CN110804022A - Preparation method of dexrazoxane - Google Patents

Preparation method of dexrazoxane Download PDF

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Publication number
CN110804022A
CN110804022A CN201911076403.3A CN201911076403A CN110804022A CN 110804022 A CN110804022 A CN 110804022A CN 201911076403 A CN201911076403 A CN 201911076403A CN 110804022 A CN110804022 A CN 110804022A
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Prior art keywords
ammonium
dexrazoxane
salt
diaminopropane
reaction
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CN201911076403.3A
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Chinese (zh)
Inventor
周崴海
徐浩宇
蔡伟
高小刚
陈子章
黄淑萍
郝秀斌
李浩冬
夏雨
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Yangtze River Pharmaceutical Group Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
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Priority to CN201911076403.3A priority Critical patent/CN110804022A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Abstract

The invention discloses a preparation method of dexrazoxane, which adopts (S) -1, 2-diaminopropane-tetraacetic acid and alkali metal salt thereof as raw materials, and ammonium salt as an ammonia source to prepare dexrazoxane.

Description

Preparation method of dexrazoxane
Technical Field
The invention relates to a drug synthesis technology, in particular to a preparation method of dexrazoxane.
Background
Dexrazoxane (Dexrazoxane) is the dextroisomer of propinimine (razoxane), also known as Dexrazoxane or Dexrazoxane, having the formula 1:
dexrazoxane is a lipophilic cyclic derivative of chelating agent ethylenediaminetetraacetic acid, is clinically used as a chemoprotectant, and is mainly used for preventing anthracycline-induced cardiotoxicity. Dexrazoxane was developed by Chiron corporation in the united states and was first marketed in italy in 1992 and approved by the FDA in 1995 at month 7.
The existing method for synthesizing dexrazoxane mainly comprises the following 3 methods: the first is to obtain the dexrazoxane by the cyclization of 1, 2-propanediamine tetraacetic acid, the second is to obtain the dexrazoxane by the cyclization of 1, 2-propanediamine tetraacetamide, and the third is to obtain the dexrazoxane by the cyclization of 1, 2-propanediamine tetraacetic acid ester.
Specifically, for the first preparation method, dexrazoxane may be synthesized by cyclizing 1, 2-propanediamine tetraacetic acid with formamide disclosed in patent WO9308172a1 at high temperature under reduced pressure. However, this method requires a high temperature condition for the reaction under reduced pressure, and concentration of formamide (boiling point: 210 ℃) requires 100 ℃ or higher, which is not easy to be industrialized and has a low yield.
As a second preparation method, dexrazoxane may be obtained by cyclization by reacting propylenediaminetetraacetic acid with 2, 2-dimethoxypropaneic acid to the corresponding tetramethyl ester under basic conditions followed by aminolysis to 1, 2-propylenediaminetetraethylamide as disclosed in European patent EP2045235A 1. Also can be obtained by the method reported by Bull Soc Chim Fance1960:382, and then obtaining the propylene diamine tetra-acetamide by strong acid hydrolysis of 1, 2-propylene diamine tetra-acetonitrile, and further obtaining the dexrazoxane by cyclization, wherein the 1, 2-propylene diamine tetra-acetonitrile can be obtained by the reaction of propylene diamine, formaldehyde and sodium cyanide.
However, in the second method, hydrolysis is required under a strong acid condition, and further cyclization with phenol, polyphosphoric acid or sodium amide is required, so that the toxicity of raw materials is high, the reaction process is long, the temperature is high, decomposition of products is easily caused, the synthesis yield is low, and the product purity is poor.
For the third preparation method, dexrazoxane can be prepared by adding formamide and a strong base (organic alcohol base or metal hydride) to 1, 2-propanediamine tetraacetic acid ester disclosed in patent CN104177301a, but this method requires that the reaction system must be operated without water, the reaction conditions are severe, and the crude product yield is low (about 60%).
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
The invention provides a simple and effective method for preparing dexrazoxane, and provides a dexrazoxane synthesis process which is simple to operate, easy to control reaction conditions, high in yield and high in purity, aiming at the problems of complex synthesis route, harsh reaction conditions, low yield and the like of the conventional dexrazoxane.
The invention provides a preparation method of dexrazoxane, which comprises the following steps:
(1) (S) -1, 2-diaminopropane-tetraacetic acid or an alkali metal salt thereof and an ammonium salt are subjected to cyclization reaction in an amide organic reagent under the heating condition;
(2) after the cyclization reaction is finished, decompressing, concentrating and steaming to remove the amide organic reagent, adding purified water for crystallization, filtering and drying to obtain dexrazoxane;
optionally, the preparation method further comprises refining the crude dexrazoxane obtained in the step (2) to obtain refined dexrazoxane.
In an embodiment of the present application, the alkali metal salt of (S) -1, 2-diaminopropane-tetraacetic acid in step (1) may be a sodium salt, preferably, a disodium salt.
In the above embodiment, the ammonium salt in the step (1) is any ammonium salt that can decompose ammonia gas under heating; including but not limited to one ammonium salt or a mixture of ammonium salts; the ammonium salt may be one or more of ammonium formate, ammonium acetate, ammonium oxalate, ammonium chloride, ammonium bromide, ammonium phosphate, diammonium hydrogen phosphate, ammonium carbonate, and ammonium hydrogen carbonate, and preferably, one or more of ammonium formate, ammonium acetate, and ammonium carbonate.
In the above embodiment, the amide-based organic solvent in step (1) is a mixed solvent of one or more of N, N-dimethylformamide, N-dimethylacetamide and 1-methyl N-methylpyrrolidone, preferably, a mixed solvent of one or two of N, N-dimethylformamide and N, N-dimethylacetamide.
In the above embodiment, the amount of the ammonium salt used in the step (1) is 2 to 20 times, preferably 6 to 12 times, the number of moles of the (S) -1, 2-diaminopropane-tetraacetic acid or its alkali metal salt.
In the above embodiment, the amount of the amide-based organic solvent used in step (1) is 2 to 8 times, preferably 4 to 6 times, the weight of (S) -1, 2-diaminopropane-tetraacetic acid or its alkali metal salt.
In the above embodiment, the reaction temperature of the cyclization reaction in step (1) is 130 ℃ to 200 ℃, preferably 145 ℃ to 156 ℃; alternatively, the cyclization reaction is carried out at a temperature at which the amide-based organic solvent is refluxed.
In the above embodiment, the reaction time of the cyclization reaction in the step (1) is 5 to 48 hours, preferably 8 to 16 hours.
In the above embodiment, the cyclization reaction described in step (1) is carried out in a reaction apparatus equipped with a water separator which separates a reflux comprising volatilized water and a solvent.
In the above embodiment, the amount of the purified water used in the step (2) is 1 to 15 times, preferably 2 to 6 times, the weight of (S) -1, 2-diaminopropane-tetraacetic acid or an alkali metal salt thereof.
In the above embodiment, the purification may be performed by recrystallization, followed by filtration and drying to obtain purified dexrazoxane; alternatively, the refining can adopt the step (4) in the Chinese patent application CN 102675227B: adding the obtained dexrazoxane (crude product) into N, N-dimethylformamide, heating for dissolving, dropwise adding a solvent, crystallizing, filtering, washing the obtained solid with the solvent, and drying to obtain pure dexrazoxane; wherein, the dropwise adding solvent and the washing solid solvent can be one or a mixed solvent of more of C1-4 alcohol solvents, acetone, tetrahydrofuran, water, aqueous solution of C1-4 alcohol solvents, aqueous solution of tetrahydrofuran and aqueous solution of acetone; the weight of the N, N-dimethylformamide is 2-6 times, preferably 2-4 times that of the solid of the crude dexrazoxane added; the heating and dissolving temperature is 40-100 ℃, and preferably 50-80 ℃; the volume of the dropwise added solvent is 3-8 times, preferably 3-6 times of the volume of the N, N-dimethylformamide; the C1-4 alcohol solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol; the solvent used for washing the solid is preferably methanol aqueous solution or acetone aqueous solution, and particularly preferably methanol aqueous solution or acetone aqueous solution with the water content of 30-70 percent by weight; the dropped organic solvent and the solid washing solvent can be the same solvent or a mixture, and can also be different solvents or mixtures; the refining process can be repeated 1 to 3 times, preferably 2 times. The refining process used repeatedly may be different from the process, solvent, and temperature used in the previous refining process within the scope of the refining method disclosed in the present invention, or the previous refining process may be repeated.
Compared with the prior art, the technical scheme disclosed by the invention starts from (S) -1, 2-diaminopropane-tetraacetic acid or alkali metal salt thereof to prepare high-purity dexrazoxane, so that the complex process operation is simplified, and the production cost and the production period are reduced. Meanwhile, by adopting the technical scheme disclosed by the invention, the problems of long-period use of high-toxicity chemical tests, severe anhydrous reaction operation, low yield, low purity and the like which are difficult to overcome are avoided, so that the environment friendliness of the synthesis process is enhanced, the utilization rate of raw materials is improved, the waste of resources is reduced, the method is more suitable for the development requirements of modern medicines, and is more suitable for the harmonious sustainable development of the modern society.
In conclusion, by adopting the technical scheme disclosed by the invention, the synthesis process with the advantages of high yield, high purity, low toxicity, low cost, short period, easiness in operation, easiness in industrialization and the like has higher application value and development prospect.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
The detection method in the present example employs HPLC condition 2 in CN 104177301A.
Example 1
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (10g) into a reaction bottle with a water separator, adding N, N-dimethylformamide (50ml) and ammonium formate (20.6g), heating to 150 ℃, separating a reflux from the water separator, stirring for reaction for 10 hours, concentrating, adding 20ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain 7.1g of crude dexrazoxane (yield 81%), wherein the purity of HPLC is 99.2%.
Adding the crude product of dexrazoxane into a reaction bottle, adding N, N-dimethylformamide (14ml), heating to 80 ℃, stirring for dissolving, adding absolute ethyl alcohol (64ml), cooling to 20-30 ℃, crystallizing, stirring for 1 hour, filtering, and drying to obtain 6.2g (yield 87%), and the HPLC purity is 99.83%.
Example 2
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (120g) into a reaction bottle with a water separator, adding N, N-dimethylformamide (480ml) and ammonium formate (240g), heating to 150 ℃, separating a reflux from the water separator, stirring for reaction for 10 hours, concentrating, adding 360ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain 83g of crude dexrazoxane (yield 81%), wherein the purity of HPLC is 98.9%.
Adding the crude dexrazoxane into a reaction bottle, adding N, N-dimethylformamide (208ml), heating to 80 ℃, stirring for dissolving, adding absolute ethyl alcohol (624ml), cooling to 20-30 ℃, crystallizing, stirring for 1 hour, filtering, and drying to obtain 70g (yield 84%), and the HPLC purity is 99.72%.
Example 3
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (15g) into a reaction bottle with a water separator, adding N, N-dimethylacetamide (60ml) and ammonium formate (25g), heating to 155 ℃, separating a reflux from the water separator, stirring for reacting for 18 hours, concentrating under reduced pressure, adding 45ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain a target product 10.3g (yield 79%), wherein the HPLC purity is 99.3%.
Example 4
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (10g) into a reaction bottle with a water separator, adding N, N-dimethylformamide (50ml) and ammonium acetate (25.6g), heating to 150 ℃, separating a reflux from the water separator, stirring for reaction for 10 hours, concentrating, adding 20ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain a target product 7.4g (yield 85%), wherein the HPLC purity is 99.1%.
Example 5
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (15g) into a reaction bottle with a water separator, adding N, N-dimethylacetamide (40ml) and ammonium formate (30g), heating to 155 ℃, separating a reflux from the water separator, stirring for reacting for 18 hours, concentrating under reduced pressure, adding 45ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain a target product 9.9g (yield 75%), wherein the HPLC purity is 99.3%.
Example 6
Preparation of dexrazoxane
Adding (S) -1, 2-diaminopropane-tetraacetic acid (10g) into a reaction bottle with a water separator, adding N, N-dimethylformamide (50ml) and ammonium carbonate (27.4g), heating to 150 ℃, separating a reflux from the water separator, stirring for reaction for 10 hours, concentrating, adding 20ml of purified water, stirring for 0.5 hour, filtering, and drying to obtain a target product 6.7g (yield 85%), wherein the HPLC purity is 99.2%.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims (9)

1. A preparation method of dexrazoxane comprises the following steps:
(1) (S) -1, 2-diaminopropane-tetraacetic acid or an alkali metal salt thereof and an ammonium salt are subjected to cyclization reaction in an amide organic reagent under the heating condition;
(2) after the cyclization reaction is finished, decompressing, concentrating and steaming to remove the amide organic reagent, adding purified water for crystallization, filtering and drying to obtain dexrazoxane;
optionally, the preparation method further comprises refining the crude dexrazoxane obtained in the step (2) to obtain refined dexrazoxane.
2. The production method according to claim 1, wherein the alkali metal salt of (S) -1, 2-diaminopropane-tetraacetic acid in step (1) is a sodium salt, preferably, a disodium salt.
3. The production method according to claim 1, wherein the ammonium salt in the step (1) is any ammonium salt that can decompose ammonia gas under heating; a mixture comprising one or more ammonium salts; optionally, the ammonium salt is one or more of ammonium formate, ammonium acetate, ammonium oxalate, ammonium chloride, ammonium bromide, ammonium phosphate, diammonium hydrogen phosphate, ammonium carbonate, and ammonium hydrogen carbonate, preferably one or more of ammonium formate, ammonium acetate, and ammonium carbonate.
4. The production method according to claim 1, wherein the amide-based organic solvent in step (1) is a mixed solvent of one or more of N, N-dimethylformamide, N-dimethylacetamide and 1-methyl N-methylpyrrolidone, preferably, one or both of N, N-dimethylformamide and N, N-dimethylacetamide.
5. The production method according to any one of claims 1 to 4, wherein the amount of the ammonium salt used in step (1) is 2 to 20 times, preferably 6 to 12 times, the number of moles of (S) -1, 2-diaminopropane-tetraacetic acid or an alkali metal salt thereof;
optionally, the amount of the amide-based organic solvent used in step (1) is 2 to 8 times, preferably 4 to 6 times, the weight of (S) -1, 2-diaminopropane-tetraacetic acid or its alkali metal salt.
6. The production method according to any one of claims 1 to 4, wherein the reaction temperature of the cyclization reaction in step (1) is 130 ℃ to 200 ℃, preferably 145 ℃ to 156 ℃; optionally, the cyclization reaction is carried out at the reflux temperature of the amide organic solvent;
optionally, the reaction time of the cyclization reaction in the step (1) is 5 to 48 hours, preferably 8 to 16 hours.
7. The production method according to any one of claims 1 to 4, wherein the cyclization reaction in step (1) is carried out in a reaction apparatus equipped with a water separator which separates a reflux.
8. The production method according to any one of claims 1 to 4, wherein the amount of the purified water used in step (2) is 1 to 15 times, preferably 2 to 6 times, the weight of (S) -1, 2-diaminopropane-tetraacetic acid or an alkali metal salt thereof.
9. The preparation method according to any one of claims 1 to 4, wherein the refining comprises recrystallization, and then filtering and drying to obtain pure dexrazoxane.
CN201911076403.3A 2019-11-06 2019-11-06 Preparation method of dexrazoxane Pending CN110804022A (en)

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CN110804022A true CN110804022A (en) 2020-02-18

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