CN100338089C - New method for preparing Ciclesonide medication for treating asthma disease - Google Patents
New method for preparing Ciclesonide medication for treating asthma disease Download PDFInfo
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- CN100338089C CN100338089C CNB2004100561106A CN200410056110A CN100338089C CN 100338089 C CN100338089 C CN 100338089C CN B2004100561106 A CNB2004100561106 A CN B2004100561106A CN 200410056110 A CN200410056110 A CN 200410056110A CN 100338089 C CN100338089 C CN 100338089C
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- ciclesonide
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Abstract
The present invention aims to provide a new preparation method of medicine-stage ciclesonide. The method is characterized in that under the function of a catalyst, after a compound shown in a second raw material formula carries out aldehyde exchange reaction with cyclohexanecarboxaldehyde, a specific epimer (R) can be farthest obtained, namely the ciclesonide.
Description
Technical field
The present invention relates to prepare the method for ciclesonide (I).
The structure of ciclesonide shown in the formula I:
Here, the preparation ciclesonide is that employing formula (II) is scattered in the solvent as starting raw material, under the effect of catalyzer, obtains with the exchange of hexahydrobenzaldehyde generation aldehyde.
The structure of the starting raw material shown in the formula II:
Wherein, R represents C
1-C
12Straight chain, branched-chain hydrocarbon, or C
3-C
5Naphthenic hydrocarbon.
Background technology
Ciclesonide is a kind of novel, non-halogenated inhalant dosage form glucocorticosteroid, and it demonstrates in the treatment of asthma than better result of treatment of existing curative and lower side effect.
In the structure of ciclesonide, C
22Chiral carbon be the R type, constitute the active group of the most critical of anti-asthma effect.
DE-4129535 discloses chemical structure and a kind of preparation method thereof of ciclesonide in 1992, its reaction is as follows:
More than reaction adopts 16 alpha-hydroxy prednisonlones and isobutyric anhydride generation esterification to obtain three esters; The hydrolysis in the dioxane that contains 13%HCL gas of three esters, do under the catalyzer with perchloric acid simultaneously and 7 days 7 nights of hexahydrobenzaldehyde reaction, obtain the equal raceme (R/S=50/50) of ratio of ciclesonide epimer, need to split with the HPLC post, technology is loaded down with trivial details, reaction time is long, and resultant ciclesonide R type (I) yield low (about 20%) costs an arm and a leg.
In addition, WO02/38584 disclosed another kind of preparation method in 2002, and its reaction is as follows:
This method is to use C
22The ketal that connects two identical groups (methyl) on the position is a starting raw material, to C
21The hydroxyl of position carries out esterification, replaces C with hexahydrobenzaldehyde again
22Ketal, the C that obtains
22Cyclohexyl acetal (ciclesonide) DL body.Ratio R/the S=97.8/2.2 of the epimer of this patent disclosure does not meet medicinal standard.So WO02/38584 also illustrates in specification sheets; On the basis of reaction, obtain the ratio of the epimer of higher R/S, need split the step that (method for splitting DE-4129535 is open) or solvent recrystallization split (method for splitting WO98/09982 is open) through the HPLC preparative column, just can reach.
Conclude above two kinds of preparation methods as can be seen, first method technology is loaded down with trivial details, low, the valuable product of cost height, yield of resultant ciclesonide R type, incompatibility suitability for industrialized production.The ratio of the epimer of the disclosed product of second method (R/S=97.8/2.2) does not meet medicinal standard.
The inventor is according to organic reaction mechanism, and through experiment repeatedly, emphasis can obtain specific epimer (R) to greatest extent at the asymmetric synthesis of this reaction, and having proposed with the acetal shown in the formula (II) is raw material, with hexahydrobenzaldehyde to C
22The alkyl acetal carries out the aldehyde permutoid reaction, obtains C
22Cyclohexyl acetal (being ciclesonide), its epimer ratio is: R/S 〉=98.5/1.5 meets medicinal standard fully.
Reaction formula is as follows:
Summary of the invention
The new preparation method of ciclesonide who the purpose of this invention is to provide a kind of pharmaceutical grade, the method is characterized in that raw material (II) is scattered in the solvent, under the effect of catalyzer, carry out the aldehyde permutoid reaction with hexahydrobenzaldehyde, can obtain specific epimer (R) to greatest extent, i.e. ciclesonide.
Raw material mix shown in the II:
Wherein, R represents C
1-C
12Straight chain, branched-chain hydrocarbon, or C
3-C
5Naphthenic hydrocarbon.
The raw material sources of formula (II) are easy, can be by 16 α hydroxyl-prednisolones (can earlier and isobutyric anhydride generation esterification), again with aldehyde RCHO (R=C
1-C
12Straight chain, branched-chain hydrocarbon; Or C
3-C
5Naphthenic hydrocarbon) carry out aldol reaction and make (USP3929768 was open in 1975).
Raw material in the reaction (II) is 1 with the mole ratio that hexahydrobenzaldehyde feeds intake: 1-10.
Reaction is by known suitable solvent of professional such as ethers (as dioxane, diisopropyl ether), ester class (as ethyl acetate, ritalin), halogenated hydrocarbon (as methylene dichloride, trichloromethane), nitro-paraffin hydro carbons (as Nitromethane 99Min., nitropropane), or do not have solvent directly promptly to make solvent and make catalyzer again with catalytic amount or more substantial sour example hydrochloric acid, sulfuric acid, perchloric acid, Tetrafluoroboric acid, methylsulfonic acid, tosic acid.
Reaction adopts the perchloric acid of 50%-70% to make catalyzer, and raw material (II) is 1 with the mole ratio of catalyst levels: 1-10.Under 0-50 ℃ temperature, the reaction times is acquisition in 2-10 hour.
In the ordinary course of things, raw material (II) and hexahydrobenzaldehyde react obtain the mixture of epimer, in this case, the degree by following suitable change reaction conditions or control reaction are carried out obtains specific epimer R.
In order to prepare R-epimer (I), can preferred following condition: the mole ratio that feeds intake as raw material (II) and hexahydrobenzaldehyde be 1: 6, reaction solvent is selected halohydrocarbon (being preferably trichloromethane) or nitroparaffins (being preferably Nitromethane 99Min.), the perchloric acid of employing 70% is made catalyzer, and raw material (II) is preferably 1: 3 with the mole ratio of catalyst levels.Temperature of reaction is 25-35 ℃, and the reaction times is 4-6 hour.R/S 〉=the 98.5/1.5 of gained ciclesonide (I).
The technique effect of invention:
1, the inventive method is asymmetric synthesis, and gained ciclesonide product R/S 〉=98.5/1.5 meets medicinal standard.
2, the product yield of the inventive method gained is 80%.
Certainly, top method explanation and the following examples only are exemplary and explanat, and its protection is not limited to this.
Embodiment
Embodiment:
In the 250ml there-necked flask of stirring is installed, drop into pregnant-1,4-diene-3, the 20-diketone, 16,17-[(ethyl methene) two (oxos)]-11-hydroxyl-21-(2-methyl isophthalic acid-carbonyl propoxy-)-, [11 β, 16 α] be the raw material 10g (0.021mol) and the Nitromethane 99Min. 50ml of formula (II), become the suspendible body under stirring, drip 70% perchloric acid 5.3ml (0.0616mol), the back drips hexahydrobenzaldehyde 15ml (0.126mol), room temperature reaction 2-10 hour, splash into 5% wet chemical 200ml, cause solution and be neutral, get the oily solid, incline and remove filtrate, gained oily solid is added the about 30ml dissolving of ethanol back rotation evaporate to dryness, collect solid.Get the about 8.8g of ciclesonide product (I), its epimer compares R/S=98.5/1.5.Total recovery about 80%.
Claims (8)
1, the preparation method of a kind of ciclesonide (I), the feature of this method are scattered in the solvent with the raw material shown in the formula (II), and under the effect of acid catalyst, carry out the aldehyde permutoid reaction and obtain with hexahydrobenzaldehyde,
The structure of ciclesonide shown in the formula I:
The structure of raw material shown in the formula II:
Among the formula II, R represents C
1-C
12Straight chain, branched hydrocarbyl or C
3-C
5Cycloalkyl group.
2,, it is characterized in that the mole ratio that starting raw material (II) and hexahydrobenzaldehyde feed intake is: 1: 1-10 according to the method for claim 1.
3, according to the method for claim 2, described starting raw material (II) is 1: 6 with the mole ratio that hexahydrobenzaldehyde feeds intake.
4,, it is characterized in that reaction solvent is: ether, ester, halohydrocarbon or nitroparaffins according to the method for claim 1.
5, according to the method for claim 4, described ether is selected from dioxane, diisopropyl ether; Ester is selected from ethyl acetate, ritalin; Halohydrocarbon is selected from methylene dichloride, trichloromethane; Nitroparaffins are selected from Nitromethane 99Min., nitropropane.
6, according to the method for claim 5, reaction solvent is trichloromethane or Nitromethane 99Min..
7,, it is characterized in that the acid catalyst that reacts is selected from hydrochloric acid, sulfuric acid, perchloric acid, Tetrafluoroboric acid, methylsulfonic acid or tosic acid according to the method for claim 1.
8, according to the method for claim 7, described acid catalyst is 70% perchloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100561106A CN100338089C (en) | 2004-08-12 | 2004-08-12 | New method for preparing Ciclesonide medication for treating asthma disease |
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|---|---|---|---|
| CNB2004100561106A CN100338089C (en) | 2004-08-12 | 2004-08-12 | New method for preparing Ciclesonide medication for treating asthma disease |
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|---|---|
| CN1626546A CN1626546A (en) | 2005-06-15 |
| CN100338089C true CN100338089C (en) | 2007-09-19 |
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| CNB2004100561106A Expired - Fee Related CN100338089C (en) | 2004-08-12 | 2004-08-12 | New method for preparing Ciclesonide medication for treating asthma disease |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2622640A1 (en) * | 2005-11-02 | 2007-05-18 | Sicor Inc. | Improved process for the preparation of ciclesonide |
| CN101857627B (en) * | 2010-06-10 | 2012-08-22 | 浙江工业大学 | Synthesis method for ciclesonide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1473164A (en) * | 2000-11-10 | 2004-02-04 | ��̹��ҽҩ��˾ | Process for production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21- dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation |
-
2004
- 2004-08-12 CN CNB2004100561106A patent/CN100338089C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1473164A (en) * | 2000-11-10 | 2004-02-04 | ��̹��ҽҩ��˾ | Process for production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21- dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation |
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Assignee: Anhui Welman Pharmaceutical Co., Ltd. Assignor: Chongqing Pharmaceutical Research Institute Co., Ltd. Contract fulfillment period: 2008.9.24 to 2018.9.24 Contract record no.: 2008340000006 Denomination of invention: New method for preparing Ciclesonide medication for treating asthma disease Granted publication date: 20070919 License type: Exclusive license Record date: 20081008 |
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| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.9.24 TO 2018.9.24; CHANGE OF CONTRACT Name of requester: ANHUI WEIERMAN PHARMACEUTICAL CO., LTD. Effective date: 20081008 |
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Granted publication date: 20070919 Termination date: 20190812 |