CN105348358A - Preparation method for dexamethasone sodium phosphate - Google Patents
Preparation method for dexamethasone sodium phosphate Download PDFInfo
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- CN105348358A CN105348358A CN201510758961.3A CN201510758961A CN105348358A CN 105348358 A CN105348358 A CN 105348358A CN 201510758961 A CN201510758961 A CN 201510758961A CN 105348358 A CN105348358 A CN 105348358A
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- dexamethasone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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Abstract
The invention relates to a preparation method for dexamethasone sodium phosphate. The preparation method comprises the following steps: a ring-opening reaction is carried out, namely, dexamethasone acetate epoxide is employed as an initial raw material, HF and DMF are added, a reaction is performed for 3h, a ring-opening reaction is carried out and a dexamethasone acetate solution is prepared; recrystallization is carried out, namely, methanol is added in the dexamethasone acetate solution, recrystallization is carried out, and dexamethasone acetate is prepared; base catalysis hydrolysis is carried out, namely, dexamethasone acetate is added in Na2CO3 and methanol, a reaction is carried out for 10min, dexamethasone is prepared; pyrophosphoryl chlorine esterification is carried out, namely, dexamethasone prepared in the third step is reacted with pyrophosphoryl chlorine and THF, and dexamethasone phosphate ester is prepared; a neutralization salt forming reaction is carried out, namely, the dexamethasone phosphate ester obtainedin the fourth step is reacted with NaOH and methanol at a reaction temperature of 20 DEG C-30 DEG C for 1h, and dexamethasone sodium phosphate is prepared. The steps are simple, raw materials are easily available, the reaction conditions are mild, the method is suitable for industrial production, and the cost is low.
Description
Technical field
The present invention relates to medical art, particularly, relate to a kind of preparation method of dexamethasone sodium phosphate.
Background technology
Dexamethasone sodium phosphate, chemistry 16 Alpha-Methyl-11 β, 17 α by name, 21 trihydroxy--9 α-pregna-fluoride-Isosorbide-5-Nitrae-diene-3,20-diketone-21-organic phosphate disodium salt, be a kind of Aeroseb-Dex, there is anti-inflammatory, antianaphylaxis, rheumatism, immunosuppressive action.The mechanism of action is: (1) anti-inflammatory action: can alleviate and prevent tissue to the reaction of inflammation, thus the performance reduced inflammation.Can inflammation-inhibiting cell, comprise scavenger cell and white corpuscle gathering at inflammation part, and suppress phagolysis, the synthesis of lysosomal release and inflammation chemistry intermediary and release.(2) immunosuppressive action: comprise prevent or T suppression cell mediation immune response, the anaphylaxis of retardance, reduce the number of T lymphocyte, monocyte, eosinophil, reduce the binding ability of immunoglobulin (Ig) and cell surface receptor, and suppress synthesis and the release of interleukin, thus reduce T lymphocyte to lymphocyte transformation, and alleviate and formerly send out expansion immunoreactive.Also can reduce immunity and check thing by basilar membrane, and the concentration of complement component and immunoglobulin (Ig) can be reduced.
Dexamethasone sodium phosphate is mainly used in supersensitivity and auto-immune inflammatory disease, be used for connective tissue disease (CTD), reactivity rheumatosis, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, ulcerative colitis, acute leukemia etc., also for some severe infections and poisoning.The complex therapy of malignant lymphoma.Within 1 hour after intramuscular injection, blood peak concentration of drug can be reached, and its plasma protein binding ratio is low compared with other corticosteroids medicine, therefore clinical its injection liquid inhibitor conventional.
Preparation method's complex process of existing dexamethasone sodium phosphate, cost are higher.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of a kind of technique dexamethasone sodium phosphate simple, with low cost.
The present invention's adopted technical scheme that solves the problem is: a kind of preparation method of dexamethasone sodium phosphate, comprises the following steps:
1), ring-opening reaction: with dexamethasone acetate epoxy material for starting raw material, add HF, DMF, temperature of reaction is-10 DEG C ~ 0 DEG C, and reaction times 3h carries out ring-opening reaction and obtains dexamethasone acetate solution;
2), recrystallization: add methyl alcohol and carry out recrystallization and obtain dexamethasone acetate in dexamethasone acetate solution;
3), alkali catalyzed hydrolysis: by step 2) dexamethasone acetate that obtains joins Na
2cO
3with in methyl alcohol, temperature of reaction 20 DEG C ~ 30 DEG C, obtains dexamethasone after reaction times 10min;
4), pyrophosphoryl chloride esterification: dexamethasone step 3) obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate;
5), be neutralized into reactant salt: dexamethasone phosphate step 4) obtained and NaOH, methyl alcohol react, temperature of reaction 20 DEG C ~ 30 DEG C, the reaction times, 1h obtained dexamethasone sodium phosphate.
Reagent used in the present invention is available reagent, and wherein HF is hydrofluoric acid, and DMF is dimethyl formamide, and the step that the present invention prepares dexamethasone sodium phosphate is simple, and raw material is easy to get, and reaction conditions is gentle, is suitable for suitability for industrialized production, and with low cost.
Further, in step 1), the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1 ~ 2:92 ~ 95:44 ~ 50.
Further, dexamethasone acetate, Na in step 3)
2cO
3, methyl alcohol mol ratio be 1 ~ 2:4 ~ 8:214 ~ 220.
Further, in step 4), the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1 ~ 3:5 ~ 8:19 ~ 25.
Further, in step 5), the mol ratio of dexamethasone phosphate, NaOH, methyl alcohol is 1 ~ 2:2 ~ 5:169 ~ 175.
To sum up, the invention has the beneficial effects as follows:
The step that the present invention prepares dexamethasone sodium phosphate is simple, and raw material is easy to get, and reaction conditions is gentle, is suitable for suitability for industrialized production, and with low cost.
Embodiment
Below in conjunction with embodiment, to the detailed description further of invention do, but embodiments of the present invention are not limited thereto.
Embodiment 1:
A preparation method for dexamethasone sodium phosphate, comprises the following steps:
1), ring-opening reaction: with dexamethasone acetate epoxy material for starting raw material, add HF, DMF, temperature of reaction is-10 DEG C, and reaction times 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1:92:44;
2), recrystallization: add methyl alcohol and carry out recrystallization and obtain dexamethasone acetate in dexamethasone acetate solution;
3), alkali catalyzed hydrolysis: by step 2) dexamethasone acetate that obtains joins Na
2cO
3with in methyl alcohol, temperature of reaction 20 DEG C, obtains dexamethasone after reaction times 10min, dexamethasone acetate, Na
2cO
3, methyl alcohol mol ratio be 1:4:214;
4), pyrophosphoryl chloride esterification: dexamethasone step 3) obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, and the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1:5:19;
5), be neutralized into reactant salt: dexamethasone phosphate step 4) obtained and NaOH, methyl alcohol react, temperature of reaction 20 DEG C, and the reaction times, 1h obtained dexamethasone sodium phosphate, the mol ratio of dexamethasone phosphate, NaOH, methyl alcohol is 1:2:169.
Embodiment 2:
A preparation method for dexamethasone sodium phosphate, comprises the following steps:
1), ring-opening reaction: with dexamethasone acetate epoxy material for starting raw material, add HF, DMF, temperature of reaction is-5 DEG C, and reaction times 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1.5:94:48;
2), recrystallization: add methyl alcohol and carry out recrystallization and obtain dexamethasone acetate in dexamethasone acetate solution;
3), alkali catalyzed hydrolysis: by step 2) dexamethasone acetate that obtains joins Na
2cO
3with in methyl alcohol, temperature of reaction 25 DEG C, obtains dexamethasone after reaction times 10min, dexamethasone acetate, Na
2cO
3, methyl alcohol mol ratio be 1.5:6:216;
4), pyrophosphoryl chloride esterification: dexamethasone step 3) obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, and the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 2:6:22;
5), be neutralized into reactant salt: dexamethasone phosphate step 4) obtained and NaOH, methyl alcohol react, temperature of reaction 25 DEG C, and the reaction times, 1h obtained dexamethasone sodium phosphate, the mol ratio of dexamethasone phosphate, NaOH, methyl alcohol is 1.5:4:173.
Embodiment 3:
A preparation method for dexamethasone sodium phosphate, comprises the following steps:
1), ring-opening reaction: with dexamethasone acetate epoxy material for starting raw material, add HF, DMF, temperature of reaction is 0 DEG C, and reaction times 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 2:95:50;
2), recrystallization: add methyl alcohol and carry out recrystallization and obtain dexamethasone acetate in dexamethasone acetate solution;
3), alkali catalyzed hydrolysis: by step 2) dexamethasone acetate that obtains joins Na
2cO
3with in methyl alcohol, temperature of reaction 30 DEG C, obtains dexamethasone after reaction times 10min, dexamethasone acetate, Na
2cO
3, methyl alcohol mol ratio be 2:8:220;
4), pyrophosphoryl chloride esterification: dexamethasone step 3) obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, and the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 3:8:25;
5), be neutralized into reactant salt: dexamethasone phosphate step 4) obtained and NaOH, methyl alcohol react, temperature of reaction 30 DEG C, and the reaction times, 1h obtained dexamethasone sodium phosphate, the mol ratio of dexamethasone phosphate, NaOH, methyl alcohol is 2:5:175.
As mentioned above, the present invention can be realized preferably.
Claims (5)
1. a preparation method for dexamethasone sodium phosphate, is characterized in that, comprises the following steps:
1), ring-opening reaction: with dexamethasone acetate epoxy material for starting raw material, add HF, DMF, temperature of reaction is-10 DEG C ~ 0 DEG C, and reaction times 3h carries out ring-opening reaction and obtains dexamethasone acetate solution;
2), recrystallization: add methyl alcohol and carry out recrystallization and obtain dexamethasone acetate in dexamethasone acetate solution;
3), alkali catalyzed hydrolysis: by step 2) dexamethasone acetate that obtains joins Na
2cO
3with in methyl alcohol, temperature of reaction 20 DEG C ~ 30 DEG C, obtains dexamethasone after reaction times 10min;
4), pyrophosphoryl chloride esterification: dexamethasone step 3) obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate;
5), be neutralized into reactant salt: dexamethasone phosphate step 4) obtained and NaOH, methyl alcohol react, temperature of reaction 20 DEG C ~ 30 DEG C, the reaction times, 1h obtained dexamethasone sodium phosphate.
2. the preparation method of a kind of dexamethasone sodium phosphate according to claim 1, is characterized in that, in step 1), the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1 ~ 2:92 ~ 95:44 ~ 50.
3. the preparation method of a kind of dexamethasone sodium phosphate according to claim 1, is characterized in that, dexamethasone acetate, Na in step 3)
2cO
3, methyl alcohol mol ratio be 1 ~ 2:4 ~ 8:214 ~ 220.
4. the preparation method of a kind of dexamethasone sodium phosphate according to claim 1, is characterized in that, in step 4), the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1 ~ 3:5 ~ 8:19 ~ 25.
5. the preparation method of a kind of dexamethasone sodium phosphate according to claim 1, is characterized in that, in step 5), the mol ratio of dexamethasone phosphate, NaOH, methyl alcohol is 1 ~ 2:2 ~ 5:169 ~ 175.
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| CN201510758961.3A CN105348358A (en) | 2015-11-10 | 2015-11-10 | Preparation method for dexamethasone sodium phosphate |
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| CN201510758961.3A CN105348358A (en) | 2015-11-10 | 2015-11-10 | Preparation method for dexamethasone sodium phosphate |
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| CN105348358A true CN105348358A (en) | 2016-02-24 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110964075A (en) * | 2018-09-30 | 2020-04-07 | 天津药业研究院有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
-
2015
- 2015-11-10 CN CN201510758961.3A patent/CN105348358A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110964075A (en) * | 2018-09-30 | 2020-04-07 | 天津药业研究院有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
| CN110964075B (en) * | 2018-09-30 | 2022-09-06 | 天津药业研究院股份有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
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Application publication date: 20160224 |