CN110964075A - Preparation method of betamethasone phosphate and sodium salt thereof - Google Patents
Preparation method of betamethasone phosphate and sodium salt thereof Download PDFInfo
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- CN110964075A CN110964075A CN201811171039.4A CN201811171039A CN110964075A CN 110964075 A CN110964075 A CN 110964075A CN 201811171039 A CN201811171039 A CN 201811171039A CN 110964075 A CN110964075 A CN 110964075A
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- Prior art keywords
- betamethasone
- phosphate
- sodium
- preparation
- reaction
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- 229950006991 betamethasone phosphate Drugs 0.000 title claims abstract description 64
- VQODGRNSFPNSQE-DVTGEIKXSA-N betamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-DVTGEIKXSA-N 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 159000000000 sodium salts Chemical class 0.000 title abstract description 7
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 claims abstract description 47
- 229960005354 betamethasone sodium phosphate Drugs 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 27
- 229960002537 betamethasone Drugs 0.000 claims abstract description 15
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 11
- -1 organic acid sodium salt Chemical class 0.000 claims abstract description 10
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 230000026731 phosphorylation Effects 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 25
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- FVNIMHIOIXPIQT-UHFFFAOYSA-N 2-methoxybutane Chemical compound CCC(C)OC FVNIMHIOIXPIQT-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004280 Sodium formate Substances 0.000 claims description 5
- CNTIXUGILVWVHR-UHFFFAOYSA-N diphosphoryl chloride Chemical compound ClP(Cl)(=O)OP(Cl)(Cl)=O CNTIXUGILVWVHR-UHFFFAOYSA-N 0.000 claims description 5
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 5
- 235000019254 sodium formate Nutrition 0.000 claims description 5
- JCRQEORWPZVZJP-UHFFFAOYSA-N 1,3-dimethoxybutane Chemical compound COCCC(C)OC JCRQEORWPZVZJP-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- OXQHJIGWZNIQDS-UHFFFAOYSA-N 2,2-dimethoxybutane Chemical compound CCC(C)(OC)OC OXQHJIGWZNIQDS-UHFFFAOYSA-N 0.000 claims description 3
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 3
- AFSYRVDDZGJTIL-UHFFFAOYSA-N oxydibutanol Chemical compound CC(O)CCOCCC(C)O AFSYRVDDZGJTIL-UHFFFAOYSA-N 0.000 claims description 3
- 229950009157 oxydibutanol Drugs 0.000 claims description 3
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- QNJRNZBXNCPKHQ-UHFFFAOYSA-N 3-methoxyhexane Chemical compound CCCC(CC)OC QNJRNZBXNCPKHQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 62
- 238000001035 drying Methods 0.000 abstract description 26
- 238000001914 filtration Methods 0.000 abstract description 21
- 239000000047 product Substances 0.000 abstract description 14
- 239000012065 filter cake Substances 0.000 abstract description 13
- 238000005406 washing Methods 0.000 abstract description 9
- 238000010438 heat treatment Methods 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 238000004134 energy conservation Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- 239000000243 solution Substances 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 206010040560 shock Diseases 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
Abstract
The invention provides a preparation method of betamethasone phosphate and a sodium salt thereof, which comprises the following steps: taking betamethasone as an initial material, carrying out phosphorylation reaction with a phosphorylation reagent at low temperature to prepare betamethasone phosphate, dissolving the betamethasone phosphate in a mixed organic solvent, and heating for reaction to obtain a refined product of the betamethasone phosphate. Reacting the obtained betamethasone phosphate with organic acid sodium salt in a reaction solvent to obtain betamethasone sodium phosphate, filtering, and washing a filter cake by a crystallization solvent. The method has the advantages of good product properties, good quality, less impurities, high yield, low product moisture, easiness in drying and good stability. The method has the advantages of simple process, short steps, cheap and easily obtained reaction raw materials, greenness and energy conservation.
Description
Technical Field
The invention relates to a synthetic process method of a raw material medicine, in particular to a synthetic process method of betamethasone phosphate and sodium thereof.
Background
The Betamethasone Sodium Phosphate (Betamethasone Sodium Phosphate) has the chemical name of 9 α -fluoro-16 β -methyl-11 β,17 α, 21-trihydroxy-1, 4-pregnadiene-3, 20-diketone-21-disodium Phosphate, is a water-soluble derivative of glucocorticoid Betamethasone, has the same effect as Betamethasone, is an excellent anti-inflammatory drug, has the characteristics of high efficacy (the anti-inflammatory effect is 40-50 times of hydrocortisone), quick response and small side effect, can improve the body function in a short time, is particularly suitable for emergency treatment of critical diseases, belongs to one of main products of intermediate-effect steroid hormone drugs, and can be mainly prepared into injections for intravenous injection, intramuscular injection, joint cavity injection or soft tissue injection, and is suitable for emergency treatment of shock and shock-like symptoms caused by serious infection and operation.
Chinese pharmacopoeia 2015 records betamethasone sodium phosphate as white or quasi-white powder; no or almost no odor; it has hygroscopicity. Under examination item [ moisture ] 0.2g of the product was collected and measured by moisture measurement method (first method 1 of 0832, general rule) until the moisture content was not more than 8.0%.
The currently reported synthetic routes of betamethasone sodium phosphate are as follows:
route 1 US patent 3564028 reports the preparation of betamethasone sodium phosphate as follows:
the route takes betamethasone as a raw material, 21-iodide is prepared by mesylation and iodination reaction, so that phosphate esterification is indirectly performed, and then salification is performed to obtain betamethasone sodium phosphate. The route has the disadvantages of long steps, low yield, complex operation and unstable product quality.
Route 2 chinese patent CN101397319A reports the preparation method of betamethasone sodium phosphate as follows:
the route is a common route at present, but inorganic base is adopted for salifying, water is easily generated in the reaction process, sodium salt has hygroscopicity, materials are not easy to dry, and the water content of products is easily unqualified.
In the prior art, the preparation of betamethasone phosphate is directly separated out from a water phase, in particular from a water phase/organic phase mixed system. The betamethasone phosphate ester has large impurity and high water content, which is about 5-8%.
In the preparation process of betamethasone sodium phosphate, inorganic sodium salt is used as a reaction reagent in the one-step salifying prior art, the betamethasone sodium phosphate has strong hygroscopicity and is not easy to dry, and the betamethasone sodium phosphate bulk drug prepared by using inorganic base has high water content, does not meet pharmacopoeia standards and is not easy to store. And the inventor discovers through a large number of experiments that betamethasone sodium phosphate is prepared by adopting inorganic bases such as sodium hydroxide and sodium bicarbonate, equivalent water is generated in the reaction, the water content is higher by about 10-15%, and the betamethasone sodium phosphate is not easy to dry and remove. The betamethasone sodium phosphate is unstable and easy to degrade under the high-temperature condition, and the stability of the product can be influenced by high-temperature long-time drying, so that the key point is to find a preparation method which is mild and does not generate water.
Disclosure of Invention
The invention aims to provide a novel method for preparing betamethasone sodium phosphate bulk drug by using betamethasone as a raw material, and the obtained product has good properties, good quality, less impurity content, high yield, low product moisture, easy drying and good stability.
The invention also provides a preparation method of the betamethasone phosphate. The inventor discovers that after betamethasone phosphate is treated by adopting a poor mixed solvent, the quality of the betamethasone phosphate is greatly improved, related substances of the betamethasone phosphate are controlled to be below 0.10%, the appearance and properties of the phosphate are improved, the phosphate is changed from powder to granular crystal, and the moisture of the betamethasone phosphate is reduced to be below 2%.
The invention also provides a preparation method of the betamethasone sodium phosphate, and the inventor effectively reduces the generation of impurities and moisture in the finished betamethasone sodium phosphate product by using the organic acid sodium salt as a reagent.
The technical scheme of the invention is as follows:
a preparation method of betamethasone phosphate comprises the following steps: taking betamethasone as an initiator, carrying out phosphorylation reaction with a phosphorylation reagent in a reaction solvent at-80 to-20 ℃ to prepare betamethasone phosphate, and recrystallizing the betamethasone phosphate in a mixed organic solvent to obtain a refined product of the betamethasone phosphate;
a preparation method of betamethasone sodium phosphate comprises the following steps: the betamethasone phosphate obtained in the previous step is used as an initial raw material and reacts with organic acid sodium salt in a reaction solvent to obtain betamethasone sodium phosphate.
In the preparation method of the betamethasone phosphate, the phosphorylation reagent is selected from one of phosphorus pentoxide, phosphorus oxychloride, polyphosphoric acid and pyrophosphoryl chloride, and the phosphorus oxychloride or the pyrophosphoryl chloride is preferably selected.
In the preparation method of the betamethasone phosphate, the molar ratio of the dosage of the phosphorylation reagent to the betamethasone is 0.4-1.0, preferably 0.6-0.8.
In the preparation method of the betamethasone phosphate, the temperature of the phosphorylation reaction is-40 ℃ to-20 ℃.
In the preparation method of the betamethasone phosphate, the reaction solvent is selected from solvents such as acetone, diethyl ether, methyl tetrahydrofuran, dioxane and the like, and tetrahydrofuran or acetone is preferred.
In the preparation method of the betamethasone phosphate, the mass-to-volume ratio (g/ml) of the reaction solvent dosage to the betamethasone is 1: 8-15.
In the preparation method of the betamethasone phosphate, the following steps are carried out: the mixed organic solvent is a mixed solvent of ethers and alkanes, the ethers are selected from methyl tert-butyl ether, methyl sec-butyl ether and dihydroxydibutyl ether, and the alkanes are selected from oxygenated alkanes, 1, 2-dimethoxyethane, 1, 2-methoxybutylethane, 1, 3-dimethoxybutane and 2, 2-dimethoxybutane.
In the preparation method of the betamethasone phosphate, the dosage of the mixed organic solvent is that according to the mass volume ratio w/v (g/ml) of the betamethasone phosphate and the mixed organic solvent, the weight is 1: 5-20, preferably 1: 10 to 15.
The volume ratio of the ether reagent to the alkane reagent is 1: 1-10, preferably 1: 1 to 5.
In the preparation method of the betamethasone phosphate, the recrystallization temperature is 40-50 ℃.
In the preparation method of the betamethasone sodium phosphate, the organic acid sodium salt is selected from one of sodium formate, sodium acetate, sodium butyrate and sodium isooctanoate, and sodium acetate is preferably selected.
In the preparation method of the betamethasone sodium phosphate, the amount of the organic acid sodium salt is 1.0-1.5, preferably 1.0-1.1, according to the molar ratio of the organic acid sodium salt to the betamethasone phosphate.
In the preparation method of betamethasone sodium phosphate, the reaction solvent is selected from methanol, ethanol, tetrahydrofuran, acetonitrile, dioxane and the like, and preferably methanol.
In the preparation method of the betamethasone sodium phosphate, the dosage of the reaction solvent is that the mass-volume ratio w/v of the mass of the betamethasone phosphate and the reaction solvent is 1: 5-20, preferably 1: 5-10.
The preparation method of the betamethasone sodium phosphate further comprises a crystallization step, wherein the crystallization solvent is ethanol, isopropanol, acetone, isopropyl ether and the like, and ethanol or acetone is preferred. The dosage of the solvent is that the mass volume ratio w/v of betamethasone sodium phosphate to the solvent is 1: 5-20, preferably 1: 5-10.
In the preparation method of betamethasone sodium phosphate, the reaction temperature is 10-50 ℃, and preferably 20-30 ℃.
According to the technical scheme, after the betamethasone phosphate is treated by the mixed solvent, the quality of the betamethasone phosphate is greatly improved, related substances of the betamethasone phosphate are controlled to be below 0.10%, the appearance and properties of the phosphate are improved, the phosphate is converted into granular crystals from powder, and the moisture of the betamethasone phosphate is reduced to 1-2%.
At present, betamethasone sodium phosphate is salified by inorganic sodium salts such as sodium hydroxide and the like, equivalent water is generated in the reaction, the betamethasone sodium phosphate is not easy to dry and remove, and the water content is higher. Through a large number of experiments, the inventor discovers that the sodium salt of the organic acid is adopted to replace the conventional inorganic base to prepare the betamethasone sodium phosphate, the reaction condition is mild, impurities are not generated basically, the yield is high, water is not generated in the reaction process, qualified products can be obtained by low-temperature short-time drying, and the problems that the betamethasone sodium phosphate is not easy to dry and the water is not easy to qualify are solved; the product has good properties, good quality, less impurities, high yield, low water content, easy drying and good stability. And the method has the advantages of simple process, short steps, cheap and easily obtained reaction raw materials, greenness and energy conservation.
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
Example 1 preparation of betamethasone phosphate
Examples 1 to 1
Adding 100mL of THF (tetrahydrofuran) and 10g of betamethasone into a reaction bottle under the protection of nitrogen, and cooling to-40 to-30 ℃. Adding 4.5g of pyrophosphoryl chloride into 10ml of THF solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-40 to-30 ℃ in the dripping process, keeping the temperature and stirring for reaction, and diluting the mixture into purified water at 0-5 ℃ after TLC (thin layer chromatography) monitoring for complete reaction. And adding sodium bicarbonate to adjust the pH value to 7-8, layering, adjusting the pH value of a water phase to 1-2 by using hydrochloric acid, filtering and drying to obtain 11.8g of a betamethasone phosphate crude product, wherein the HPLC content is 95.5%, and the water content is 5.3%. Adding the crude product into 180ml methyl tert-butyl ether/1, 2-methoxybutane (1: 2), heating to 45 deg.C, stirring under constant temperature, slowly cooling to room temperature after reaction, filtering, and drying to obtain refined betamethasone phosphate 10.36 g. HPLC content 99.9%, water 1.5%.
Examples 1 to 2
Adding 150mL of acetone and 10g of betamethasone into a reaction bottle under the protection of nitrogen, and cooling to-30 to-20 ℃. Adding 2.3g of phosphorus oxychloride into 20ml of acetone solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-30 to-20 ℃ in the dripping process, keeping the temperature, stirring for reaction, monitoring by TLC (thin layer chromatography), and diluting the mixture into purified water at 0-5 ℃. Adding sodium bicarbonate to adjust pH to 7-8, separating layers, adjusting pH of water phase to 1-2 with hydrochloric acid, filtering, and drying. Adding the filter cake into 150ml dihydroxydibutyl ether/2, 2-dimethoxybutane (1: 5), heating to 50 deg.C, stirring at 50 deg.C, slowly cooling to room temperature after reaction, filtering, and drying to obtain refined betamethasone phosphate 10.9 g. HPLC content 99.8%, water 1.6%.
Comparative examples 1 to 2
Adding 150mL of acetone and 10g of betamethasone into a reaction bottle under the protection of nitrogen, and cooling to-30 to-20 ℃. Adding 2.3g of phosphorus oxychloride into 20ml of acetone solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-30 to-20 ℃ in the dripping process, keeping the temperature, stirring for reaction, monitoring by TLC (thin layer chromatography), and diluting the mixture into purified water at 0-5 ℃. Adding sodium bicarbonate to adjust pH to 7-8, separating layers, adjusting pH of water phase to 1-2 with hydrochloric acid, filtering, and drying. Adding the filter cake into 180ml ethanol/chloroform (1: 10), heating to 50 deg.C, stirring at 50 deg.C, slowly cooling to room temperature after reaction, filtering, and drying to obtain refined betamethasone phosphate 11.7g, HPLC content 95.9%, and water content 6.5%.
Examples 1 to 3
Under the protection of nitrogen, 120mL of methyltetrahydrofuran and 10g of betamethasone are added into a reaction bottle and cooled to-60 ℃. Adding 7g of polyphosphoric acid into 30ml of methyl tetrahydrofuran solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-60 ℃ in the dripping process, keeping the temperature and stirring for reaction, and diluting the mixture into purified water at 0-5 ℃ after TLC (thin layer chromatography) monitoring reaction is completed. Adding sodium bicarbonate to adjust pH to 7-8, layering, adjusting pH of water phase to 1-2 with hydrochloric acid, filtering, and drying to obtain crude betamethasone phosphate 11.6g, HPLC content of 96.5%, and water content of 7.1%.
Adding the crude product into 200ml methyl sec-butyl ether/1, 3-dimethoxybutane (1: 10), heating to 48 deg.C, stirring at 50 deg.C, slowly cooling to room temperature after reaction, filtering, and drying to obtain refined betamethasone phosphate 11.0 g. HPLC content 99.6%, water 1.3%.
Examples 1 to 4
Adding 80mL of acetone and 10g of betamethasone into a reaction bottle under the protection of nitrogen, and cooling to-55 ℃. Adding 3.5g of pyrophosphoryl chloride into 30ml of acetone solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-55 ℃ during the dripping process, and keeping the temperature and stirring for reaction. After completion of the TLC monitoring reaction, the mixture was diluted to purified water at 0 ℃ to 5 ℃. Adding sodium bicarbonate to adjust pH to 7-8, separating layers, adjusting pH of water phase to 1-2 with hydrochloric acid, filtering, and drying. Adding the filter cake into 100ml methyl sec-butyl ether/1, 2-methoxybutane (1: 8), heating to 42 deg.C, stirring while maintaining the temperature, slowly cooling to room temperature after the reaction is finished, filtering, and drying to obtain 11.2g refined betamethasone phosphate. HPLC content 99.5%, water 1.5%.
Examples 1 to 5
Under the protection of nitrogen, 90mL of THF and 10g of betamethasone are added into a reaction bottle and cooled to-25 ℃. Adding 2.9g of phosphorus oxychloride into 40ml of THF solution, slowly dripping into a reaction bottle, keeping the temperature of the reaction solution at-25 ℃ during the dripping process, and keeping the temperature and stirring for reaction. After completion of the TLC monitoring reaction, the mixture was diluted to purified water at 0 ℃ to 5 ℃. Adding sodium bicarbonate to adjust pH to 7-8, separating layers, adjusting pH of water phase to 1-2 with hydrochloric acid, filtering, and drying. Adding the filter cake into 120ml methyl tert-butyl ether/1, 3-dimethoxybutane (1: 3), heating to 45 deg.C, stirring at 45 deg.C for 4 hr, slowly cooling to room temperature for about 4 hr, filtering, and drying to obtain refined betamethasone phosphate 11.5 g. HPLC content 99.7%, water 1.4%.
Example 2 preparation of betamethasone sodium phosphate
Example 2-1
Adding 5g of betamethasone phosphate and 30ml of methanol into a reaction bottle, stirring and dissolving, dripping a methanol solution containing 0.95g of sodium acetate at 25 ℃ until the reaction solution is neutral, continuing stirring and reacting, dripping 40ml of acetone, stirring for 2 hours, filtering, washing a filter cake with acetone, and performing forced air drying for 4-5 hours to obtain 5.45g of betamethasone sodium phosphate, wherein the water content is 1.3 percent, and the HPLC purity is 99.98 percent. Comparative example 2-1
Adding 5g of betamethasone phosphate and 30ml of methanol into a reaction bottle, stirring and dissolving, dripping a methanol solution containing 0.44g of sodium hydroxide (the molar number of the sodium acetate is the same as that of the sodium acetate in the embodiment 2-1) at 25 ℃ until the reaction solution is neutral, continuing stirring and reacting, dripping 40ml of acetone, stirring for 2 hours, filtering, washing a filter cake with the acetone, and performing forced air drying for 24 hours to obtain 6.22g of betamethasone sodium phosphate, wherein the water content is 14.2 percent, and the HPLC purity is 99.60 percent; continuously drying for 24 hours at the temperature of 40-50 ℃ to obtain 6.01g of betamethasone sodium phosphate and 11.1% of water; drying for 24h at 50-60 ℃ to obtain 5.59g of betamethasone sodium phosphate, 4.6% of water and 93.89% of HPLC purity.
Examples 2 to 2
Adding 5g of betamethasone phosphate and 50ml of ethanol into a reaction bottle, stirring for dissolving, dripping ethanol solution containing 0.76g of sodium formate at the temperature of 20 ℃ until the reaction solution is neutral, continuously stirring for reaction, dripping 70ml of isopropanol, stirring for 2 hours, filtering, washing a filter cake with the isopropanol, and drying by blowing air for 4-5 hours to obtain 5.41g of betamethasone sodium phosphate, wherein the water content is 1.5 percent, and the HPLC purity is 99.97 percent.
Comparative example 2-2
Adding 5g of betamethasone phosphate and 50ml of ethanol into a reaction bottle, stirring and dissolving, dripping ethanol solution containing 0.57g of sodium methoxide (the molar number of the sodium formate is the same as that of the sodium formate in the embodiment 2-2) at the temperature of 20 ℃ until the reaction solution is neutral, continuously stirring and reacting, dripping 70ml of isopropanol, stirring for 2 hours, filtering, washing a filter cake by the isopropanol, drying for 24 hours at the temperature of 40-50 ℃, and obtaining 5.81g of betamethasone sodium phosphate, 3.5% of water and 94.69% of HPLC purity.
Examples 2 to 3
Adding 5g of betamethasone phosphate and 90ml of THF into a reaction bottle, stirring for dissolving, dripping a THF solution containing 1.74g of sodium butyrate at 30 ℃ until the reaction solution is neutral, continuing stirring for reaction, dripping 40ml of acetone, stirring for 2 hours, filtering, washing a filter cake with acetone, and drying by blowing for 4-5 hours to obtain 5.43g of betamethasone sodium phosphate, wherein the water content is 1.6 percent, and the purity of HPLC is 99.98 percent.
Comparative examples 2 to 3
Adding 5g of betamethasone phosphate and 90ml of THF into a reaction bottle, stirring and dissolving, dripping a THF solution containing 1.25g of sodium bicarbonate (the molar number of sodium butyrate is the same as that of the embodiment 2-3) at the temperature of 30 ℃ until the reaction solution is neutral, continuing stirring and reacting, dripping 40ml of acetone, stirring for 2 hours, filtering, washing a filter cake with the acetone, drying for 24 hours at the temperature of 40-50 ℃, and obtaining 6.31g of betamethasone sodium phosphate, 14.4 percent of water and 99.38 percent of HPLC purity; after drying for 24 hours at 30 ℃ under vacuum condition, detecting 6.02g of betamethasone sodium phosphate and 10.1% of water; drying the mixture for 24 hours at 50-60 ℃ to obtain 5.68g of tamsulosin sodium phosphate, 4.7% of water and 95.68% of HPLC purity.
Examples 2 to 4
Adding 5g betamethasone phosphate and 70ml THF into a reaction bottle, stirring and dissolving, dripping THF solution containing 2.0g sodium isooctanoate at 50 ℃ until the reaction solution is neutral, continuing stirring and reacting, dripping 40ml ethanol, stirring for 2h, filtering, washing a filter cake with ethanol, and drying by blowing for 4-5h to obtain 5.42g betamethasone sodium phosphate, wherein the water content is 1.7 percent, and the HPLC purity is 99.96 percent.
Examples 2 to 5
Adding 5g of betamethasone phosphate and 50ml of methanol into a reaction bottle, stirring for dissolving, dripping a methanol solution containing 1.0g of sodium acetate at 40 ℃ until the reaction solution is neutral, continuing stirring for reaction, dripping 40ml of ethanol, stirring for 2 hours, filtering, washing a filter cake with the ethanol, and performing forced air drying for 4-5 hours to obtain 5.43g of betamethasone sodium phosphate, wherein the water content is 1.4 percent, and the purity of HPLC is 99.98 percent.
While specific embodiments of the present invention have been described in detail, the description is merely illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (10)
1. A preparation method of betamethasone phosphate is characterized by comprising the following steps: taking betamethasone as an initiator, carrying out phosphorylation reaction with a phosphorylation reagent in a reaction solvent at-80 to-20 ℃ to prepare betamethasone phosphate, and recrystallizing the betamethasone phosphate in a mixed organic solvent to obtain a refined product of the betamethasone phosphate;
2. a preparation method of betamethasone sodium phosphate is characterized by comprising the following steps: the betamethasone phosphate obtained in claim 1 is used as a starting material and reacts with organic acid sodium salt in a reaction solvent to obtain betamethasone sodium phosphate.
3. The method for preparing betamethasone phosphate according to claim 1, wherein the method comprises the following steps: the phosphorylation reagent is selected from one of phosphorus pentoxide, phosphorus oxychloride, polyphosphoric acid and pyrophosphoryl chloride.
4. The method for preparing betamethasone phosphate according to claim 1, wherein the method comprises the following steps: the mixed organic solvent is a mixed solvent of ethers and alkanes, the ethers are selected from methyl tert-butyl ether, methyl sec-butyl ether and dihydroxydibutyl ether, and the alkanes are selected from oxygenated alkanes, 1, 2-dimethoxyethane, 1, 2-methoxybutylethane, 1, 3-dimethoxybutane and 2, 2-dimethoxybutane.
5. The method for preparing betamethasone phosphate according to claim 4, wherein the method comprises the following steps: the volume ratio of the ether reagent to the alkane reagent is 1: 1 to 10.
6. The method for preparing betamethasone phosphate according to claim 4, wherein the method comprises the following steps: the dosage of the mixed organic solvent is that the mass volume ratio (g/ml) of the betamethasone phosphate to the mixed organic solvent is 1: 5 to 20.
7. The method for preparing betamethasone phosphate according to claim 1, wherein the method comprises the following steps: the temperature of recrystallization is 40-50 ℃.
8. The preparation method of betamethasone sodium phosphate according to claim 2, characterized in that: the organic acid sodium salt is selected from one of sodium formate, sodium acetate, sodium butyrate and sodium isooctanoate.
9. The preparation method of betamethasone sodium phosphate according to claim 8, wherein the preparation method comprises the following steps: the mol ratio of the organic acid sodium salt to the betamethasone phosphate is 1.0-1.5: 1.
10. the preparation method of betamethasone sodium phosphate according to claim 8, wherein the preparation method comprises the following steps: the reaction solvent is selected from methanol, ethanol, tetrahydrofuran, acetonitrile and dioxane.
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