to obtain a crude product; and dissolving the crude product, adsorbing by using cation and anion exchange resin, then filtering, devitrifying and drying to obtain a 3-aminopropyl aminoethyl phosphorothioate trihydrate fine product. The 3-aminopropyl aminoethyl phosphorothioate trihydrate is synthesized by using the synthesis method. Compared with the prior art, the synthesis method has the advantages of increasing the reaction efficiency and shortening the reaction time; and the obtained 3-aminopropyl aminoethyl phosphorothioate trihydrate is higher in purity.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, be specifically related to a kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids.
Background technology
Three hydration 3-aminopropyl amine ethyl phosphorothioic acids are amifostine, and amifostine belongs to a kind of organosulfur for phosphate compound.Can be used as the auxiliary therapeutical agent of tumor radiotherapy or cytotoxicity chemotherapy.This medicine is normal cell protective agent, is mainly used in the assisting therapy of various cancers.Before being carried out to chemotherapy, the kinds cancer patients such as lung cancer, ovarian cancer, mammary cancer, nasopharyngeal carcinoma, bone tumor, digestive tract tumor, hematological system tumor apply this medicine, can obviously alleviate kidney, marrow, heart, ear and neural toxicity that chemotherapeutics produces, and not reduce the curative effect of chemotherapeutics.Before radiotherapy, this medicine of application can significantly reduce xerostomia and catarrhal generation.
Up to now, according to pertinent literature, the method for synthetic amifostine mainly contains following two kinds:
The first: be raw material with 2-monoethanolamine, through two-step reaction chlorination, obtain 2-chloroethyl amine hydrochloride, then react with sodium carbonate, the reactant obtaining reacts with 3-bromopropyl isoindole woods in sodium hydride and DMF solvent, after reaction, products therefrom, through two step brominations under Hydrogen bromide, react with sodium thiophosphate after bromination again and obtains S-2-(3-aminopropyl amino) ethyl phosphorothioic acid is amifostine.This synthetic route reactions steps is various, and yield is lower, and needed reagent sodium hydride alkalescence is strong, larger to the corrodibility of conversion unit, has danger to a certain degree.And cost is high, be unsuitable for commercial scale production.
The second: with 1,3-propylene diamine is raw material, react at 0～5 ℃ with oxyethane, products therefrom is through Hydrogen bromide bromination, bromination after product reacts with sodium thiophosphate in DMSO that to obtain S-2-(3-aminopropyl amino) ethyl phosphorothioic acid is amifostine, the oxyethane total recovery of take is only 29.4%.The method is with 1,3-propylene diamine is raw material, intermediate (2-(3-aminopropyl is amino) monobromoethane hydrobromate through condensation, bromination, salify system, yield is 5.5%～70%, and bromination temperature is high is 150 ℃, require bromizating agent to use the excessive decades of times that reaches, the reaction times reaches 48 hours, wayward; And institute's output brominated product oxidation is serious, and color is dark, and yield is low, high to equipment requirements.
Patent documentation about amifostine preparation method aspect mainly contains: 1, application number is 201110431844.8, name is called the patent of invention of " preparation method of amifostine "; 2, application number is 201210110491.6, name is called the application for a patent for invention of " preparation method of amifostine ".
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids.Utilizing the synthetic three hydration 3-aminopropyl amine ethyl phosphorothioic acids of technical solution of the present invention is amifostine, compared with prior art, improved reaction efficiency, shortened the reaction times, and the purity of products obtained therefrom three hydration 3-aminopropyl amine ethyl phosphorothioic acids is higher.
In order to address the above problem, the technical solution used in the present invention is:
The synthetic method that the invention provides a kind of three hydration 3-aminopropyl amine ethyl phosphorothioic acids, described synthetic method comprises the following steps:
A, first by raw material N-(2-hydroxyethyl)-1,3-propylene diamine adds in reaction vessel, according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 2～4mL, under agitation condition, add Hydrogen bromide, after Hydrogen bromide adds, under 15～30 ℃ of conditions, reaction 30～90min, steams excessive Hydrogen bromide by the decompression of gained reactant after reaction; Then according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 3～5mL, to steaming in excessive hydrobromic reactant, adds Hydrogen bromide again, is heated to 90～130 ℃, reaction 15～30h; After reaction finishes, its reactant is carried out to aftertreatment, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates;
B, first 12 water sodium thiophosphates and water are added in reaction vessel, the N-(2-bromotrifluoromethane)-1 that adds step a to prepare after stirring and dissolving, 3-propylene diamine two hydrobromates, described N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates and 12 water sodium thiophosphates between the two the mol ratio of add-on be 0.9～1.0:1,12 water sodium thiophosphates and the water mass ratio between the two is 1:1～2, then stirring reaction 1～3h at ambient temperature; After reaction finishes, in gained reaction solution, add gac to decolour, the add-on of gac is N-(2-bromotrifluoromethane)-1,0.01～0.05 times of 3-propylene diamine two hydrobromate weight, after decolouring, filter, in gained filtrate, add dehydrated alcohol, be cooled to 0～20 ℃ and carry out crystallization, crystallization 1～5h, filters and obtains three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products after crystallization;
C, the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that step b is obtained are soluble in water, and the consumption of water is 1～7 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight; After dissolving, with 717 anionite-exchange resin and 732 Zeo-karbs, adsorb successively, the consumption of 717 anionite-exchange resin and 732 Zeo-karbs is 0.05～0.5 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after absorption, filter, in gained filtrate, add dehydrated alcohol, be cooled to 0～10 ℃ and carry out crystallization 1～3h, after crystallization, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal, filter, be dried, after being dried, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work.
According to the synthetic method of three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, described in step a, after reaction, the decompression of gained reactant is steamed to excessive Hydrogen bromide, when its decompression steams, vacuum tightness is that 0.09MPa, temperature are 85 ℃; Described hydrobromic concentration is 48%.
According to the synthetic method of three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, described in step a, its reactant is carried out to aftertreatment, its treatment process is: first gained reactant is distilled, remove excessive Hydrogen bromide; According to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the ratio of 3～5mL, 95% ethanol to add 95% ethanol, heating for dissolving, after dissolving, add gac, the add-on of gac is N-(2-hydroxyethyl)-1,0.05 times of 3-propylene diamine weight, stirring 30min decolours, after decolouring, filter, gained filtrate goes to crystallization 3h under 0 ℃ of condition after naturally cooling to room temperature, after crystallization, filters, and after filtering, gained crystal was 55 ℃ of forced air dryings 2 hours, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates.
Synthetic method according to three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, adds dehydrated alcohol in the filtrate of gained described in step b, and the add-on of its dehydrated alcohol is 1～3 times that in step b, water adds weight.
According to the synthetic method of three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that described in step c, step b obtained are soluble in water, described water is pure water or deionized water, and temperature during dissolving is 10～30 ℃.
Synthetic method according to three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, adds dehydrated alcohol in the filtrate of gained described in step c, and the add-on of its dehydrated alcohol is 0.5～3 times of water consumption in step c.
According to the synthetic method of three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, described in step c, filter, be dried, when it is dry, temperature is 15～30 ℃, be 48h time of drying.
According to the synthetic method of three above-mentioned hydration 3-aminopropyl amine ethyl phosphorothioic acids, purity >=99.6% of three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work described in step c, mercaptans content≤0.1%, other impurity≤0.1%, total impurities≤0.3%.
positive beneficial effect of the present invention:
1, in synthetic method of the present invention, wherein prepare N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates adopt substep preparation, and by N-(2-hydroxyethyl)-1,3-propylene diamine reacts salify prior to Hydrogen bromide, then carries out bromo.Can effectively avoid thus Hydrogen bromide concentration to reduce, thereby improve reaction efficiency, Reaction time shorten.
2,, in the present invention's three hydration 3-aminopropyl amine ethyl phosphorothioic acid building-up processes, without adding polar aprotic solvent, reaction finishes directly to add activated carbon decolorizing afterwards, thereby has improved three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product quality.
3, the present invention is carrying out in treating process three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products, use anion-cation exchange resin adsorption-edulcoration technology, thereby effectively remove the impurity in three hydration 3-aminopropyl amine ethyl phosphorothioic acids, reduce recrystallization number of times, obtain three high-purity hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal.Finally obtain purity >=99.6% of product, mercaptans content≤0.1% in product, other impurity≤0.1%, total impurities≤0.3%.
accompanying drawing explanation:
The nmr spectrum of Fig. 1 embodiment of the present invention 1 products obtained therefrom;
The liquid chromatogram of Fig. 2 embodiment of the present invention 1 products obtained therefrom.
embodiment:
Below in conjunction with embodiment, further set forth the present invention, but do not limit content of the present invention.
Embodiment 1:
the synthetic method of the present invention's three hydration 3-aminopropyl amine ethyl phosphorothioic acids, the detailed step of this synthetic method is as follows:
A, first by raw material N-(2-hydroxyethyl)-1,3-propylene diamine adds in reaction vessel, according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 2mL, under agitation condition, add Hydrogen bromide (hydrobromic concentration is 48%), after Hydrogen bromide adds, under 25 ℃ of conditions, reaction 60min, steams excessive Hydrogen bromide (when decompression steams, vacuum tightness is that 0.09MPa, temperature are 85 ℃) by the decompression of gained reactant after reaction; Then according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 4mL, to steaming in excessive hydrobromic reactant, adds Hydrogen bromide again, is heated to 110 ℃, reaction 22h; After reaction finishes, its reactant is carried out to aftertreatment, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates;
Described its reactant is carried out to aftertreatment, treatment process is: first gained reactant is distilled, remove excessive Hydrogen bromide; According to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the ratio of 4mL 95% ethanol to add 95% ethanol, heating for dissolving, after dissolving, add gac, the add-on of gac is N-(2-hydroxyethyl)-1,0.05 times of 3-propylene diamine weight, stirring 30min decolours, after decolouring, filter, gained filtrate goes to crystallization 3h under 0 ℃ of condition after naturally cooling to room temperature, after crystallization, filters, and after filtering, gained crystal was 55 ℃ of forced air dryings 2 hours, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates;
B, first 12 water sodium thiophosphates and water are added in reaction vessel, the N-(2-bromotrifluoromethane)-1 that adds step a to prepare after stirring and dissolving, 3-propylene diamine two hydrobromates, described N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates and 12 water sodium thiophosphates between the two the mol ratio of add-on be 1:1,12 water sodium thiophosphates and the water mass ratio between the two is 1:1.5, then stirring reaction 2h at ambient temperature; After reaction finishes, in gained reaction solution, add gac to decolour, the add-on of gac is N-(2-bromotrifluoromethane)-1,0.03 times of 3-propylene diamine two hydrobromate weight, filters after decolouring, in gained filtrate, adds dehydrated alcohol, the add-on of dehydrated alcohol is 2 times that in this step, water adds weight, be cooled to 5～10 ℃ and carry out crystallization, crystallization 3h, filters and obtains three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products after crystallization;
C, the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that step b is obtained are dissolved in deionized water, and temperature during dissolving is 10～30 ℃, and the consumption of deionized water is 3 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after dissolving, with 717 anionite-exchange resin and 732 Zeo-karbs, adsorb successively, the consumption of 717 anionite-exchange resin and 732 Zeo-karbs is 0.2 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after absorption, filter, in gained filtrate, add dehydrated alcohol, the add-on of dehydrated alcohol is 2 times of deionized water consumption in this step, be cooled to 0～5 ℃ and carry out crystallization 1.5h, after crystallization, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal, filter, dry, when dry, temperature is 15～30 ℃, be 48h time of drying, after dry, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work.
Purity >=99.6% of products obtained therefrom three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work, mercaptans content≤0.1%, other impurity≤0.1%, total impurities≤0.3%.The liquid chromatogram of products obtained therefrom three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work is shown in accompanying drawing 2, and nmr spectrum refers to accompanying drawing 1.
Embodiment 2: substantially the same manner as Example 1, difference is:
In step a: according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 4mL, under agitation condition, add Hydrogen bromide (hydrobromic concentration is 48%), after Hydrogen bromide adds under 30 ℃ of conditions, reaction 30min, steams excessive Hydrogen bromide (when decompression steams, vacuum tightness is that 0.09MPa, temperature are 85 ℃) by the decompression of gained reactant after reaction; Then according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 3mL, to steaming in excessive hydrobromic reactant, adds Hydrogen bromide again, is heated to 90 ℃, reaction 30h;
In step b: described N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates and 12 water sodium thiophosphates between the two the mol ratio of add-on be 0.9:1,12 water sodium thiophosphates and the water mass ratio between the two is 1:1, then stirring reaction 3h at ambient temperature; After reaction finishes, in gained reaction solution, add gac to decolour, the add-on of gac is N-(2-bromotrifluoromethane)-1,0.02 times of 3-propylene diamine two hydrobromate weight, after decolouring, filter, in gained filtrate, add dehydrated alcohol, the add-on of dehydrated alcohol is 1 times that in this step, water adds weight, be cooled to 10～20 ℃ and carry out crystallization, crystallization 5h;
In step c: the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that step b is obtained are dissolved in pure water, and temperature during dissolving is 10～30 ℃, the consumption of deionized water is 5 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after dissolving, with 717 anionite-exchange resin and 732 Zeo-karbs, adsorb successively, the consumption of 717 anionite-exchange resin and 732 Zeo-karbs is 0.5 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after absorption, filter, in gained filtrate, add dehydrated alcohol, the add-on of dehydrated alcohol is 1 times of deionized water consumption in this step, be cooled to 5～10 ℃ and carry out crystallization 2h, after crystallization, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal, filter, dry, when dry, temperature is 15～30 ℃, be 48h time of drying.
Embodiment 3: substantially the same manner as Example 1, difference is:
In step a: according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 3mL, under agitation condition, add Hydrogen bromide (hydrobromic concentration is 48%), after Hydrogen bromide adds under 15 ℃ of conditions, reaction 90min, steams excessive Hydrogen bromide (when decompression steams, vacuum tightness is that 0.09MPa, temperature are 85 ℃) by the decompression of gained reactant after reaction; Then according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 5mL, to steaming in excessive hydrobromic reactant, adds Hydrogen bromide again, is heated to 130 ℃, reaction 15h;
In step b: described N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates and 12 water sodium thiophosphates between the two the mol ratio of add-on be 0.95:1,12 water sodium thiophosphates and the water mass ratio between the two is 1:2, then stirring reaction 1.5h at ambient temperature; After reaction finishes, in gained reaction solution, add gac to decolour, the add-on of gac is N-(2-bromotrifluoromethane)-1,0.05 times of 3-propylene diamine two hydrobromate weight, after decolouring, filter, in gained filtrate, add dehydrated alcohol, the add-on of dehydrated alcohol is 1 times that in this step, water adds weight, be cooled to 0～10 ℃ and carry out crystallization, crystallization 2h;
In step c: the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that step b is obtained are dissolved in deionized water, and temperature during dissolving is 10～30 ℃, the consumption of deionized water is 2 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after dissolving, with 717 anionite-exchange resin and 732 Zeo-karbs, adsorb successively, the consumption of 717 anionite-exchange resin and 732 Zeo-karbs is 0.1 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after absorption, filter, in gained filtrate, add dehydrated alcohol, the add-on of dehydrated alcohol is 3 times of deionized water consumption in this step, be cooled to 0～10 ℃ and carry out crystallization 2h, after crystallization, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal, filter, dry, when dry, temperature is 15～30 ℃, be 48h time of drying.
Claims (8)
1. a synthetic method for three hydration 3-aminopropyl amine ethyl phosphorothioic acids, is characterized in that, described synthetic method comprises the following steps:
A, first by raw material N-(2-hydroxyethyl)-1,3-propylene diamine adds in reaction vessel, according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 2～4mL, under agitation condition, add Hydrogen bromide, after Hydrogen bromide adds, under 15～30 ℃ of conditions, reaction 30～90min, steams excessive Hydrogen bromide by the decompression of gained reactant after reaction; Then according to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the hydrobromic ratio of 3～5mL, to steaming in excessive hydrobromic reactant, adds Hydrogen bromide again, is heated to 90～130 ℃, reaction 15～30h; After reaction finishes, its reactant is carried out to aftertreatment, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates;
B, first 12 water sodium thiophosphates and water are added in reaction vessel, the N-(2-bromotrifluoromethane)-1 that adds step a to prepare after stirring and dissolving, 3-propylene diamine two hydrobromates, described N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates and 12 water sodium thiophosphates between the two the mol ratio of add-on be 0.9～1.0:1,12 water sodium thiophosphates and the water mass ratio between the two is 1:1～2, then stirring reaction 1～3h at ambient temperature; After reaction finishes, in gained reaction solution, add gac to decolour, the add-on of gac is N-(2-bromotrifluoromethane)-1,0.01～0.05 times of 3-propylene diamine two hydrobromate weight, after decolouring, filter, in gained filtrate, add dehydrated alcohol, be cooled to 0～20 ℃ and carry out crystallization, crystallization 1～5h, filters and obtains three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products after crystallization;
C, the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that step b is obtained are soluble in water, and the consumption of water is 1～7 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight; After dissolving, with 717 anionite-exchange resin and 732 Zeo-karbs, adsorb successively, the consumption of 717 anionite-exchange resin and 732 Zeo-karbs is 0.05～0.5 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product weight, after absorption, filter, in gained filtrate, add dehydrated alcohol, be cooled to 0～10 ℃ and carry out crystallization 1～3h, after crystallization, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal, filter, be dried, after being dried, obtain three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work.
2. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, it is characterized in that: described in step a, after reaction, the decompression of gained reactant is steamed to excessive Hydrogen bromide, when its decompression steams, vacuum tightness is that 0.09MPa, temperature are 85 ℃; Described hydrobromic concentration is 48%.
3. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, it is characterized in that, described in step a, its reactant is carried out to aftertreatment, its treatment process is: first gained reactant is distilled, remove excessive Hydrogen bromide; According to 1g N-(2-hydroxyethyl)-1,3-propylene diamine adds the ratio of 3～5mL, 95% ethanol to add 95% ethanol, heating for dissolving, after dissolving, add gac, the add-on of gac is N-(2-hydroxyethyl)-1,0.05 times of 3-propylene diamine weight, stirring 30min decolours, after decolouring, filter, gained filtrate goes to crystallization 3h under 0 ℃ of condition after naturally cooling to room temperature, after crystallization, filters, and after filtering, gained crystal was 55 ℃ of forced air dryings 2 hours, obtain N-(2-bromotrifluoromethane)-1,3-propylene diamine two hydrobromates.
4. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, is characterized in that: in the filtrate of gained described in step b, add dehydrated alcohol, the add-on of its dehydrated alcohol is 1～3 times that in step b, water adds weight.
5. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, it is characterized in that: the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude products that described in step c, step b obtained are soluble in water, described water is pure water or deionized water, and temperature during dissolving is 10～30 ℃.
6. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, is characterized in that: in the filtrate of gained described in step c, add dehydrated alcohol, the add-on of its dehydrated alcohol is 0.5～3 times of water consumption in step c.
7. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, is characterized in that: described in step c, filter, be dried, when it is dry, temperature is 15～30 ℃, and be 48h time of drying.
8. the synthetic method of three hydration 3-aminopropyl amine ethyl phosphorothioic acids according to claim 1, it is characterized in that: purity >=99.6% of three hydration 3-aminopropyl amine ethyl phosphorothioic acid fine work described in step c, mercaptans content≤0.1%, other impurity≤0.1%, total impurities≤0.3%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3892824A (en) * | 1968-12-16 | 1975-07-01 | Southern Res Inst | S-{107 -({107 -aminoalkylamino)alkyl dihydrogen phosphorothioates |
| CN1752092A (en) * | 2005-11-17 | 2006-03-29 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The synthetic method of 3-aminopropylaminoethylthiophosphoric |
| CN102399238A (en) * | 2011-12-21 | 2012-04-04 | 开封明仁药业有限公司 | Preparation method for amifostine |
| CN102659836A (en) * | 2012-04-16 | 2012-09-12 | 南京臣功制药股份有限公司 | Method for preparing amifostine |
| CN103396439A (en) * | 2013-08-01 | 2013-11-20 | 沈阳药科大学 | Synthetic method for thiophosphate cell protective agent-amifostine |
-
2013
- 2013-12-14 CN CN201310678609.XA patent/CN103694272A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3892824A (en) * | 1968-12-16 | 1975-07-01 | Southern Res Inst | S-{107 -({107 -aminoalkylamino)alkyl dihydrogen phosphorothioates |
| CN1752092A (en) * | 2005-11-17 | 2006-03-29 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The synthetic method of 3-aminopropylaminoethylthiophosphoric |
| CN102399238A (en) * | 2011-12-21 | 2012-04-04 | 开封明仁药业有限公司 | Preparation method for amifostine |
| CN102659836A (en) * | 2012-04-16 | 2012-09-12 | 南京臣功制药股份有限公司 | Method for preparing amifostine |
| CN103396439A (en) * | 2013-08-01 | 2013-11-20 | 沈阳药科大学 | Synthetic method for thiophosphate cell protective agent-amifostine |
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Application publication date: 20140402 |