CN101412732B - Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof - Google Patents
Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof Download PDFInfo
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Abstract
The invention relates to the field of chemosynthesis, a trihydrate 3-aminopropyl amine ethyl thiophosphoric acid(amifostine)stable crystal and a preparation method thereof. The method comprises the following steps: step one, according to the molar ratio of between 1.01 to 1.0 and 1.2 to 1.0, N-(2-bromethyl)-1,3-propane diamine bi-hydrobromide and sodium thiophosphate are dissolved in water, are added with a polar aprotic solvent as an accelerant and react at a temperature of between 10 and 40 DEG C; after reaction, the mixture is directly cooled to precipitate a coarse product of trihydrate amifostine; step two, the coarse product of the trihydrate amifostine obtained in the step one is subjected to primary recrystallization and purification, is dissolved in the water and is precipitated out through methanol to obtain anhydrous amifostine; and step three, the anhydrous amifostine obtained in the step two is subjected to secondary recrystallization and purification, is dissolved in thewater and is decolored through active carbon; and the trihydrate amifostine crystal is precipitated out through ethanol. The purity of the crystal is more than or equal to 99.5 percent; the content of mercaptan is less than or equal to 0.1 percent; the content of other relevant substances is less than or equal to 0.1 percent; and a product is stable and is suitable for scale production.
Description
Technical field
The present invention relates to the field of chemical synthesis, more specifically, relate to a kind of general cytoprotective three hydration 3-aminopropyl amine ethyl phosphorothioic acids and (have another name called: high purity stable crystal and preparation method thereof amifostine).
Background technology
3-aminopropyl amine ethyl phosphorothioic acid, commodity be called amifostine (amifostine, amifostine claim WR-2721 again, and Ethyol), its structural formula is:
Amifostine is to be screened from 4400 compounds by Americans in uniform the fifties, and code name is WR2721, as the protective material of nuclear radiation.Amifostine is dephosphorylate group after alkaline phosphatase (AKP) activation in vivo, becomes the active metabolite H that contains free sulfhydryl groups
2N-(CH
2)
3-NH-(CH
2)
2-SH, it optionally takes in normal tissue cell, removes oxyradical, thereby repairs the molecule of damage.Amifostine is the cytoprotective of wide spectrum, and preclinical study shows that amifostine almost can optionally be protected all healthy tissuess (except that central nervous system), and to the effect of tumor tissues unprotect.In addition, the result of treatment that amifostine can thing that remarkably influenced is taken medicine.U.S. FDA is in the cytoprotective medicine of approval listing in 1996, and Chinese SFDA is in calendar year 2001 approval listing, and commodity are called amifostine, amifostine, Ethyol.
At present relevant research work comprises:
1) (Piper etc. such as Piper, J.Med.Chem., 12,236,1969) with sodium thiophosphate and N-(2-bromotrifluoromethane)-1, the two hydrobromate reactions of 3-propylene diamine, with N, dinethylformamide (DMF) is the accelerated reaction of aprotic, polar medium, but product is anhydrous amifostine, and the back yield of purifying has only 30%.
2) (USP3 such as Piper, 892,824) with sodium thiophosphate and N-(2-bromotrifluoromethane)-1, the two hydrobromates of 3-propylene diamine are 15～20 ℃ of reactions down, add aprotic, polar medium DMF accelerated reaction, the reaction back adds a large amount of methyl alcohol (being about 6.5 times of quantity of solvent) and makes sinking agent in reaction solution, obtain a hydration amifostine, the back yield 91% of purifying.
3) (Li Jiaming etc. such as Li Jiaming, the Anhui chemical industry, 2,2000) with 12 water sodium thiophosphates and N-(2-bromotrifluoromethane)-1, the two hydrobromates of 3-propylene diamine do not add DMF 15～20 ℃ of reactions down, and the reaction back directly adds sinking agent ethanol (being about 2 times of quantity of solvent), obtain amifostine trihydrate, yield 80%.
4) virgin Ceng Shou, (Acta Pharmaceutica Sinica, 16,302,1981 such as Li Lu; ZL200510114897) with sodium thiophosphate and N-(2-bromotrifluoromethane)-1, the two hydrobromate reaction with same mole of 3-propylene diamine, with dimethyl sulfoxide (DMSO) (DMSO) is the aprotic, polar medium, be lower than under 20 ℃ of conditions and react, the ethanol sedimentation that reaction solution adds 1.6 times of quantity of solvent goes out product, separate out product with the weak caustic solution dissolving again, add methanol purification and obtain anhydrous amifostine, yield 70%.
In the above synthetic method, all in reactant solution, add a large amount of methyl alcohol or ethanol sinking agent.Institute's synthetic product has also only carried out qualitative analysis, and purity, crystallographic property and stability are failed clearly.And in actual applications, amifostine trihydrate purity is high more, and stability is good more, in preparation and storage process, change very little, product decomposition of little like this, the generation adverse side effect reacts also just little.Therefore, people are devoted to develop three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal of high purity stable.
Summary of the invention
Therefore, the object of the present invention is to provide the amifostine crystal-three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal of a kind of purity height, good stability.
Another object of the present invention is to provide three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline preparation methods of above-mentioned purity height, good stability.
The inventor improves and has optimized the synthetic and purifying process of amifostine by unremitting effort, thereby has obtained a kind of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal of high purity stable.Press 40KV at pipe, pipe stream 100mA, Cu target K a, test angle 4-60 °, 6 °/min, 1 ° of non-proliferation slit, anti-diffuse-reflectance slit: 1 °, receive slit 0.15mm, this crystalline X-ray powder diffraction data are as follows:
| Sequence number | The d value | I/ |
| 1 | 10.6～10.8 | 50～70 |
| 2 | 5.3～5.4 | 100 |
| 3 | 2.6～2.7 | 25～40 |
| 4 | 2.15～2.16 | 4～8 |
| 5 | 1.79～1.80 | 1～5 |
Wherein d is a spacing, I/I
0Be relative intensity.
The invention provides above-mentioned three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline preparation methods, this method steps is as follows:
Step 1: with reactant N-(2-bromotrifluoromethane)-1, two hydrobromates of 3-propylene diamine and sodium thiophosphate are by 1.01～1.2: 1.0 molar ratio is dissolved in the water, and adds polar aprotic solvent as promotor, 10～40 ℃ of reactions; After the reaction, reactant solution need not be analysed by alcohol, and directly thick product amifostine trihydrate crude product is separated out in cooling;
Step 2: the amifostine trihydrate crude product that step 1 is obtained carries out the recrystallization purification first time, is about to the amifostine trihydrate dissolving crude product in water, separates out with methyl alcohol then, obtains not having the crystal water amifostine;
Step 3: the no crystal water amifostine that step 2 is obtained carries out the recrystallization purification second time, being about to not have the crystal water amifostine is dissolved in the water, and with 0.1～1.5% activated carbon decolorizing of no crystal water amifostine weight, separate out the amifostine trihydrate crystal with ethanol then, its purity 〉=99.5%, mercaptans content≤0.1%, other its related substances≤0.1% (by U.S. USP29).
In above-mentioned preparation method, institute's water is pure water or deionized water.
Be described more specifically preparation method of the present invention below.
In described step 1, reactant N-(2-bromotrifluoromethane)-1, two hydrobromates of 3-propylene diamine and sodium thiophosphate place the water stirring and dissolving by the molar ratio of 1.01～1.20:1.0, and preferred 1.03～1.10:1.0; Dissolving used water weight is N-(2-bromotrifluoromethane)-1,1.3～3.8 times of the two hydrobromate add-ons of 3-propylene diamine, and preferred 1.7～2.5 times; 10～40 ℃ of solvent temperature scopes; Described polar aprotic solvent is a dimethyl sulfoxide (DMSO), and the add-on of dimethyl sulfoxide (DMSO) is N-(2-bromotrifluoromethane)-1, and the two hydrobromates of 3-propylene diamine add 1.0～2.8 times of weight; Temperature of reaction is controlled at 10～40 ℃, and preferred 15～25 ℃; Check reaction soln with silver nitrate solution in the reaction process, do not separate out to there being black precipitate; After reaction finishes, with reaction product solution directly cooling be cooled to-15 ℃～10 ℃, preferred-10 ℃～5 ℃, kept 2～24 hours, filter three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystal crude product.
In described step 2, promptly recrystallization is purified for the first time: with the amifostine trihydrate crude product of pure water dissolving step 1 preparation, the pure water consumption is 1.0～6.0 times of amifostine trihydrate crude product weight, and preferred 2.5～4.5 times; 15～45 ℃ of solvent temperatures; After the dissolving, add methyl alcohol, it is to add 0.1～0.8 times of pure water amount that methyl alcohol adds weight, and preferred 0.2～0.6 times; Be cooled to 20 ℃～-15 ℃, preferred range is 8 ℃～-5 ℃, separates out no crystal water amifostine.
In described step 3, promptly recrystallization is purified for the second time: with the no crystal water amifostine of pure water dissolving step 2 preparations, water consumption is 1.0～6.0 times of the no crystal water amifostine weight of adding, and preferred 2.5～4.5 times; 15～45 ℃ of solvent temperatures; And preferred 0.1～1.5% the gac that adds no crystal water amifostine weight decolours, and stirs more than 15 minutes, then filtration; In gained filtrate, add ethanol, ethanol add weight be add 0.05～0.4 times of pure water amount, and preferred 0.1～0.3 times; Be cooled to 20 ℃～-15 ℃, preferred range is 8 ℃～-5 ℃, separates out the amifostine crystal that contains three crystal water.
Filter according to a conventional method then, drying.After the filtration, use the ethanolic soln washing crystal, vacuum-drying, three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystalline compounds of high purity stable.
By three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystal that the inventive method obtains, yield is greater than 65%, purity 〉=99.5%, mercaptans content≤0.1%, other impurity≤0.1%, its stability improves greatly, thereby side effect significantly reduces, and can be used for useful in preparing drug formulations and uses.
Description of drawings
Figure 1A and Figure 1B are three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline XRPD spectrogram and the data that the embodiment of the invention 1 obtains.
Fig. 2 A and Fig. 2 B are three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline XRPD spectrogram and the data that the embodiment of the invention 2 obtains.
Fig. 3 is the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline X ray single crystal diffraction figure that the embodiment of the invention 1 and 2 obtains.
Fig. 4 and Fig. 5 are respectively the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline electron micrographs that embodiment 1 and 2 obtains, clearly show that from figure three hydration 3-aminopropyl amine ethyl phosphorothioic acids are to exist with crystalline form, and be the flats crystal.
Embodiment
The preparation of three hydration 3-aminopropyl amine ethyl phosphorothioic acids of embodiment 1 high purity stable
Step 1: synthetic
In the 50L stainless steel cauldron, add pure water 13.6kg, 12 water sodium thiophosphate 19.2mol (7.6kg), stir and add N-(2-bromotrifluoromethane)-1 down, the two hydrobromate 19.8mol (6.8kg of 3-propylene diamine, 3% is excessive), slowly add 11.0kg DMSO, keep temperature of reaction simultaneously and be no more than 25 ℃.After dripping DMSO, with silver nitrate solution monitoring reaction solution, do not separate out to there being black precipitate, reaction finishes, and reaction soln is cooled to 0 ℃, per hour stirs 5 minutes, keeps 18 hours.Centrifuging gets three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product 6.1kg.
Step 2: recrystallization is purified for the first time
In 50L stainless steel crystallization kettle, add the 22.0kg pure water, the 3-aminopropyl amine ethyl phosphorothioic acid crude product 6.1kg of step preparation in the adding, dissolving at room temperature adds gac 95.0g, stirs 15 minutes under the room temperature, filter, add methyl alcohol 8.7kg in the mother liquor, logical cooling water temperature to 0 ℃ was kept 18 hours, centrifuging, getting a recrystallizing and refining does not have crystal water 3-aminopropyl amine ethyl phosphorothioic acid 4.8kg.
Step 3: recrystallization is purified for the second time
In 50L stainless steel crystallization kettle, add the 20.0kg pure water, add the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid 4.8kg that the first time, recrystallization obtained, at room temperature stirring and dissolving adds gac 75.0g, stirred 15 minutes under the room temperature, filter, add ethanol 3.2kg in the mother liquor, logical cooling water temperature to 0 ℃, kept 18 hours, centrifuging, 30 ℃ of vacuum-dryings get three hydration 3-aminopropyl amine ethyl phosphorothioic acid 3.6kg.Adopt HPLC method (by 29 editions official methods of the U.S.) to analyze purity 99.81%, mercaptans content 0.021%, other related substances 0.078%.
Adopt the D/MAX-2400X x ray diffractometer x, press 40KV at pipe, pipe stream 100mA, Cu target K a, test angle 4-60 °, 6 °/min, 1 ° of non-proliferation slit, anti-diffuse-reflectance slit: 1 °, receive slit 0.15mm, record this crystal X-ray powder diffraction pattern shown in Figure 1A and Figure 1B.
Fig. 4 is the crystalline electron micrograph that this embodiment obtains, and clearlys show that from figure three hydration 3-aminopropyl amine ethyl phosphorothioic acids are to exist with crystalline form, and is the flat sheet-like crystal.
The preparation of three hydration 3-aminopropyl amine ethyl phosphorothioic acids of embodiment 2 high purity stables
Step 1: synthetic
In the 50L stainless steel cauldron, add pure water 13.6kg, 12 water sodium thiophosphate 19.2mol (7.6kg), stir and add N-(2-bromotrifluoromethane)-1 down, the two hydrobromate 19.5mol (6.7kg of 3-propylene diamine, 2% is excessive), stirring and dissolving slowly adds 11.0kgDMSO, keeps temperature of reaction simultaneously and is no more than 25 ℃, with silver nitrate solution monitoring reaction solution, do not separate out to there being black precipitate, reaction finishes, and reaction soln is cooled to 0 ℃, per hour stirred 5 minutes, kept 18 hours, centrifuging gets 3-aminopropyl amine ethyl phosphorothioic acid solid 6.0kg.
Step 2: recrystallization is purified for the first time
In 50L stainless steel crystallization kettle, add the 22.0kg pure water, add synthetic 3-aminopropyl amine ethyl phosphorothioic acid crude product 6.0kg, at room temperature stirring and dissolving adds gac 95.0g, stirs 15 minutes under the room temperature, filter, add methyl alcohol 8.7kg in the mother liquor, logical cooling water temperature to 0 ℃ was kept 18 hours, centrifuging gets white solid 4.8kg.
Step 3: recrystallization is purified for the second time
In 50L stainless steel crystallization kettle, add the 20.0kg pure water, add the 3-aminopropyl amine ethyl phosphorothioic acid crude product 4.8kg of recrystallization purification for the first time, under stirring at room, dissolve, add gac 75.0g, stirred 15 minutes under the room temperature, filter, add ethanol 3.2kg in the mother liquor, logical cooling water temperature to 0 ℃, kept 18 hours, centrifuging, 30 ℃ of vacuum-dryings get three hydration 3-aminopropyl amine ethyl phosphorothioic acid 3.5kg.Purity assay 99.85%, mercaptans content 0.020%, other related substances 0.071%.
Adopt the D/MAX-2400X x ray diffractometer x, press 40KV at pipe, pipe stream 100mA, Cu target K a, test angle 4-60 °, 6 °/min, 1 ° of non-proliferation slit, anti-diffuse-reflectance slit: 1 °, receive slit 0.15mm, record this crystal X-ray powder diffraction pattern shown in Fig. 2 A and Fig. 2 B.
Fig. 5 is the crystalline product electron micrograph that this embodiment obtains, and clearlys show that from figure three hydration 3-aminopropyl amine ethyl phosphorothioic acids are to exist with crystalline form, and is the flat sheet-like crystal.
Table 1 has provided the contrast of amifostine content and its related substances on three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal of the inventive method preparation and the market:
As can be seen from Table 1, the amifostine trihydrate crystalline content of the present invention's preparation will be higher than the amifostine trihydrate that market is purchased, and related substance mercaptan, disulfide and other related substance all are significantly less than the product that existing market is purchased simultaneously.
The stability test of embodiment 4 high-purity three hydration 3-aminopropyl amine ethyl phosphorothioic acids
In the 10mL cillin bottle of the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal sealing that method described in the embodiment 1 makes, be under 40 ℃ and be saved to for 8 weeks, behind the stability test end cycle, water-content, mercaptans content and the amifostine content of crystallized pirimiphos-methyl in the test bottle, water-content is by the karl Fischer titration measuring.Because amifostine can generate [2-[3-aminopropyl] amino under the stability test condition] sulfur alcohol and phosphoric acid, can represent amifostine stability so measure the content of this mercaptan.Mercaptan and amifostine analysis on Content detection method are pressed USP29 (29 editions official methods of the U.S.).
According to 2005 editions two appendix XIXC medicine stability tests of Chinese Pharmacopoeia governing principle, to investigating with the stability of the inventive method synthetic amifostine trihydrate.Get three batch samples respectively and carry out accelerated test, experimental result sees Table 2:
Table 2. amifostine trihydrate accelerated test is investigated the result
With same condition the no crystal water amifostine raw material by the document preparation is carried out accelerated test, it the results are shown in Table 3.
The no crystal water amifostine of table 3. raw material main body purity accelerated test is investigated the result
Accelerated test result shows that the inventive method synthetic amifostine trihydrate accelerated tests is in the time of 6 months, and the equal conformance with standard of every investigation index is stipulated.Stability improves a lot than no crystalline amifostine stability tool.
Above result shows, the inventive method synthetic amifostine trihydrate Heat stability is good can be preserved 4 ℃ of following long periods.
Three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal structure determinations of embodiment 5 embodiment of the invention 1 and 2 preparations
The crystalline structure of three hydration 3-aminopropyl amine ethyl phosphorothioic acids is determined.At room temperature finish crystal measurement, the mensuration of unit cell and the collection of data with the molybdenum radiation.
Structure is found the solution by direct method and is accurate through complete matrix method of least squares and fourier method of finite difference.All non-hydrogen atoms are anisotropically accurate, and the hydrogen atom that is connected to the Sauerstoffatom of nitrogen and water is located also isotropically accurate by the fourier difference diagram.
Crystallization among the chirality spacer P2:2:2 of compound, three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline structure figure as shown in Figure 3.Used instrument CCDX ray single crystal diffractometer, model Bruker Smart APEXII type.
Table 4. three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal X-single crystal diffraction data
Table 5. location parameter and temperature factor parameter
Bond distance and the bond angle of table 6.DS1
Claims (8)
1. hydration 3-aminopropyl amine ethyl phosphorothioic acid crystalline preparation method is characterized in that this method steps is as follows:
Step 1: with reactant N-(2-bromotrifluoromethane)-1, two hydrobromates of 3-propylene diamine and sodium thiophosphate are by 1.01～1.2: 1.0 molar ratio is dissolved in the water, add dimethyl sulfoxide (DMSO) as promotor, the add-on of dimethyl sulfoxide (DMSO) is N-(2-bromotrifluoromethane)-1, and the two hydrobromates of 3-propylene diamine add 1.0～2.8 times of weight; 10～40 ℃ of reactions; After the reaction, directly thick product three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products are separated out in cooling;
Step 2: the three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products that step 1 is obtained carry out the recrystallization purification first time, with three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal dissolving crude products in water, separate out with methyl alcohol then, it is to add 0.1～0.8 times of pure water amount that methyl alcohol adds weight, obtains not having crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal;
Step 3: the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal that step 2 is obtained carries out the recrystallization purification second time, to there be crystal water 3-aminopropyl amine ethyl phosphorothioic acid dissolution of crystals in water, and use activated carbon decolorizing, separate out three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal with ethanol then;
Wherein institute's water is a pure water.
2. preparation method as claimed in claim 1 is characterized in that, in described step 1, and reactant N-(2-bromotrifluoromethane)-1, two hydrobromates of 3-propylene diamine and sodium thiophosphate are by 1.03～1.10: 1.0 molar ratio places the water stirring and dissolving; Dissolving used water weight is N-(2-bromotrifluoromethane)-1,1.3～3.8 times of the two hydrobromate add-ons of 3-propylene diamine; 10～40 ℃ of solvent temperature scopes; Temperature of reaction is controlled at 10～40 ℃; Check reaction soln with silver nitrate solution in the reaction process, do not separate out to there being black precipitate; After reaction finishes, with reaction product solution directly cooling be cooled to-15 ℃～10 ℃, kept 2～24 hours, filter three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products.
3. preparation method as claimed in claim 2 is characterized in that, in described step 1, and reactant N-(2-bromotrifluoromethane)-1, two hydrobromates of 3-propylene diamine and sodium thiophosphate are by 1.03～1.10: 1.0 molar ratio places the water stirring and dissolving; Dissolving used water weight is N-(2-bromotrifluoromethane)-1,1.7～2.5 times of the two hydrobromate add-ons of 3-propylene diamine; 10～40 ℃ of solvent temperature scopes; Temperature of reaction is controlled at 15～25 ℃; Check reaction soln with silver nitrate solution in the reaction process, do not separate out to there being black precipitate; After reaction finishes, with reaction product solution directly cooling be cooled to-10 ℃～5 ℃, kept 2～24 hours, filter three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products.
4. preparation method as claimed in claim 3, it is characterized in that, in described step 2, with three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products of pure water dissolving step 1 preparation, the pure water consumption is 1.0～6.0 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude product weight; 15～45 ℃ of solvent temperatures; Be cooled to 20 ℃～-15 ℃, separate out no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal.
5. preparation method as claimed in claim 4, it is characterized in that, in described step 2, with three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude products of pure water dissolving step 1 preparation, the pure water consumption is 2.5～4.5 times of three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal crude product weight; 15～45 ℃ of solvent temperatures; After the dissolving, add methyl alcohol, it is to add 0.2～0.6 times of pure water amount that methyl alcohol adds weight; Be cooled to 8 ℃～-5 ℃, kept 18 hours, separate out no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal.
6. as claim 4 or 5 described preparation methods, it is characterized in that, in described step 2, also comprise activated carbon decolorizing.
7. preparation method as claimed in claim 4, it is characterized in that, in described step 3, with the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal of pure water dissolving step 2 preparations, water consumption is 1.0～6.0 times of the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal weight of adding; 15～45 ℃ of solvent temperatures; And the adding gac decolours stirring, filtration then; In gained filtrate, add ethanol, ethanol add weight be add 0.05～0.4 times of pure water amount; Be cooled to 20 ℃～-15 ℃, separate out the 3-aminopropyl amine ethyl phosphorothioic acid crystal that contains three crystal water.
8. preparation method as claimed in claim 7, it is characterized in that, in described step 3, with the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal of pure water dissolving step 2 preparations, water consumption is 2.5～4.5 times of the no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal weight of adding; 15～45 ℃ of solvent temperatures; And 0.1～1.5% the gac that adds no crystal water 3-aminopropyl amine ethyl phosphorothioic acid crystal weight decolours, and stirs more than 15 minutes, then filtration; In gained filtrate, add ethanol, ethanol add weight be add 0.1～0.3 times of pure water amount; Be cooled to 8 ℃～-5 ℃, kept 18 hours, separate out the 3-aminopropyl amine ethyl phosphorothioic acid crystal that contains three crystal water.
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| CN102260288B (en) * | 2010-06-08 | 2014-02-26 | 成都大有得药业有限公司 | Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate |
| CN103396439B (en) * | 2013-08-01 | 2016-04-27 | 沈阳药科大学 | The synthetic method of thiophosphate cell protective agent-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 |
| CN103509048B (en) * | 2013-10-15 | 2016-04-20 | 大连理工大学 | A kind of preparation method of green amifostine |
| CN104530119A (en) * | 2014-06-19 | 2015-04-22 | 大连理工大学 | Preparation method and application of amifostine dihydrate |
| CN106674272A (en) * | 2016-12-27 | 2017-05-17 | 张家港市华天药业有限公司 | Processing method for amifostine |
| CN109694386B (en) * | 2019-01-23 | 2021-03-23 | 美罗药业股份有限公司 | Preparation method of amifostine trihydrate |
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