CN104558082A - Synthetic method of beclomethasone dipropionate - Google Patents
Synthetic method of beclomethasone dipropionate Download PDFInfo
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- CN104558082A CN104558082A CN201310483525.0A CN201310483525A CN104558082A CN 104558082 A CN104558082 A CN 104558082A CN 201310483525 A CN201310483525 A CN 201310483525A CN 104558082 A CN104558082 A CN 104558082A
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- 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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Abstract
The invention relates to a synthetic method of beclomethasone dipropionate. According to the method, beclomethasone 11, 17, 21-tripropionate is taken as the raw material and reacts in an organic solvent with a gluconic acid solution or an aqueous solution of ester capable of being converted into gluconic acid in water to prepare beclomethasone dipropionate.
Description
Invention field
The present invention relates to a kind of with beclometasone 11,17,21-tripropionate for raw material, prepare BD synthetic method by aqueous gluconic acid.
Background technology
BD (CAS:5534-09-8) is a kind of common glucocorticoid medicine, and concrete structure is as follows, can make the multiple formulation such as paste, inhalation, in order to treat tetter, asthma, rhinitis etc.
BD is succeeded in developing at first by GlaxoSmithKline PLC company of Britain, goes on the market after obtaining the approval of U.S. FDA in June, 1980, loaded British Pharmacopoeia, American Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan and Chinese Pharmacopoeia.Because two beclometasone aerosol formulations is more more effective and economical than oral pharmaceutical in control rhinallergosis symptom and treatment asthma.Within 1986, Japanese Di Ren company develops two beclometasone nasal spray.Within 1996, Schering Plough company develops the aerosol for treating asthma, and commodity are called Vanceril, and 2000 annual sales amounts reach 1.27 hundred million dollars.At home, after Zhun Gelansu Chongqing pharmaceutical Co. Ltd in 1992 produces propionic acid beclometasone aerosol, within 1994, new east station of Guangzhou health medicine company also obtains aerosol certification, has assigned 14 certifications number so far.Now, multiple producers such as upper Hisense friendship, Shanghai balance pharmacy, star morning sunlight is answered in Shanghai, how Guangzhou helps public affairs, the anti-occasion in Shandong, Shandong are glad can produce two beclometasone preparation.
The local anti-inflammatory effect of two beclometasone double propionate is quite powerful, is the several times of dexamethasone.This is because two beclometasone contains l, 2-double bond, 9 α-chlorine, 11 beta-hydroxies, the functional groups such as 16 Beta-methyls and 17,21-, two propionic acid ester groups, wherein the introducing of dipropionic acid ester group contribute to increase steroidal fat-soluble, be not easy by organism degrades.
The synthetic technology of BD was studied with regard to there being scientist in the 60 to 70's of last century, the documents such as such as BE649171, BE827275, NL7503788, but just further do not develop after US4655971 disclosed in 1987.The method of the introducing of the dipropionic acid ester group related in BD, usually adopts following three kinds of methods to be main: first method is introducing 17 α-propionic acid ester, then protects 11 hydroxyls, then introduces 21 propionic esters, to 11 hydroxyl deprotections.Second method utilizes triethyl orthopropionate and 17 α, 2l-dihydroxyl to react and generates former propionic ester, and under acetic acid exists, hydrolysis becomes 17 α-propionic acid esters, then introduces 21-propionic ester.The third method is 9, and 11 groups are on the intermediate basis of double bond or epoxy, and by the group of 21 hydroxyls with transformation 9,11 after propionic anhydride protection, introduce 11-hydroxyl, 9-chlorine, then introduces 17 α-propionic acid esters.
The method of synthetic ester has more easy method in fact, and such as alcohol all can directly obtain corresponding ester to acid, acid anhydrides or acyl chloride reaction.
Do not use the reason of more easy method mainly because beclometasone (CAS:4419-39-0) is 11,17,21 exist oh group respectively, cause the esterification simultaneously of 3 hydroxyls when carrying out esterification simultaneously, and cannot 17, under the condition of 21 ester group reservations, optionally by 11 hydrolysis of ester group.Just because of this inevitable technical barrier above-mentioned, so the method for the introducing of the dipropionic acid ester group related in BD just have employed above-mentioned more complicated synthetic route.
Summary of the invention
The present invention relates to a kind of with beclometasone 11,17,21-tripropionate for raw material, prepare BD synthetic method with aqueous gluconic acid or the reactant aqueous solution that can be converted into the ester of gluconic acid in water in organic solvent.We are through constantly research, be surprised to find, beclometasone reacts with propionic anhydride or propionyl chloride under organic solvent and specific catalysts conditions, beclometasone 11,17,21-tripropionate can be obtained, beclometasone 11,17,21-tripropionate can the propionic ester of selective hydrolysis 11 by reacting with aqueous gluconic acid, obtains BD.
A kind of method preparing BD, it is characterized in that formula 1 compound adds aqueous gluconic acid in organic solvent or can be converted into the aqueous solution of the ester of gluconic acid in water, stirring reaction, obtain BD, its Chinese style 1 compound and gluconic acid or the mol ratio that can be converted into the ester of gluconic acid in water are 1:1-10
A kind of described method preparing BD, the mol ratio that it is characterized in that described formula 1 compound and gluconic acid or can be converted into the ester of gluconic acid in water is 1:2-8.
A kind of described method preparing BD, the mol ratio that it is characterized in that described formula 1 compound and gluconic acid or can be converted into the ester of gluconic acid in water is 1:2-5.
A kind of described method preparing BD, the content that it is characterized in that described aqueous gluconic acid or can be converted into the aqueous solution of the ester of gluconic acid in water is 1% to saturated solution.
A kind of described method preparing BD, the content that it is characterized in that described aqueous gluconic acid or can be converted into the aqueous solution of the ester of gluconic acid in water is 50%.
A kind of described method preparing BD, is characterized in that temperature of reaction is 20-80 DEG C.
A kind of described method preparing BD, is characterized in that temperature of reaction is 30-50 DEG C.
A kind of described method preparing BD, it is characterized in that organic solvent is one or more in the ester of the alcohol of 1-3 carbon, the ether of a 2-5 carbon, the ketone of a 3-4 carbon, acetonitrile, DMF, N-Methyl pyrrolidone, the alkyl chloride of 1-2 carbon, a 2-5 carbon.
A kind of described method preparing BD, it is characterized in that organic solvent is methyl alcohol, ethanol, ether, tetrahydrofuran (THF), 1, one or both in 4-dioxane, acetone, acetonitrile, methyl-sulphoxide, DMF, N-Methyl pyrrolidone, methylene dichloride, chloroform, ethyl acetate.
A kind of described method preparing BD, is characterized in that organic solvent is one or both in N-Methyl pyrrolidone, DMF, tetrahydrofuran (THF), acetonitrile.
A kind of described method preparing BD, is characterized in that in organic solvent containing the water being less than 10%.
The described method preparing BD, the ester that it is characterized in that to be converted in water gluconic acid is one or both in glucose-gamma lactone, dextrose-delta-lactone.
A kind of compound of formula 1 structure:
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.Person skilled should be understood that the equivalent replacement done technical characteristic of the present invention, or improves accordingly, still belongs within protection scope of the present invention.
DMAP:4-dimethyl aminopyridine
HPLC: high performance liquid chromatography
Mmol: mmole
Glu: gluconic acid or the ester of gluconic acid can be converted in water
Triester: beclometasone 11,17,21-tripropionate
Diester thing: beclometasone 17,21-double propionate
The preparation method of beclometasone 11,17,21-tripropionate:
Get beclometasone 1mmol and be placed in 20ml methylene dichloride; logical N2 protection; temperature is cooled to 0 ~ 5 DEG C; and add 5ml pyridine and 0.05mmolDMAP at this temperature; then be under the condition of 0-5 DEG C in temperature, slowly add 4mmol propionyl chloride, then under the condition of 0 DEG C, stir the mixture that obtains; reaction is finished and is added acetic acid and be adjusted to PH neutrality; wash with water, then use methylene dichloride 10ml × 3 time aqueous phase extracted, methylene dichloride merges mutually; concentrated; pour methyl alcohol and carry out recrystallization, obtain beclometasone 11,17; 21-tripropionate 0.91mmol, content 98%.Once obtain beclometasone 11,17, the 21-tripropionate 0.85mmol of content 99.5% again by recrystallizing methanol, following is a list its ultimate analysis and C
13nMR data.
Ultimate analysis: C31H41ClO8 C, 64.91; H, 7.12
C
13NMR：
In following examples, the content of beclometasone 11,17,21-tripropionate is 98.8%.
The analytical procedure of beclometasone 11,17,21-tripropionate, beclometasone 17,21-double propionate:
Chromatographic column is octadecylsilane chemically bonded silica is weighting agent, and theoretical plate number calculates should be not less than 2500 by beclometasone peak.Moving phase is methyl alcohol: water=74:26 (v:v).Detector is 240hm wavelength UV detectors.Flow velocity is lml/min.Sample size, 5 μ l.Column temperature is room temperature.
Product molar yield: the ratio referring to the mole number of beclometasone 11,17, the 21-tripropionate added in mole number that the weight of dried product exhibited calculates according to beclometasone 17,21-double propionate molecular weight and reaction.
Embodiment 1:
By beclometasone 11,17,21-tripropionate 1mmol organic solvent 50ml with 50% aqueous gluconic acid mix, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
Embodiment 2:
By beclometasone 11,17,21-tripropionate 1mmol organic solvent 50ml with 50% aqueous gluconic acid mix, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
Embodiment 3:
By beclometasone 11,17,21-tripropionate 1mmol is in the glucono delta lactone aqueous solution of organic solvent 50ml and 50%, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
In embodiment 3 average reaction time comparatively embodiment 2 extend 2 hours.
Embodiment 4:
According to the operating process in embodiment 3, be only change glucono delta lactone into glucose-gamma lactone, its experimental result does not have the difference on statistical significance.
Embodiment 5:
By beclometasone 11,17,21-tripropionate 1mmol mixes with aqueous gluconic acid at organic solvent 50ml, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
Embodiment 6:
By beclometasone 11,17,21-tripropionate 1mmol is in organic solvent 50ml and glucono delta lactone aqueous solution, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
Embodiment 7:
By beclometasone 11,17,21-tripropionate 1mmol is in organic solvent 50ml and gluconic acid-gamma lactone aqueous solution, react to reacting end (the 1 hour beclometasone 17 in interval under assigned temperature, 21-double propionate content rising change is less than 1%), be evaporated to organic solvent-free taste, be cooled to 0 DEG C, be diluted in frozen water.Filtration drying obtains beclometasone 17,21-double propionate.
Proved by above-mentioned experiment, at N-Methyl pyrrolidone, N, the effect of reacting in the organic solvent of dinethylformamide, tetrahydrofuran (THF) or acetonitrile has some superiority, and the content especially as the triester of raw material obviously declines, and the content of product diester thing also obviously rises simultaneously.
Claims (10)
1. prepare the method for BD for one kind, it is characterized in that formula 1 compound adds aqueous gluconic acid in organic solvent or can be converted into the aqueous solution of the ester of gluconic acid in water, stirring reaction, obtain BD, its Chinese style 1 compound and gluconic acid or the mol ratio that can be converted into the ester of gluconic acid in water are 1:1-10
2. a kind of method preparing BD as claimed in claim 1, the mol ratio that it is characterized in that described formula 1 compound and gluconic acid or can be converted into the ester of gluconic acid in water is 1:2-5.
3. a kind of method preparing BD as claimed in claim 1, the content that it is characterized in that described aqueous gluconic acid or can be converted into the aqueous solution of the ester of gluconic acid in water is 1% to saturated solution.
4. a kind of method preparing BD as claimed in claim 1, the content that it is characterized in that described aqueous gluconic acid or can be converted into the aqueous solution of the ester of gluconic acid in water is 50%.
5. a kind of method preparing BD as claimed in claim 1, is characterized in that temperature of reaction is 20-80 DEG C.
6. a kind of method preparing BD as claimed in claim 1, it is characterized in that organic solvent is one or more in the ester of the alcohol of 1-3 carbon, the ether of a 2-5 carbon, the ketone of a 3-4 carbon, acetonitrile, DMF, N-Methyl pyrrolidone, the alkyl chloride of 1-2 carbon, a 2-5 carbon.
7. a kind of method preparing BD as claimed in claim 1, is characterized in that organic solvent is one or both in N-Methyl pyrrolidone, DMF, tetrahydrofuran (THF), acetonitrile.
8. a kind of method preparing BD as claimed in claim 1, is characterized in that in organic solvent containing the water being less than 10%.
9. a kind of method preparing BD as claimed in claim 1, the ester that it is characterized in that to be converted in water gluconic acid is one or both in glucose-gamma lactone, dextrose-delta-lactone.
10. the compound of formula 1 structure:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104558083A (en) * | 2013-10-16 | 2015-04-29 | 天津金耀集团有限公司 | Synthetic method of beclomethasone dipropionate organic-free solvent |
| CN111944002A (en) * | 2020-07-29 | 2020-11-17 | 河南利华制药有限公司 | Beclomethasone dipropionate intermediate and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024131A (en) * | 1974-03-27 | 1977-05-17 | Plurichemie Anstalt | 16-Methyl-9α-halo steroid esters, ethers and preparation thereof |
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2013
- 2013-10-16 CN CN201310483525.0A patent/CN104558082B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024131A (en) * | 1974-03-27 | 1977-05-17 | Plurichemie Anstalt | 16-Methyl-9α-halo steroid esters, ethers and preparation thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104558083A (en) * | 2013-10-16 | 2015-04-29 | 天津金耀集团有限公司 | Synthetic method of beclomethasone dipropionate organic-free solvent |
| CN104558083B (en) * | 2013-10-16 | 2018-08-31 | 天津金耀集团有限公司 | A kind of synthetic method of beclomethasone dipropionate organic solvent-free |
| CN111944002A (en) * | 2020-07-29 | 2020-11-17 | 河南利华制药有限公司 | Beclomethasone dipropionate intermediate and preparation method thereof |
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| CN104558082B (en) | 2018-01-23 |
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