CN118085006A - Method for large-scale preparation of budesonide - Google Patents
Method for large-scale preparation of budesonide Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 23
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 title claims abstract description 20
- 229960004436 budesonide Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- SEKYBDYVXDAYPY-ILNISADRSA-N (8s,9s,10r,11s,13s,14s,16r,17s)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 SEKYBDYVXDAYPY-ILNISADRSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- 238000001291 vacuum drying Methods 0.000 claims description 20
- 239000008367 deionised water Substances 0.000 claims description 17
- 229910021641 deionized water Inorganic materials 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 239000013078 crystal Substances 0.000 claims description 16
- 238000000967 suction filtration Methods 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012286 potassium permanganate Substances 0.000 claims description 8
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000003287 bathing Methods 0.000 claims description 4
- LJAOOBNHPFKCDR-UHFFFAOYSA-K chromium(3+) trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cr+3] LJAOOBNHPFKCDR-UHFFFAOYSA-K 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 230000000052 comparative effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
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- 239000007858 starting material Substances 0.000 description 2
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
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- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
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- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
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- Steroid Compounds (AREA)
Abstract
The present disclosure provides a process for the large-scale preparation of budesonide, characterized in that it comprises the steps of: (1) Deriving from a compound of formula I16 α,17 α, 21-trihydroxybstae-1, 4,9 (11) -triene-3, 20-dione-21-acetate; (2) Deriving 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4,9 (11) -triene-3, 20-dione-21-acetate from 16α,17α, 21-trihydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (1) above; (3) Deriving from 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (2) above to obtain 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate; (4) Deriving 16α -hydroxyprednisolone from 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (3) above; and (5) obtaining budesonide from 16 alpha-hydroxy prednisolone obtained in the step (4).
Description
Technical Field
The present disclosure relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for large-scale preparation of budesonide.
Background
Budesonide is widely used as a glucocorticoid with high-efficiency local anti-inflammatory effect, can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune response and reduce antibody synthesis, thereby reducing the release and activity of allergic active mediums such as histamine and the like, and can alleviate enzymatic processes excited during antigen-antibody binding, inhibit synthesis and release of bronchoconstrictor substances and alleviate contraction response of smooth muscle. Clinically used for patients with glucocorticoid dependent or independent bronchial asthma and asthmatic chronic bronchitis.
The method for preparing budesonide in the prior art has the defects of low yield and poor safety, and is difficult to realize large-scale production and needs to be solved.
Disclosure of Invention
In order to solve the problems, the present disclosure provides a novel method for synthesizing budesonide, which has the advantages of high yield, safety, reliability and mass production.
In particular, a first aspect of the present disclosure provides a process for the large-scale preparation of budesonide comprising the steps of:
(1) Deriving from a compound of formula I16 α,17 α, 21-trihydroxybstae-1, 4,9 (11) -triene-3, 20-dione-21-acetate;
(2) Deriving 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4,9 (11) -triene-3, 20-dione-21-acetate from 16α,17α, 21-trihydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (1) above;
(3) Deriving from 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (2) above to obtain 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate;
(4) Deriving 16α -hydroxyprednisolone from 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (3) above; and
(5) And (3) deriving budesonide from the 16 alpha-hydroxy prednisolone obtained in the step (4).
In a preferred embodiment, the step (1) comprises:
In a reaction vessel, 100g of raw material compound 1, 2L of dimethyl sulfoxide and 50ml of formic acid are sequentially added, after stirring for 0.5h at room temperature, the temperature is raised to 40 ℃ and 2.4L of potassium permanganate solution (prepared by mixing potassium permanganate and water according to the weight ratio of 1:20) is added dropwise, after the dropwise addition is completed for 0.5h, the reaction is carried out for 1h, then the reaction vessel is cooled to room temperature and 1L of saturated sodium bisulfite solution is added for quenching reaction, then after 80% of solvent is removed by reduced pressure distillation, 200ml of diethyl ether is added and ice bath is carried out for 2h, a large amount of white solid is precipitated, and 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate is obtained after suction filtration and vacuum drying.
In a preferred embodiment, the step (2) comprises:
In a reaction vessel, 100g of the 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate, 70g of N-bromosuccinimide, 2L of dimethyl sulfoxide, 500ml of 1.0mol/L perchloric acid aqueous solution and 500ml of deionized water are sequentially added, the temperature is raised to 40 ℃ and the reaction solution is reacted for 1 hour, saturated sodium bicarbonate solution is used for neutralizing the reaction solution to be neutral, then the solvent of 40% is distilled off under reduced pressure, 100ml of diethyl ether is added and the ice bath is carried out for 2 hours, a large amount of crystals are separated out, and the 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate is obtained after suction filtration and vacuum drying.
In a preferred embodiment, the step (3) comprises:
In a reaction vessel, sequentially adding 100g of 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy pregna-1, 4-diene-3, 20-dione-21-acetate, 30ml of thioglycolic acid and 300ml of dimethyl sulfoxide, fully stirring, sequentially adding 200ml of acetone, 3g of chromium trichloride hexahydrate and 20g of zinc powder, heating to 40 ℃ and reacting for 1h, decompressing and distilling to remove 60% of solvent, adding 500ml of deionized water and 100ml of diethyl ether, ice-bathing for 2h, precipitating a large amount of crystals, filtering, and vacuum-drying to obtain 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy pregna-1, 4-diene-3, 20-dione-21-acetate.
In a preferred embodiment, the step (4) comprises:
In a reaction vessel, 100g of 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate, 1L of methanol and 1L of dichloromethane are sequentially added, after the mixture is fully stirred, 200mL of aqueous sodium hydroxide solution (prepared by mixing sodium hydroxide and water according to the weight ratio of 1:20) is dropwise added, the temperature is raised to 40 ℃ and the mixture reacts for 1h, 4mL of glacial acetic acid is added to neutralize the reaction solution, 60% of solvent is removed by reduced pressure distillation, 500mL of deionized water and 100mL of diethyl ether are added to the remainder and ice bath is carried out for 2h, a large amount of crystals are separated out, and the 16 alpha-hydroxy prednisolone is obtained after suction filtration and vacuum drying.
In a preferred embodiment, said step (5) comprises:
In a reaction vessel, 90g of 16 alpha-hydroxy prednisolone, 1L of acetonitrile and 1L of dichloromethane are sequentially added, after full stirring, 36ml of n-butyraldehyde and 0.8L of 9.5mol/L hydrochloric acid are sequentially added, after stirring and reacting for 1h at room temperature, 500ml of deionized water are added, liquid separation is carried out, the aqueous phase is extracted by dichloromethane (1L multiplied by 2), organic phases are combined, after 80% of solvent is distilled off under reduced pressure, 1L of methanol and 200ml of diethyl ether are added, then the temperature is raised to 50 ℃ until the solution is clear and transparent, then ice bath is carried out rapidly for 2h, a large amount of crystals are separated out, and budesonide is obtained after suction filtration and vacuum drying.
A second aspect of the present disclosure provides budesonide prepared by the process of the first aspect described above.
The above as well as additional features, aspects, and advantages of the present application will become more readily apparent with reference to the following detailed description.
Detailed description of the preferred embodiments
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification, definitions, will control.
All percentages, parts, ratios, etc. are by weight unless otherwise specified.
The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
When an amount, part by weight, or other numerical value or parameter is given as either a range, preferred range, or a series of upper preferable values and lower preferable values, it is understood that all ranges formed from any larger range limit or preferred value and any smaller range limit or preferred value, whether or not the ranges are separately disclosed. For example, when a range of "1 to 5" is described, the described range should be understood to include a range of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. Where a range of values is described herein, unless otherwise stated, the range is intended to include the range endpoints and all integers and fractions within the range.
Furthermore, the indefinite articles "a" and "an" preceding an element or component of the present disclosure are intended to mean that the element or component is present (i.e., occurs) no limitation on the number of times. Thus, "a" or "an" is to be understood to include one or at least one of the elements or components in the singular, unless the amount is explicitly stated as being the singular, the plural as well.
Unless specifically stated otherwise, the materials, methods, and examples described herein are illustrative only and not intended to be limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described herein.
The present disclosure is described in detail below.
Examples
Raw materials
All starting materials were purchased from the company of the chemical industry development of tzerland (Shanghai) (TCI SHANGHAI), wherein starting material compound 1 is a compound of the following formula I:
example 1
A process for preparing budesonide comprising the steps of:
1) Preparation of 16α,17α, 21-Trihydroxypregna-1, 4,9 (11) -trien-3, 20-dione-21-acetate
Sequentially adding 100g of raw material compounds 1 and 2L of dimethyl sulfoxide and 50ml of formic acid into a reaction container, stirring at room temperature for 0.5h, heating to 40 ℃ and dropwise adding 2.4L of potassium permanganate solution (prepared by mixing potassium permanganate and water according to a weight ratio of 1:20), reacting for 1h after the dropwise adding is completed within 0.5h, cooling to room temperature, adding 1L of saturated sodium bisulfite solution, quenching reaction, then distilling under reduced pressure to remove 80% of solvent, adding 200ml of diethyl ether, ice-bathing for 2h, precipitating a large amount of white solid, filtering, and vacuum-drying to obtain 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate (yield 95.2%);
2) Preparation of 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate
In a reaction vessel, adding 100g of the 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate, 70g of N-bromosuccinimide, 2L of dimethyl sulfoxide, 500ml of 1.0mol/L perchloric acid aqueous solution and 500ml of deionized water in turn, heating to 40 ℃ and reacting for 1h, neutralizing the reaction solution with saturated sodium bicarbonate solution to be neutral, then distilling under reduced pressure to remove 40% of solvent, adding 100ml of diethyl ether and ice-bath for 2h, precipitating a large amount of crystals, filtering and vacuum-drying to obtain 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate (yield 96.8%);
3) Preparation of 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate
Sequentially adding 100g of 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate, 30ml of thioglycolic acid and 300ml of dimethyl sulfoxide into a reaction vessel, fully stirring, sequentially adding 200ml of acetone, 3g of chromium trichloride hexahydrate and 20g of zinc powder, heating to 40 ℃ and reacting for 1h, decompressing and distilling to remove 60% of solvent, adding 500ml of deionized water and 100ml of diethyl ether, ice-bathing for 2h, precipitating a large amount of crystals, filtering, and vacuum-drying to obtain 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate (yield is 85.7%);
4) Preparation of 16 alpha-hydroxy prednisolone
Sequentially adding 100g of 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate, 1L of methanol and 1L of dichloromethane into a reaction vessel, fully stirring, dropwise adding 200mL of sodium hydroxide aqueous solution (prepared by mixing sodium hydroxide and water according to the weight ratio of 1:20), heating to 40 ℃ and reacting for 1h, adding 4mL of glacial acetic acid to neutralize the reaction solution, carrying out reduced pressure distillation to remove 60% of solvent, adding 500mL of deionized water and 100mL of diethyl ether into the remainder and carrying out ice bath for 2h, precipitating a large amount of crystals, carrying out suction filtration and vacuum drying to obtain 16 alpha-hydroxy prednisolone (yield 94.4%);
5) Preparation of budesonide
In a reaction vessel, 90g of 16 alpha-hydroxy prednisolone, 1L of acetonitrile and 1L of dichloromethane are sequentially added, after full stirring, 36ml of n-butyraldehyde and 0.8L of 9.5mol/L of hydrochloric acid are sequentially added, stirring is carried out at room temperature for reaction for 1h, 500ml of deionized water is added, liquid separation is carried out, the aqueous phase is extracted by dichloromethane (1L multiplied by 2), the organic phases are combined, 80% of solvent is removed by reduced pressure distillation, 1L of methanol and 200ml of diethyl ether are added, then the temperature is raised to 50 ℃ until the solution is clear and transparent, then ice bath is carried out rapidly, a large amount of crystals are separated out, and the budesonide (yield is 97.7%) is obtained after suction filtration and vacuum drying.
Comparative example 1
Substantially the same as in example 1, except that step 1) was as follows:
In a reaction vessel, 100g of raw material compound 1, 2L of acetone and 50ml of formic acid are sequentially added, after stirring for 0.5h at room temperature, 2.4L of potassium permanganate solution (prepared by mixing potassium permanganate and water according to the weight ratio of 1:20) is dropwise added, after the dropwise addition is completed within 0.5h, the reaction is carried out for 1h again, then the reaction vessel is cooled to room temperature, 1L of saturated sodium bisulfite solution is added for quenching reaction, after 80% of solvent is removed by reduced pressure distillation for 2h in an ice bath, a large amount of white solid is separated out, and 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate (yield 88.2%) is obtained after suction filtration and vacuum drying
Comparative example 2
Substantially the same as in example 1, except that step 2) was as follows:
In a reaction vessel, 100g of the above 16 alpha, 17 alpha, 21-trihydroxybis-1, 4,9 (11) -triene-3, 20-dione-21-acetate, 70g of N-bromosuccinimide, 2L of dimethyl sulfoxide, 500ml of 1.0mol/L perchloric acid aqueous solution and 500ml of deionized water were sequentially added, the temperature was raised to 40 ℃ and reacted for 1 hour, the reaction solution was neutralized with saturated sodium bicarbonate solution, then distilled under reduced pressure to remove 40% of the solvent, 100ml of deionized water was added and ice-bath for 2 hours, a large amount of crystals were precipitated, and after suction filtration and vacuum drying, 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate was obtained (yield 91.2%).
Comparative example 3
Substantially the same as in example 1, except that step 3) was as follows:
In a reaction vessel, 100g of 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate, 30ml of thioglycolic acid and 300ml of dimethyl sulfoxide are sequentially added, after full stirring, 200ml of acetone, 3g of chromium trichloride hexahydrate and 20g of zinc powder are sequentially added, after heating to 40 ℃ and reacting for 1h, after reducing pressure and distilling to remove 60% of solvent, 500ml of deionized water is added and ice bath is carried out for 2h, a large amount of crystals are separated out, and after suction filtration and vacuum drying, 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate is obtained (yield 77.3%).
Comparative example 4
Substantially the same as in example 1, except that step 4) is as follows:
In a reaction vessel, 100g of the 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate, 1L of methanol and 1L of dichloromethane are sequentially added, after the mixture is fully stirred, 200mL of aqueous sodium hydroxide solution (prepared by mixing sodium hydroxide and water according to the weight ratio of 1:20) is dropwise added, the temperature is raised to 40 ℃ and the mixture is reacted for 1h, 4mL of glacial acetic acid is added to neutralize the reaction solution, 60% of solvent is removed by reduced pressure distillation, 500mL of deionized water is added to the remainder and ice bath is carried out for 2h, a large amount of crystals are separated out, and the 16 alpha-hydroxy prednisolone (the yield is 89.0%) is obtained after suction filtration and vacuum drying.
Comparative example 5
Substantially the same as in example 1, except that step 5) was as follows:
In a reaction vessel, 90g of 16 alpha-hydroxy prednisolone, 1L of acetonitrile and 1L of dichloromethane are sequentially added, after full stirring, 36ml of n-butyraldehyde and 0.8L of 9.5mol/L of hydrochloric acid are sequentially added, after stirring and reacting for 1h at room temperature, 500ml of deionized water is added, liquid separation is carried out, the aqueous phase is extracted by dichloromethane (1L multiplied by 2), the organic phases are combined, after 80% of solvent is distilled off under reduced pressure, 1L of methanol is added, then the temperature is raised to 50 ℃ until the solution is clear and transparent, then ice bath is carried out rapidly, a large amount of crystals are separated out, and budesonide (yield 91.9%) is obtained after suction filtration and vacuum drying.
While specific embodiments of the present disclosure have been described above, it will be appreciated by those skilled in the art that these are examples only, and the scope of the disclosure is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the principles and spirit of the disclosure, but such changes and modifications fall within the scope of the disclosure.
Claims (7)
1. A process for the large-scale preparation of budesonide, characterized in that it comprises the steps of:
(1) Deriving from a compound of formula I16 α,17 α, 21-trihydroxybstae-1, 4,9 (11) -triene-3, 20-dione-21-acetate;
(2) Deriving 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4,9 (11) -triene-3, 20-dione-21-acetate from 16α,17α, 21-trihydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (1) above;
(3) Deriving from 9α -bromo-11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (2) above to obtain 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate;
(4) Deriving 16α -hydroxyprednisolone from 11β,16α,17α, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione-21-acetate obtained in step (3) above; and
(5) And (3) deriving budesonide from the 16 alpha-hydroxy prednisolone obtained in the step (4).
2. The method of claim 1, wherein step (1) comprises:
In a reaction vessel, 100g of raw material compound 1, 2L of dimethyl sulfoxide and 50ml of formic acid are sequentially added, after stirring for 0.5h at room temperature, the temperature is raised to 40 ℃ and 2.4L of potassium permanganate solution (prepared by mixing potassium permanganate and water according to the weight ratio of 1:20) is added dropwise, after the dropwise addition is completed for 0.5h, the reaction is carried out for 1h, then the reaction vessel is cooled to room temperature and 1L of saturated sodium bisulfite solution is added for quenching reaction, then after 80% of solvent is removed by reduced pressure distillation, 200ml of diethyl ether is added and ice bath is carried out for 2h, a large amount of white solid is precipitated, and 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate is obtained after suction filtration and vacuum drying.
3. The method of claim 1, wherein step (2) comprises:
In a reaction vessel, 100g of the 16 alpha, 17 alpha, 21-trihydroxy pregna-1, 4,9 (11) -triene-3, 20-diketone-21-acetate, 70g of N-bromosuccinimide, 2L of dimethyl sulfoxide, 500ml of 1.0mol/L perchloric acid aqueous solution and 500ml of deionized water are sequentially added, the temperature is raised to 40 ℃ and the reaction solution is reacted for 1 hour, saturated sodium bicarbonate solution is used for neutralizing the reaction solution to be neutral, then the solvent of 40% is distilled off under reduced pressure, 100ml of diethyl ether is added and the ice bath is carried out for 2 hours, a large amount of crystals are separated out, and the 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate is obtained after suction filtration and vacuum drying.
4. The method of claim 1, wherein the step (3) comprises:
In a reaction vessel, sequentially adding 100g of 9 alpha-bromo-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy pregna-1, 4-diene-3, 20-dione-21-acetate, 30ml of thioglycolic acid and 300ml of dimethyl sulfoxide, fully stirring, sequentially adding 200ml of acetone, 3g of chromium trichloride hexahydrate and 20g of zinc powder, heating to 40 ℃ and reacting for 1h, decompressing and distilling to remove 60% of solvent, adding 500ml of deionized water and 100ml of diethyl ether, ice-bathing for 2h, precipitating a large amount of crystals, filtering, and vacuum-drying to obtain 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy pregna-1, 4-diene-3, 20-dione-21-acetate.
5. The method of claim 1, wherein the step (4) comprises:
In a reaction vessel, 100g of 11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1, 4-diene-3, 20-diketone-21-acetate, 1L of methanol and 1L of dichloromethane are sequentially added, after the mixture is fully stirred, 200mL of aqueous sodium hydroxide solution (prepared by mixing sodium hydroxide and water according to the weight ratio of 1:20) is dropwise added, the temperature is raised to 40 ℃ and the mixture reacts for 1h, 4mL of glacial acetic acid is added to neutralize the reaction solution, 60% of solvent is removed by reduced pressure distillation, 500mL of deionized water and 100mL of diethyl ether are added to the remainder and ice bath is carried out for 2h, a large amount of crystals are separated out, and the 16 alpha-hydroxy prednisolone is obtained after suction filtration and vacuum drying.
6. The method according to claim 1, wherein the step (5) comprises:
In a reaction vessel, 90g of 16 alpha-hydroxy prednisolone, 1L of acetonitrile and 1L of dichloromethane are sequentially added, after full stirring, 36ml of n-butyraldehyde and 0.8L of 9.5mol/L hydrochloric acid are sequentially added, after stirring and reacting for 1h at room temperature, 500ml of deionized water are added, liquid separation is carried out, the aqueous phase is extracted by dichloromethane (1L multiplied by 2), organic phases are combined, after 80% of solvent is distilled off under reduced pressure, 1L of methanol and 200ml of diethyl ether are added, then the temperature is raised to 50 ℃ until the solution is clear and transparent, then ice bath is carried out rapidly for 2h, a large amount of crystals are separated out, and budesonide is obtained after suction filtration and vacuum drying.
7. Budesonide prepared by a process according to any one of the preceding claims 1-6.
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