CN109384827A - A kind of budesonide industrialized process for preparing - Google Patents
A kind of budesonide industrialized process for preparing Download PDFInfo
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- CN109384827A CN109384827A CN201710665134.9A CN201710665134A CN109384827A CN 109384827 A CN109384827 A CN 109384827A CN 201710665134 A CN201710665134 A CN 201710665134A CN 109384827 A CN109384827 A CN 109384827A
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- budesonide
- hydrochloric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
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Abstract
The present invention relates to a kind of budesonide industrialized process for preparing.Specifically, 16 alpha-hydroxy prednisonlones are reacted with n-butanal is made budesonide the present invention relates in aqueous hydrochloric acid solution, methylene chloride and acetonitrile.Method of the invention has the advantages such as industrially implementable, favorable reproducibility.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of budesonide industrialized process for preparing.
Background technique
Budesonide (budesonide) is a kind of non-halogenated glucocorticoid researched and developed by AstraZeneca drugmaker, in
It is listed in Sweden within 1981.It has very strong local anti-inflammatory effect, can inhibit the bronchial spasm of early stage and the metamorphosis in advanced stage
Reaction is one of the important drugs for treating allergic asthma.22 carbon of budesonide are R and S chirality stereoisomer, R structure
Type antiphlogistic effects ratio S configuration it is 2~3 times high.At present since separately synthesized R type isomers is relatively difficult, actually answering
In, usually using the mixture of two kinds of isomers.
The synthetic route and technique of budesonide have many reports both at home and abroad.WO9211280,CN103724396,
CN103665093, CN103694306 and CN102060906 etc. all disclose the method for splitting for preparing R- budesonide；
EP0164636 and CN101717428 is all made of 16 alpha-hydroxy prednisonlones and passes through the method that single step reaction prepares budesonide；
CN101279997, which is disclosed, reacts the method for synthesizing budesonide, total recovery 23% by five steps by Econopred.
It is reacted in dilute hydrochloric acid with n-butanal in WO201612089 using 16 alpha-hydroxy prednisonlones, finds reproducibility not after industrialization
It is good, it can only be using the method for reducing reaction temperature.Currently, also comparing of reporting of the Research Literature of budesonide industrialized production
It is few, from laboratory synthesis technology be amplified to industrialized production reaction condition control it is not clear, this is all up for further
Research.
Summary of the invention
On the one hand, the present invention provides a kind of preparation method of budesonide (compound 1), comprising: in aqueous hydrochloric acid solution, two
In chloromethanes and acetonitrile, 16 alpha-hydroxy prednisonlones (intermediate 6) are reacted with n-butanal.
Specifically, the present invention provides a kind of preparation method of budesonide (compound 1), comprising: by aqueous hydrochloric acid solution and
N-butanal, which adds in the methylene chloride and acetonitrile of 16 alpha-hydroxy prednisonlones (intermediate 6), to be reacted.
In certain embodiments of the present invention, the concentration of the aqueous hydrochloric acid solution is 8~10mol/L；Preferred hydrochloric acid
Concentration of aqueous solution is 9.6mol/L.
In certain embodiments of the present invention, the volume ratio of aqueous hydrochloric acid solution, methylene chloride and acetonitrile is 1:1~1.5:
1~1.5；The volume ratio of preferred aqueous hydrochloric acid solution, methylene chloride and acetonitrile is 1:1.25:1.25.
In certain embodiments of the present invention, 16 alpha-hydroxy prednisonlones (intermediate 6) and the molar ratio of n-butanal are
1:1.2~2；Preferably 1:1.67.
In certain embodiments of the present invention, 16 alpha-hydroxy prednisonlones (intermediate 6) of every 1mol, hydrochloric acid used
The total volume of aqueous solution, methylene chloride and acetonitrile is 9~11L, and preferred total volume is 10.5L.
In certain embodiments of the present invention, by aqueous hydrochloric acid solution and n-butanal add to 16 alpha-hydroxy prednisonlones (in
Mesosome 6) methylene chloride and acetonitrile in, temperature at this time remains -5 DEG C~5 DEG C.
In certain embodiments of the present invention, the reaction temperature of the reaction is -5 DEG C~room temperature or 0 DEG C~room temperature.
In certain embodiments of the present invention, the reaction time of the reaction is 1h~2h.
In certain embodiments of the present invention, the reaction preferably carries out under the protection of inert gas such as nitrogen.
In certain embodiments of the present invention, described further includes post-processing step after reaction, the post-processing step
Suddenly include: plus water, and be extracted with dichloromethane, then plus isopropyl ether, crystallization is concentrated.
Specifically, the post-processing step includes: to add water and stir into reaction system, methylene chloride is extracted, and gained is organic
Layer is successively washed, is dried, being filtered, and isopropyl ether is added in filtrate, and stirring is concentrated into certain volume, cooling crystallization.
In certain embodiments of the present invention, in the post-processing step, the volume of added water is reaction solution volume
0.2-0.3 times；The time added water and stirred is 10~30min.
In certain embodiments of the present invention, in the post-processing step, gained organic layer is through lye such as saturated carbon
Sour hydrogen sodium solution and such as anhydrous sodium sulfate drying of saturated sodium chloride solution washing, desiccant.
In certain embodiments of the present invention, in the post-processing step, the volume of isopropyl ether be added is added water
2-3 times of volume, stirring, is concentrated into 2~2.2 times of volumes (volume is in terms of L) of 6 charged material weight of intermediate (weight is in terms of kg).
Further, in certain embodiments of the present invention, it further includes purification that the post-processing, which obtains budesonide crude product,
Step, the purification step include: to be recrystallized using methanol to budesonide crude product.
Specifically, the purification step includes: that methanol is added in budesonide crude product, and dissolved clarification, concentration, then cooling, filtering
And drying, obtain budesonide highly finished product.
In certain embodiments of the present invention, in the purification step, the volume (volume is in terms of L) that methanol is added is cloth
8 times or more or 10 times or more of desonide crude product weight (weight is in terms of kg).
In certain embodiments of the present invention, the purification step carries out under the protection of inert gas such as nitrogen.
In certain embodiments of the present invention, in the purification step, concentration is by reaction solution volume (volume is in terms of L)
It is concentrated into 1.8-2.2 times of budesonide crude product weight (weight is in terms of kg)；It is concentrated at normal pressure and 65 DEG C and carries out.
In certain embodiments of the present invention, in the purification step, cooling temperature is 10~20 DEG C；Stand crystallization 8-
10 hours.
On the other hand, the present invention provides a kind of 16 alpha-hydroxy prednisonlones (intermediate 6) preparation methods, including walk as follows
It is rapid:
(a) intermediate 2 dissolves in acetone and water, and formic acid and potassium permanganate is added, and reaction obtains intermediate 3；
(b) water, N-bromosuccinimide (NBS) and perchloric acid are added in the tetrahydrofuran solution of intermediate 3, is reacted
Obtain intermediate 4；
(c) in acetone, six hydrated chromium trichlorides and zinc powder, the DMF solution of thioacetic acid and intermediate 4, reaction is added dropwise
Obtain intermediate 5；
(d) intermediate 5 dissolves in methanol and methylene chloride, and sodium hydrate methanol solution is added dropwise, and reaction obtains intermediate
6。
Specifically, the present invention provides a kind of 16 alpha-hydroxy prednisonlones (intermediate 6) preparation methods, including walk as follows
It is rapid:
(a) it is stirred at room temperature down, the dissolution in acetone and water (volume ratio 1:0.052) of intermediate 2；Sequentially add formic acid and
Reaction is stirred at room temperature in potassium permanganate；Saturation solution of sodium bisulfite quenching reaction is added, filters and removes manganese dioxide and some solid
Acetone is evaporated off in body impurity, filtrate decompression, filters, filter cake washes to obtain intermediate 3；
(b) successively water, NBS and perchloric acid are added in the THF solution of intermediate 3, reaction is stirred at room temperature；Use unsaturated carbonate
Hydrogen sodium solution neutralization reaction liquid, and added in water, crystallization is stirred at room temperature, filters, filter cake washes to obtain intermediate 4；
(c) it is stirred at room temperature down, six hydrated chromium trichlorides and zinc powder are in acetone；Successively by thioacetic acid, intermediate 4
DMF solution drops in above-mentioned solution, and drop finishes, and reaction is stirred at room temperature.It removes acetone under reduced pressure, purified water stirring and crystallizing is added, filter,
Filter cake methanol: methylene chloride (volume ratio 1: 1) is stirred at reflux 1h, filters while hot, and filtrate concentration is cooled to room temperature crystallization,
Filter to obtain intermediate 5；
(d) it is stirred at room temperature down, the dissolution in methanol and methylene chloride (volume ratio 1: 1) of intermediate 5；Sodium hydroxide is added dropwise
Methanol solution, drop finish, room temperature reaction.It after glacial acetic acid neutralization reaction liquid is added, is concentrated, water stirring is added in residue, filter, filter
Cake is washed with water, and obtains intermediate 6.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This.
Synthetic route of the invention is as follows:
Embodiment 1:16 α, 17 α, the pregnant steroid -1,4,9 (11) of 21- trihydroxy-triene-3,20-diketone -21- acetic acid esters are (intermediate
Body 3)
Intermediate 2 (purity 99%, 1kg, 2.73mol), acetone (50L) and purified water (2.6L) are added in reaction kettle,
Dissolution is stirred at room temperature；Formic acid (0.4L, 10.60mol) and potassium permanganate (1.2kg, 7.59mol) are sequentially added, is stirred at room temperature anti-
Answer 1h.Saturation solution of sodium bisulfite (10L) quenching reaction is added, filters and removes manganese dioxide and some solid impurities, filtrate
It removes acetone under reduced pressure, there are a large amount of white solids to be precipitated, filter, filter cake washes to obtain intermediate 3 (1.01kg, 92.2%).mp 214
~215 DEG C.ESI-MS(m/z):401[M+H]+。
Embodiment 2:9 alpha-brominated -11 β, 16 α, 17 α, the pregnant steroid -1,4- diene -3,20- diketone -21- acetic acid of 21- tetrahydroxy
Ester (intermediate 4)
During successively water (6L), NBS (0.62kg, 3.48mol) and 1.75mol/L perchloric acid (3.3L, 5.78mol) are added to
In THF (26L) solution of mesosome 3 (1kg, 2.50mol), reaction 1h is stirred at room temperature.It is neutralized with saturated sodium bicarbonate solution (3L)
Crystallization is stirred at room temperature in reaction solution, and being added in purified water (100L), filter, filter cake wash intermediate 4 (1.17kg,
94.5%).133~135 DEG C of mp；ESI-MS(m/z):497[M+H]+；1H NMR (500MHz, CDCl3) δ: 7.30 (d, J=
10.0Hz, 1H), 6.15 (d, J=10.0Hz, 1H), 5.90 (s, 1H), 5.34 (d, J=5.25Hz, 1H), 4.60 (m, 2H),
4.51 (m, 1H), 4.48 (brs, 1H), 4.27 (brs, 1H), 4.09 (d, J=5.3Hz, 1H), 2.51 (m, 1H), 2.27 (m,
1H), 2.19 (s, 3H), 1.74~1.99 (m, 4H), 1.51 (d, J=13.0Hz, 1H), 1.42 (s, 3H), 1.38 (s, 1H),
0.90~1.00 (m, 2H), 0.86 (s, 3H).
Embodiment 3:11 β, 16 α, 17 α, the pregnant steroid -1,4- diene -3,20- diketone -21- acetic acid esters (intermediate of 21- tetrahydroxy
5)
Acetone (3L), six hydrated chromium trichlorides (28g, 0.11mol) and zinc powder (200g, 3.08mol) are added into reaction kettle
In, it is stirred at room temperature；Successively DMF (2L) solution of thioacetic acid (300ml, 4.33mol), intermediate 4 (1kg, 2.02mol) is dripped
To in above-mentioned reaction solution, drop finishes, and reaction 2h is stirred at room temperature.It removes acetone under reduced pressure, purified water (10L) stirring and crystallizing is added, filter,
Filter cake methanol: methylene chloride (1: 1,20L) is stirred at reflux 1h, filters while hot, and 65 DEG C of normal pressures of filtrate are concentrated into 2L, is cooled to room
Warm crystallization filters to obtain intermediate 5 (634.6g, 75.3%).211~213 DEG C of mp；ESI-MS(m/z):419[M+H]+；1H NMR
(500MHz, CDCl3) δ: 7.32 (d, J=10.2Hz, 1H), 6.17 (d, J=10.2Hz, 1H), 5.89 (s, 1H), 5.35 (d, J
=5.2Hz, 1H), 4.63 (m, 2H), 4.50 (m, 1H), 4.45 (brs, 1H), 4.28 (brs, 1H), 4.10 (d, J=5.2Hz,
1H), 2.52 (m, 1H), 2.26 (m, 1H), 2.20 (s, 3H), 1.75~1.98 (m, 5H), 1.53 (d, J=13.1Hz, 1H),
1.41 (s, 3H), 1.36 (s, 1H), 1.01~1.10 (m, 2H), 0.84 (s, 3H).
Embodiment 4:16 alpha-hydroxy prednisonlone (intermediate 6)
Intermediate 5 (600g, 1.44mol), methanol (6L) and methylene chloride (6L) are added in reaction kettle, are stirred at room temperature molten
Solution；It is added dropwise 0.5mol/L sodium hydrate methanol solution (600ml, 0.30mol), drop finishes, and reacts at room temperature 2h.Glacial acetic acid is added
It after (21ml, 0.37mol) neutralization reaction liquid, is concentrated under reduced pressure, purified water (1.2L) stirring is added in residue, there is white solid analysis
Out, suction filtration, filter cake are washed with purified water (600ml), obtain white solid intermediate 6 (491.7g, 91.1%).Mp 229~230
℃；ESI-MS(m/z):377[M+H]+。
Embodiment 5: budesonide (compound 1)
It is successively that n-butanal (purity 99%, 180ml, 2.00mol) is dropped to by 9.6mol/L hydrochloric acid (3.6L) and intermediate 7
In the acetonitrile (4.5L) and methylene chloride (4.5L) solution of intermediate 6 (450g, 1.20mol), drop finishes, and reaction 1h is stirred at room temperature.
It is added purified water (2.5L), stirs 30min, liquid separation, water phase is extracted with methylene chloride (1L × 2), merges organic phase, successively with full
It washs with sodium bicarbonate solution (2L × 3) and saturated sodium chloride solution (2L), is dried, filtered with anhydrous sodium sulfate, filtrate is added
Isopropyl ether (5L), stirs evenly, and 65 DEG C of normal pressures are concentrated into 1L, are cooled to room temperature, complete to crystallization, filters to obtain budesonide crude product
(431g)。
Budesonide purification:
Under nitrogen protection, anhydrous methanol (4310mL) and budesonide crude product (431g) are added in tetra- mouthfuls of reaction flasks of 5L,
It is stirred at reflux to dissolved clarification, maintains temperature normal pressure concentrate solution to 800ml~900ml；After concentration, cooling controls feed liquid temperature
Degree 10~20 DEG C standings crystallization 10 hours, filter, filter cake in 48~52 DEG C decompression drying 6 hours, obtain budesonide refine
Product, yield 95% detect dissolvent residual according to the method that 2015 editions pharmacopeia are recorded, methylene chloride, acetonitrile and isopropyl are not detected
Ether has residual, and Determination of Residual Methanol is in prescribed limit.221~231 DEG C of mp；ESI-MS(m/z):431[M+H]+；1H NMR
(500MHz,CDCl3) δ: 7.31 (d, J=10.2Hz, 0.5H), 7.30 (d, J=10.0Hz, 0.5H), 6.25~6.27 (m,
1H), 6.02 (s, 1H), 4.91~5.17 (m, 1H), 4.61~4.91 (m, 1H), 4.56~4.61 (d, J=20.0Hz, 1H),
4.49~4.56 (m, 1H), 4.20~4.26 (d, J=20.0Hz, 1H), 2.85 (brs, 2H), 2.58 (m, 1H), 2.35 (m,
1H), 2.01~2.19 (m, 3H), 1.55~1.83 (m, 5H), 1.50 (s, 1H), 1.47 (s, 3H), 1.32~1.44 (m, 2H),
1.09~1.21 (m, 2H), 0.89~0.99 (m, 6H).
Embodiment 6 and embodiment 7
Budesonide crude product has been made in step same as Example 5, and budesonide highly finished product have further been made, and receives
Rate and embodiment 5 are similar.
Embodiment 8 detect respectively implement the budesonide crude product of 5, embodiment 6 and embodiment 7 and the purity of highly finished product and
Configuration ratio, see the table below
Wherein, the list of embodiment 5, embodiment 6 and the resulting budesonide highly finished product of embodiment 7 is miscellaneous less than 0.1%.
Wherein, budesonide method for detecting purity (HPLC normalization method) is as follows:
Chromatographic column Thermo ODS Hypersil (150mm × 4.6mm, 3 μm)；Mobile phase A sodium phosphate buffer (takes phosphorus
Acid dihydride sodium 3.17g adds water 1000ml to dissolve, is adjusted to pH (3.2 ± 0.1): acetonitrile with phosphoric acid: ethyl alcohol (68: 32: 2), B phosphoric acid
Sodium buffer (pH3.2): acetonitrile (50: 50), gradient elution；Flow velocity 1.0ml/min；Detection wavelength 240nm；50 DEG C of column temperature.
Claims (10)
1. a kind of preparation method of budesonide, comprising: in aqueous hydrochloric acid solution, methylene chloride and acetonitrile, 16 Alpha-hydroxies sprinkle Buddhist nun
The reaction of Song Longyu n-butanal,
2. preparation method described in claim 1, wherein aqueous hydrochloric acid solution and n-butanal are added to 16 alpha-hydroxy prednisonlones
It is reacted in methylene chloride and acetonitrile and budesonide is made.
3. preparation method claimed in claims 1-2, wherein the concentration of aqueous hydrochloric acid solution is 8~10mol/L；Preferred hydrochloric acid
Concentration of aqueous solution is 9.6mol/L.
4. preparation method claimed in claims 1-2, wherein the volume ratio of aqueous hydrochloric acid solution, methylene chloride and acetonitrile be 1:1~
1.5:1~1.5；The volume ratio of preferred aqueous hydrochloric acid solution, methylene chloride and acetonitrile is 1:1.25:1.25.
5. preparation method claimed in claims 1-2, wherein the molar ratio of 16 alpha-hydroxy prednisonlones and n-butanal is 1:1.2
~2；Preferably 1:1.67.
6. preparation method claimed in claims 1-2, wherein 16 alpha-hydroxy prednisonlones of every 1mol, hydrochloric acid used are water-soluble
The total volume of liquid, methylene chloride and acetonitrile is 9~11L, and preferred total volume is 10.5L.
7. preparation method claimed in claims 1-2, wherein reaction temperature is -5 DEG C~room temperature or 0 DEG C~room temperature.
8. preparation method claimed in claims 1-2, wherein the reaction time is 1h~2h.
9. preparation method claimed in claims 1-2, wherein described further include post-processing step after reaction, is located after described
Reason step includes: plus water, and is extracted with dichloromethane, then plus isopropyl ether, concentration crystallization obtain budesonide crude product.
10. preparation method as claimed in claim 9, wherein further include using methanol after post-processing to budesonide crude product
It is recrystallized.
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| CN201710665134.9A CN109384827A (en) | 2017-08-07 | 2017-08-07 | A kind of budesonide industrialized process for preparing |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018932A (en) * | 2019-11-28 | 2020-04-17 | 奥锐特药业股份有限公司 | 9-position dehalogenation method for steroid compound |
| CN111253457A (en) * | 2020-03-20 | 2020-06-09 | 浙江神洲药业有限公司 | Method for preparing 16 α -hydroxy prednisolone |
| CN112375114A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of prednisolone acetate |
| CN115819487A (en) * | 2022-11-25 | 2023-03-21 | 湖南醇健制药科技有限公司 | Preparation method of budesonide intermediate |
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| US20090259037A1 (en) * | 2008-04-11 | 2009-10-15 | Roberto Lenna | Process for preparing budesonide |
| CN103275168A (en) * | 2013-05-27 | 2013-09-04 | 浙江仙琚制药股份有限公司 | Method for preparing budesonide |
| WO2016120891A1 (en) * | 2015-01-30 | 2016-08-04 | Coral Drugs Pvt. Ltd. | Novel process for preparation of glucocorticoid steroids |
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2017
- 2017-08-07 CN CN201710665134.9A patent/CN109384827A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090259037A1 (en) * | 2008-04-11 | 2009-10-15 | Roberto Lenna | Process for preparing budesonide |
| CN103275168A (en) * | 2013-05-27 | 2013-09-04 | 浙江仙琚制药股份有限公司 | Method for preparing budesonide |
| WO2016120891A1 (en) * | 2015-01-30 | 2016-08-04 | Coral Drugs Pvt. Ltd. | Novel process for preparation of glucocorticoid steroids |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018932A (en) * | 2019-11-28 | 2020-04-17 | 奥锐特药业股份有限公司 | 9-position dehalogenation method for steroid compound |
| CN111253457A (en) * | 2020-03-20 | 2020-06-09 | 浙江神洲药业有限公司 | Method for preparing 16 α -hydroxy prednisolone |
| WO2021184502A1 (en) * | 2020-03-20 | 2021-09-23 | 浙江神洲药业有限公司 | Method for preparing 16alpha-hydroxyprednisolone |
| US11618766B2 (en) | 2020-03-20 | 2023-04-04 | Zhejiang Shenzhou Pharmaceutical Company Limited | Method for preparing 16Alpha-hydroxyprednisolone |
| CN112375114A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of prednisolone acetate |
| CN115819487A (en) * | 2022-11-25 | 2023-03-21 | 湖南醇健制药科技有限公司 | Preparation method of budesonide intermediate |
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