CN1752092A - The synthetic method of 3-aminopropylaminoethylthiophosphoric - Google Patents
The synthetic method of 3-aminopropylaminoethylthiophosphoric Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of 3-aminopropylaminoethylthiophosphoric, be with reactant sodium thiophosphate and N-(2-hydroxyethyl)-1, moles such as the two hydrobromates of 3-propylene diamine place the water dissolution afterreaction altogether and separate out with alcohol and obtain solid product, it is characterized in that, reactant is cooled to about 5 ℃ earlier after placing water, the limit drips dimethyl sulfoxide (DMSO) DMS0 limit and is warming up to reactant gradually and all dissolves then, and temperature is no more than 20 ℃ in the temperature-rise period.Adopt the inventive method, can improve end product purity, and make purification process be easy to carry out, overall yield can reach 70%.
Description
Technical Field
The invention relates to the field of chemical synthesis, and particularly relates to a method for synthesizing a cell protective agent 3-aminopropyl aminoethyl thiophosphate.
Background
WR2721 (amifosine) is a cytoprotective (radioprotective) agent approved by FDA1996 in the United states under the trade name amifostine, Ethylol, Ethiofos, chemically 3-aminopropylaminoethylthiophosphate. Its cytoprotective effect is that because of the higher PH value and stronger base phosphatase activity in normal tissues, it can be dephosphorylated quickly and completely to form pharmacologically active free sulfhydryl metabolite (code number WR-1065), thus protecting non-tumor tissues from the toxic action in chemotherapy and radiotherapy, and reducing the incidence of infection related to neutropenia caused by cyclophosphamide and cisplatin in the course of chemotherapy of advanced ovarian cancer. It has high radioprotective effect and low toxicity, can protect normal tissues from being damaged by radiation, has little protective effect on malignant tumor, and can be used for radiotherapy.
WR2721 belongs to the group of latent mercapto compounds, PO3H2The group plays a role of a carrier in vivo and can shield sulfydryl so that the sulfydryl is gradually released to play roles in reducing toxicity and prolonging effective time. The synthesis method disclosed in the U.S. takes sodium thiophosphate and dihydrobromide as reactants and Dimethylformamide (DMF) as an aprotic polar medium to improve the activity of 3-aminopropyl aminoethyl thiophosphorylation reaction (J Med Chem 12, 236, 1969 such as Piper JR, etc.), but in the synthesis process of the method, the purity of the obtained product is low, the purification process is very difficult, the yield is low when a purer product is obtained, and the yield is about 30%.
Summary of the invention
The invention aims to provide a synthesis method of 3-aminopropyl aminoethyl thiophosphate with high purity and high yield.
The invention discloses a synthesis method of 3-aminopropyl aminoethyl thiophosphoric acid, which comprises the steps of dissolving reactants of sodium thiophosphate and N- (2-hydroxyethyl) -1, 3-propane diamine double hydrobromide with equal mol in water, reacting, and precipitating with alcohol to obtain a solid product, and is characterized in that the reactants are placed in the water, then are cooled to about 5 ℃, and are gradually heated while dimethyl sulfoxide DMSO is dripped until the reactants are completely dissolved, and the temperature is not more than 20 ℃ in the heating process.
The synthesis method also comprises the step of dissolving the obtained solid product by using a weak base aqueous solution and then carrying out alcohol precipitation again.
The synthesis method specifically comprises the following steps:
the method comprises the following steps: putting the reactants of sodium thiophosphate, N- (2-hydroxyethyl) -1, 3-propane diamine double hydrobromide and water into a reactor, stirring and cooling to 5 ℃;
step two: gradually raising the temperature while dropwise adding dimethyl sulfoxide while stirring, wherein the temperature is not more than 20 ℃ until the reactants are completely dissolved;
step three: continuously stirring until the reaction solution is detected to have no black precipitate by using a silver nitrate solution, and obtaining a product solution after the reaction is finished;
step four: continuously dropwise adding 95% ethanol into the product solution, standing for a moment, and standing overnight to obtain asolid product;
step five: dissolving the solid product with weak base water solution, dripping methanol to gradually separate out purified solid, standing for 30 min, and filtering;
step six: and (3) soaking and washing the purified solid by using methanol, draining, and drying under an infrared lamp to obtain a final product, namely the 3-aminopropyl aminoethyl thiophosphate.
In the synthesis method, the weak base aqueous solution in the step five is an aqueous solution of one of sodium carbonate, sodium bicarbonate, ammonia water or triethylamine, the weak base aqueous solution is a dilute solution with the mass percentage concentration of 3-5%, and the ammonia water is prepared from concentrated ammonia water and water according to the volume ratio of 3: 1-1: 3.
Dimethyl sulfoxide is adopted as a cosolvent, and reactants are dissolved at the temperature of below 20 ℃, so that the purity of a reaction product can be improved; in addition, the invention adopts weak base solution to purify the solid product, which can further improve the purity of the product, facilitate the purification operation and improve the yield of the product.
Detailed Description
The invention controls the reaction process and purification conditions to enable sodium thiophosphate to react with N- (2-bromoethyl) -1, 3-propane diamine double hydrobromide to obtain high-purity 3-aminopropyl aminoethyl thiophosphate.
Example one
Preparation of sodium thiophosphate
In the present invention, sodium thiophosphate can be imported directly from foreign countries. The invention also provides a preparation method for saving cost.
(mono) trichloro sulfur phosphorus PSCl3The preparation of (1):
196 g of sulfur powder and 18 g of anhydrous aluminum trichloride are taken and put into a 3000ml flask which is provided with a reflux condenser pipe and added with phosphorus trichloride (PCl)3)500 ml. The reaction solution was immediately boiled vigorously and rapidly cooled in an ice-water bath. Stopping boiling, and completely dissolving the sulfur powder. Removing the ice water bath, changing the water bath to heat to 95 ℃, continuing to react for 2 hours, cooling,washed 2 times with ice water. The opalescent liquid is separated. Drying with anhydrous calcium chloride. The yield is 67.5-86% at the temperature of distilling bp.124-126 ℃.
Sodium (di) thiophosphate Na3SPO3·10H2Preparation of O
Taking 490 g of NaOH, adding 1620ml of water, stirring and dissolving (heating the aqueous solution to 60 ℃), and adding the PSCl prepared by the method once3290 g, the temperature rises rapidly and reflux occurs. After the reaction was slowed down, the reaction mixture was heated for 1.5 hours. After the reaction, the reaction solution was poured into a beaker and rapidly cooled to precipitate a white solid. The beaker was placed in a refrigerator overnight. Filtered and dissolved in 1000ml of water. Filtering to remove impurities. 2400ml of absolute ethanol was added to the filtrate. Cooling to obtain white solid, and naturally drying. m.p.60-61 ℃ yield is about 78-93%.
Elemental analysis of the product of step (ii) calculated% P8.61; found% P.8.59. The product that is indeed obtained is sodium thiophosphate Na3SPO3·10H2O。
Preparation of di, N- (2-hydroxyethyl) -1, 3-propanediamine double hydrobromide
Preparation of (mono) N- (2-hydroxyethyl) -1, 3-propanediamine (II)
666 g (9mol) of 1, 3-propanediamine and 666ml of absolute ethanol were placed in a suitable three-necked flask (equipped with a stirrer, a dropping funnel, a thermometer and the like). The mixture was cooled to 0 ℃ with ice salt, and a mixed solution of ethylene oxide (400 g) and absolute ethanol (360ml) was slowly added dropwise with stirring. The addition was completed over about 2 hours (the reaction temperature was maintained at. + -. 2 ℃ during the addition). After the addition was complete, the reaction was continued at 8 ℃ or lower for 40 minutes. The ethanol was then recovered using a 10 cm short fractionating column. Then removing the fractionating column to recover propane diamine (bp.132-150 deg.C, distilling the remainder under reduced pressure with water pump. bp.190 deg.C/16 mmHg. yield is about 80-90%, while the existing literature (Piper JR et al J Med Chem 12, 236, 1969; pharmaceutical industry (2), 10, 1982) reports that the yield is only 20-49.7%.
Preparation of (di) N- (2-bromoethyl) -1, 3-propanediamine dihydrobromide salt
300 g of the product (II) obtained in the previous step was taken out and poured into a three-necked flask equipped with a fractionating column (about 40cm in height), and the mixture was stirred with dropping 40% hydrobromic acid (3000ml) under cooling in an ice bath. After the addition, water and hydrobromic acid are slowly distilled out by heating (bath temperature is 100-150 ℃) to react for 20 hours, and 2000ml of water and hydrobromic acid are co-distilled. Then, about 200ml of hydrobromic acid is distilled off under reduced pressure. The residue was cooled and 1000ml of acetone was added. Solid is precipitated and collected by filtration. Washed twice with acetone. And (5) recrystallizing with absolute ethyl alcohol. A white solid was obtained. m.p.203-205 ℃. Yield: 74.3-77.2%. The mother liquor is recovered to obtain 94 g of m.p.197-200 DEG C
Preparation and purification of tri, 3-aminopropyl aminoethyl thiophosphate
And (2) sequentially adding 72 g of sodium thiophosphate prepared in the step one, 76.4 g of double-hydrobromide prepared in the step two and 160ml of distilled water into a three-neck flask, stirring, naturally reducing the temperature in the flask to about 5 ℃ (solid is not completely dissolved) under the cooling of ice water, dropwise adding 120ml of dimethyl sulfoxide (DMSO) while gradually increasing the reaction temperature to be not more than 20 ℃, and removing the ice bath after the addition is finished. Continuously stirring until the reaction solution is detected to have no black precipitate by using a silver nitrate solution, and obtaining a product solution after the reaction is finished; and continuously dropwise adding 260ml of 95% ethanol into the solution, and standing for a moment overnight to obtain a solid.
The solid was dissolved in about 80ml of 4% triethylamine, and 260ml of methanol was added dropwise to gradually precipitate a solid, which was left to stand for 30 minutes. And (6) filtering and collecting. The mixture was rinsed with methanol and dried. Drying under an infrared lamp to obtain the final product 3-aminopropyl aminoethyl thiophosphate. m.p.156 ℃. The yield was about 70.8%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.45, H7.36, N11.71; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
Example II,
The first step and the second step are the same as the first embodiment. In the third step, the obtained solid is dissolved by about 80ml of ammonia water (the volume ratio of concentrated ammonia water to water is 1: 1), and the solid product is purified to finally obtain the final product, namely 3-aminopropyl aminoethyl thiophosphate m.p.159 ℃. The yield of step three of this example was 71.3%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.34, H7.36, N11.82; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
Example III,
The first step and the second step are the same as the first embodiment. In the third step, the obtained solid is dissolved by about 90ml of ammonia water (the volume ratio of concentrated ammonia water to water is 1: 3), and the solid product is purified to finally obtain the final product, namely 3-aminopropyl aminoethyl thiophosphate m.p.158 ℃. The yield of step three of this example was 70.3%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.37, H7.36, N11.75; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
Example four,
The first step and the second step are the same as the first embodiment. In the third step, the obtained solid is dissolved by about 60ml of ammonia water (the volume ratio of concentrated ammonia water to water is 3: 1), and the solid product is purified to finally obtain the final product, namely 3-aminopropyl aminoethyl thiophosphate m.p.158 ℃. The yield of step three of this example was 71.9%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.87, H7.36, N11.25; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
Example V,
The first step and the second step are the same as the first embodiment. In the third step, the obtained solid is dissolved by 5 percent sodium bicarbonate solution, and the product solid is purified to finally obtain the final product of 3-aminopropyl aminoethyl thiophosphate m.p.157 ℃. The yield of step three of this example was 72.1%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.80, H7.36, N11.18; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
Example six,
The first step and the second step are the same as the first embodiment. In the third step, the obtained solid is dissolved by 3 percent sodium carbonate solution, and the product solid is purified to finally obtain the final product 3-aminopropyl aminoethyl thiophosphate m.p.159 ℃. The yield of step three of this example was 71.2%.
Elemental analysis: calculated% C25.85, H7.37, N12.11; found% C25.81, H7.36, N11.17; the product was indeed obtained as 3-aminopropylaminoethyl phosphorothioate.
In the third step of the invention, the reactant is controlled to be dissolved below 20 ℃, and dimethyl sulfoxide (DMSO) is used as an aprotic polar medium to improve the activity of the reaction, so that the purity of the reaction product is improved; in addition, the method adopts the dilute weak base solution to purify the solid product, can further improve the purity of the final product, ensures that the purification operation is easy to carry out, and improves the yield of the product. Compared with the technology disclosed in the United states, the reaction efficiency of DMSO adopted by the method is 4 times that of DMF, and the pure final product 3-aminopropyl aminoethyl thiophosphate can be obtained, the yield of the method can reach 70%, and the total yield is improved by more than 2 times compared with the technology in the United states.
Claims (7)
1. A synthetic method of 3-aminopropyl aminoethyl thiophosphoric acid is characterized in that reactants of sodium thiophosphate and N- (2-hydroxyethyl) -1, 3-propane diamine double hydrobromide which are equimolar are put into water to be dissolved and then react, and alcohol is used for separating out to obtain a solid product, wherein the reactants are put into the water and then are cooled to about 5 ℃, and then dimethyl sulfoxide DMSO is dripped while the temperature is gradually raised until the reactants are completely dissolved, and the temperature is not more than 20 ℃ in the temperature raising process.
2. The synthesis method according to claim 1, further comprising the step of re-precipitating the solid product after dissolving the solid product with a weak base aqueous solution.
3. The synthesis method according to claim 1 or 2, characterized in that it comprises in particular the following steps:
the method comprises the following steps: putting the reactants of sodium thiophosphate, N- (2-hydroxyethyl) -1, 3-propane diamine double hydrobromide and water into a reactor, stirring and cooling to 5 ℃;
step two: gradually raising the temperature while dropwise adding dimethyl sulfoxide while stirring, wherein the temperature is not more than 20 ℃ until the reactants are completely dissolved;
step three: continuously stirring until the reaction solution is detected to have no black precipitate by using a silver nitrate solution, and obtaining a product solution after the reaction is finished;
step four: continuously dropwise adding 95% ethanol into the product solution, standing for a moment, and standing overnight to obtain a solid product;
step five: dissolving the solid product with weak base water solution, dripping methanol to gradually separate out purified solid, standing for 30 min, and filtering;
step six: and (3) soaking and washing the purified solid by using methanol, draining, and drying under an infrared lamp to obtain a final product, namely the 3-aminopropyl aminoethyl thiophosphate.
4. The method of claim 3, wherein the weak base aqueous solution in step five is an aqueous solution of one of sodium carbonate, sodium bicarbonate, ammonia water, or triethylamine.
5. The synthesis method according to claim 4, wherein the weak base aqueous solution has a mass percentage concentration of 3-5%.
6. The synthesis method according to claim 4, wherein the mass percentage concentration of the sodium carbonate and sodium bicarbonate solution is 3-5%.
7. The synthesis method according to claim 4, wherein the ammonia water is prepared from concentrated ammonia water and water according to the volume ratio of 3: 1-1: 3.
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| CNB2005101148971A CN100365001C (en) | 2005-11-17 | 2005-11-17 | Synthesis method of 3-amino propylomine ethyl thio phosphoric acid |
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| CNB2005101148971A CN100365001C (en) | 2005-11-17 | 2005-11-17 | Synthesis method of 3-amino propylomine ethyl thio phosphoric acid |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412732B (en) * | 2008-09-02 | 2011-09-07 | 大连美罗药业股份有限公司 | Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof |
| CN102260288A (en) * | 2010-06-08 | 2011-11-30 | 成都大有得药业有限公司 | Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate |
| 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 |
| CN103694272A (en) * | 2013-12-14 | 2014-04-02 | 郑州大明药物科技有限公司 | Synthesis method of 3-aminopropyl aminoethyl phosphorothioate trihydrate |
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| 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 |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412732B (en) * | 2008-09-02 | 2011-09-07 | 大连美罗药业股份有限公司 | Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof |
| CN102260288A (en) * | 2010-06-08 | 2011-11-30 | 成都大有得药业有限公司 | Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate |
| 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 |
| 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 |
| CN102659836B (en) * | 2012-04-16 | 2014-10-15 | 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 |
| CN103396439B (en) * | 2013-08-01 | 2016-04-27 | 沈阳药科大学 | The synthetic method of thiophosphate cell protective agent-amifostine |
| CN103694272A (en) * | 2013-12-14 | 2014-04-02 | 郑州大明药物科技有限公司 | Synthesis method of 3-aminopropyl aminoethyl phosphorothioate trihydrate |
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