CN102276522B - Method for preparing roflumilast and intermediate of roflumilast - Google Patents
Method for preparing roflumilast and intermediate of roflumilast Download PDFInfo
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- CN102276522B CN102276522B CN 201110160005 CN201110160005A CN102276522B CN 102276522 B CN102276522 B CN 102276522B CN 201110160005 CN201110160005 CN 201110160005 CN 201110160005 A CN201110160005 A CN 201110160005A CN 102276522 B CN102276522 B CN 102276522B
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- GLKVMXXYMNTCJX-UHFFFAOYSA-N Cc(cncc1Cl)c1N Chemical compound Cc(cncc1Cl)c1N GLKVMXXYMNTCJX-UHFFFAOYSA-N 0.000 description 1
- LBLBOIFGYPHXGS-UHFFFAOYSA-N O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Cl Chemical compound O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Cl LBLBOIFGYPHXGS-UHFFFAOYSA-N 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Nc(c(Cl)cnc1)c1Cl Chemical compound O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Nc(c(Cl)cnc1)c1Cl MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing an intermediate compound (I) of roflumilast, and the roflumilast by using the intermediate compound (I). The method comprises that: an active derivative of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid reacts with 4-amino-3,5-dichloropyridine in an aprotic polar solvent in the presence of an acid binding agent to prepare the intermediate compound (I), then the intermediate compound (I) is subjected to hydrolysis to obtain the roflumilast. The product purity of the prepared roflumilast through the method provided by the present invention can reach more than 99%, and the yield is good and stable, the cost is low, and the method is substantially applicable for the industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a kind of method for preparing roflumilast (Roflumilast), the invention also discloses the new intermediate of synthetic roflumilast.
Background technology
Roflumilast (Roflumilast), chemistry N-(3,5-dichloropyridine-4-yl) by name-3-cyclo propyl methoxy-4-difluoromethoxybenzoamine amine (IV), structural formula is as follows:
It is the inhibitor of phosphodiesterase-4 (PDE-4), in March, 2011, FDA approval roflumilast is used for the treatment of chronic obstructive pulmonary disease (COPD), reduces serious COPD acute attack (increasing the weight of) frequency, relief of symptoms deterioration.Each 0.5mg once a day.In Europe and U.S.'s listing.
Patent WO95/01338 has described the preparation method of roflumilast and as the purposes of PDE-4 inhibitor among the CN1046939C.WO03/099334, CN1635909A have described the preparation method of a kind of oral preparations of roflumilast.
The synthetic route of the roflumilast of present existing bibliographical information is route as follows:
Normally 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (V) is made 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride (II), II again with 4-amino-3,5-dichloropyridine (III) condensation forms amide compound (IV), i.e. roflumilast.
Among the preparation method of the roflumilast of in WO95/01338, describing, the tetrahydrofuran solution of the 3-cyclo propyl methoxy of 0.0275mol-4-difluoro-methoxy Benzoyl chloride is added drop-wise to 0.03mol 4-amino-3, in the tetrahydrofuran (THF) suspension of 5-dichloropyridine and 0.066mol sodium hydride, temperature of reaction is 15～20 degree.
But in patent CN200480001216.4, think that this method is not suitable at the highly purified roflumilast of industrial preparation yet, it has proposed to use 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride and excessive 4-amino-3, the anionic reactive of 5-dichloropyridine, when so preparing roflumilast, can effectively avoid generating by product: N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-hydroxybenzamide.Therefore patent CN200480001216.4 is actually and has proposed a kind of effective minimizing by product N-(3,5-dichloropyridine-4-yl)-the method for preparing roflumilast that 3-cyclo propyl methoxy-4-hydroxybenzamide generates, the feature of the method is when the preparation roflumilast, the 4-that uses amino-3, the mol ratio of the reactive derivative of the negatively charged ion of 5-dichloropyridine and 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid is 1.5 to 3.0, most preferably is 2.2.
Summary of the invention
The invention discloses a kind of method for preparing roflumilast.
The contriver is in carrying out the study on the synthesis process of roflumilast; be surprised to find; using 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride (II) and 4-amino-3; in 5-dichloropyridine (III) condensation course; can be difficult to generate two acylate 4-(N, N-two (3-cyclo propyl methoxy-4-difluoro-methoxy benzoyl)) amino-3,5-dichloropyridine (I) with avoiding; and (I) by basic hydrolysis, can obtain roflumilast (IV).
Under certain condition, 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride and 4-amino-3,5-dichloropyridine generation condensation can almost completely generate diacetyl thing (I) with high yield.
The structural formula of midbody compound (I) is as follows:
The available following method preparation of midbody compound (I):
Reaction conditions is as follows: 20 ℃ under 100 ℃, in the mixed solution that contains compound III, DMF and pyridine, add the DMF solution contain Compound I I, 10 minutes to 10 hours reaction times, and get final product.
Pyridine is as acid binding agent in the above-mentioned reaction.
Preferred 45 ℃～55 ℃ of temperature of reaction.Preferred 5 hours of reaction times.
Under these conditions, II and III generation condensation can almost completely generate diacetyl thing (I) with high yield.
Further research is found, with directly basic hydrolysis of midbody compound (I), can be converted into roflumilast by high yield.
Reaction formula is as follows:
Macromolecule alkali for hydrolysis is preferred: midbody compound (I) is dissolved in the organic solvent, is 5%～90% alkaline aqueous solution by adding concentration, under 20 ℃～100 ℃ temperature, stirs 10 minutes to 24 hours, and get final product.Per-cent of the present invention all is weight percentage.
Organic solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF), acetone, dioxane or DMF preferably.
The aqueous solution of the preferred sodium hydroxide of alkaline aqueous solution, potassium hydroxide, lithium hydroxide or yellow soda ash wherein.
The aqueous solution that contains roflumilast after the hydrolysis can obtain roflumilast (IV) and 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (V) step by step by regulating pH.Comprise alkaline hydrolyzate adjusting pH to 7～8, roflumilast namely precipitates, and filters the collecting precipitation thing, is drying to obtain.Dry thing is further recrystallization also, the roflumilast of acquisition, and common content is higher than 99.0%, and maximum single contaminant is not more than 0.1%; Especially, can reach content and be higher than 99.5%, maximum single contaminant is not more than 0.05%.
Filter the mother liquor behind the roflumilast crude product, further be acidified to pH＜3 after, 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (V) is precipitated out, by conventional processing as filtering, drying, the regenerant that the recrystallization acquisition conforms to quality requirements, content is higher than 99.0% usually.Can reuse.
Therefore, in aftertreatment, the present invention can obtain first roflumilast by adjusted stepwise acidity, further reclaims 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (V) after the acidifying.
Positively effect of the present invention has been to provide a kind of easy method to prepare roflumilast, product purity is high, yield is good and stable, very be fit to suitability for industrialized production, and solved the problem of the two acidylate by products that in condensation course, produce, creatively by product effectively is converted into the product roflumilast, yield and quality product have been improved, use the roflumilast of the present invention's preparation to be used for making the preparation clinical application, because the purity height will make clinical use curative effect higher, side effect is less; And 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (V) can effective recycling among the present invention, has reduced cost.Overcome previous methods and used the highly basic yield undesirable, operation steps is comparatively loaded down with trivial details, the unsettled shortcoming of quality product and yield.
Embodiment
Embodiment 1
The preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride (II)
35 gram 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acids (V) and 210 milliliters of toluene are mixed, add sulfur oxychloride 160 grams, add 1 milliliter of N, dinethylformamide (DMF) catalysis, 90 ℃ of reactions 5 hours, toluene and excessive sulfur oxychloride are removed in distillation, are light yellow crystalloid solid 38 grams after the remaining cooling, are 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride (II).Can be directly used in the next step.
4-(N, N-two (3-cyclo propyl methoxy-4-difluoro-methoxy benzoyl)) amino-3, the preparation of 5-dichloropyridine (I)
With 38 gram 4-amino-3,5-dichloropyridine (III) and 50 milliliters of DMF are mixed, add 60 gram pyridines, be heated to 50 ℃, drip 38 gram 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chlorides (II) of above-described embodiment 1 preparation at the solution of 50 milliliters of DMF, dripped in 30 minutes and finish, continue reaction 5 hours.The thin-layer chromatography demonstration reacts completely, and reaction finishes, and reaction solution is poured in 500 milliliters of frozen water, regulate pH less than 3 with concentrated hydrochloric acid, add 500 milliliters of ethyl acetate layerings, ethyl acetate layer is used 200 milliliter of 5% sodium hydrogen carbonate solution successively, the washing of 200 mL of saline, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, remainingly adds an amount of hexanaphthene, slowly separates out white crystals, filters, and 40 ℃ of vacuum-dryings obtain 41 gram white crystals (I), yield 94%, mp:71.5～73.5 ℃.δ
1H-NMR(CDCl
3，500MHz)δ0.36(4H，m)，δ0.65(4H，m)，δ1.24(2H，m)，δ3.84(4H，d)，δ6.64(2H，t)，δ7.07(2H，d)，δ7.31～7.33(4H，m)，δ8.59(2H，s)。
13C-NMR(CDCl
3，125MHz)δ3.3，9.9，74.2，77.0，113.5，115.1，115.5，117.6，121.8，122.1，131.4，131.7，143.2，144.0，149.1，150.5，170.2。
IR(KBr)ν3433，3087，3011，2928，1716，1685，1604，1551，1509，1464，1427，1407，1329，1281，1196，1127，1058，1026，835，816cm
-1。
MS(EI)m/e：643(M
++1)，167(100)。
Embodiment 2
The preparation of roflumilast (IV)
With 50 gram (0.078mol) 4-(N; N-two (3-cyclo propyl methoxy-4-difluoro-methoxy benzoyl)) amino-3; 5-dichloropyridine (I) is dissolved in 400 milliliters of ethanol; add 100 milliliters of 20% aqueous sodium hydroxide solutions; 70 ℃ of reactions 20 minutes, thin-layer chromatography showed that two acylates react completely.Remove ethanol under reduced pressure, 200 milliliters of frozen water of remaining adding, the salt acid for adjusting pH is 7～8, separate out a large amount of white solids, stirred 30 minutes, make to be uniformly dispersed, filter filtrate for later use, filter cake washing, 50 ℃ of vacuum-dryings, obtaining 30 gram white powders is the roflumilast crude product, with 150 milliliters of Virahol recrystallizations, 60 ℃ of vacuum-drying 4 hours obtains 28 gram white crystals, yield 89%, HPLC purity: 99.9%, mp:158.9～159.5 ℃.
1H-NMR(CDCl
3，500MHz)δ0.37(2H，m)，δ0.66(2H，m)，δ1.30(1H，m)，δ3.93(2H，d)，δ6.74(1H，t)，δ7.25(1H，dd)，δ7.47(1H，dd)，δ7.57(1H，d)，δ7.94(1H，s)，δ8.53(2H，s)。
13C-NMR(CDCl
3，125MHz)δ3.2，10.0，74.2，77.0，113.6，114.3，115.7，117.7，120.0，122.3，129.1，130.8，139.8，143.9，148.3，150.9，163.8。
IR(KBr)ν3415，3258，3028，2925，2877，1652，1597，1502，1483，1401，1305，1280，1199，1156，1008，808，748。
MS(EI)m/e：403(M
++1)(100)。
With the mother liquor behind the above-mentioned filtration roflumilast crude product, further with hcl acidifying to pH＜3, generate a large amount of white solids in the solution, stirred 30 minutes, after being uniformly dispersed, filter 60 ℃ of vacuum-dryings, obtaining 19 gram white powders is the 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid, the rate of recovery 95%.Obtain white crystals after the recrystallizing methanol, HPLC purity: 99.6%, mp:120.0～120.5 ℃,
1H-NMR (CDCl
3, 500MHz) δ 0.39～0.41 (2H, m), δ 0.68～0.72 (2H, m), δ 1.34 (1H, m), δ 3.97 (2H, d), δ 6.77 (1H, t), δ 7.25～7.28 (1H, dd), δ 7.69 (1H, s), δ 7.74 (1H, dd).
Embodiment 3
The preparation of roflumilast
With 16.3 gram (0.1mol) 4-amino-3,5-dichloropyridine (III) and 50 milliliters of DMF are mixed, add 9.6 gram sodium hydrides (60% content is in mineral oil), stir lower, drip 25 gram (0.062mol) 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chlorides (II) of above-described embodiment 1 method preparation at the solution of 50 milliliters of DMF at 20 ℃, dripped in 30 minutes and finish, continue reaction 10 hours.Thin-layer chromatography shows that acyl chlorides transforms fully, and reaction finishes, and reaction solution is poured in 500 milliliters of frozen water, regulate pH less than 3 with concentrated hydrochloric acid, add 500 milliliters of ethyl acetate layerings, ethyl acetate layer is used 200 milliliter of 5% sodium hydrogen carbonate solution successively, the washing of 200 mL of saline, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, obtains light brown oily thing 24 grams, and HPLC detects and shows that roflumilast is about 3: 1 with two acylate ratios in the oily matter.This oily matter is dissolved in 280 milliliters of ethanol, adds 70 milliliters of 20% aqueous sodium hydroxide solutions, 60 ℃ of reactions 30 minutes, thin-layer chromatography showed that two acylates react completely.Remove ethanol under reduced pressure, 150 milliliters of frozen water of remaining adding, the salt acid for adjusting pH is 7-8, separate out a large amount of white solids, stirred 30 minutes, make to be uniformly dispersed, filter, filtrate for later use, filter cake washing, 60 ℃ of vacuum-dryings, obtaining 17 gram white powders is the roflumilast crude product, obtain 16 gram white crystals, HPLC purity: 99.9%, mp:158.5-159.4 ℃ with 100 milliliters of Virahol recrystallizations.
With the mother liquor behind the above-mentioned filtration roflumilast crude product, further with hcl acidifying to pH＜3, generate a large amount of white solids in the solution, stirred 30 minutes, and after being uniformly dispersed, filtered, 60 ℃ of vacuum-dryings, obtaining 3 gram white powders is the 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid.Obtain white crystals after the recrystallizing methanol, HPLC purity: 99.5%, mp:119.5～120.5 ℃.
Claims (8)
1. the midbody compound of a structural formula (I):
2. the preparation method of the midbody compound of claim 1 (I) comprising:
Under 20 ℃ to 100 ℃ condition, in the mixed solution that contains compound III, DMF and pyridine, add the DMF solution that contains compound ii, 10 minutes to 10 hours reaction times, and get final product.
3. the method for claim 2, wherein temperature of reaction is 45 ℃～55 ℃.
4. the method for claim 2, wherein the reaction times is 5 hours.
5. method for preparing roflumilast, comprise: the midbody compound (I) of claim 1 is dissolved in the organic solvent, is 5%～90% alkaline aqueous solution by adding concentration, under 20 ℃～100 ℃ temperature, stirred 10 minutes to 24 hours, and get final product.
6. the method for claim 5, wherein organic solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF), acetone, dioxane or DMF.
7. the method for claim 5, wherein alkaline aqueous solution is the aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide or yellow soda ash.
8. the method for claim 5 also comprises alkaline hydrolyzate is regulated pH to 7～8, and roflumilast namely precipitates, and filters the collecting precipitation thing, is drying to obtain.
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| CN102603623A (en) * | 2011-12-26 | 2012-07-25 | 北京赛林泰医药技术有限公司 | Method for preparing high-purity roflumilast |
| CN102617340B (en) * | 2012-03-05 | 2014-03-26 | 山西仟源制药股份有限公司 | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid |
| US9321726B2 (en) | 2012-10-17 | 2016-04-26 | Interquim, S.A. | Process for preparing roflumilast |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5712298A (en) * | 1993-07-02 | 1998-01-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| WO2005026095A1 (en) * | 2003-09-12 | 2005-03-24 | Ranbaxy Laboratories Limited | Process for the preparation of roflumilast |
| WO2006040645A1 (en) * | 2004-10-11 | 2006-04-20 | Ranbaxy Laboratories Limited | N-(3,5-dichloropyridin-4-yl)-2,4,5-alkoxy and 2,3,4-alkoxy benzamide derivatives as pde-iv (phophodiesterase type-iv) inhibitors for the treatment of inflammatory diseases such as asthma |
-
2011
- 2011-06-15 CN CN 201110160005 patent/CN102276522B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5712298A (en) * | 1993-07-02 | 1998-01-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| WO2005026095A1 (en) * | 2003-09-12 | 2005-03-24 | Ranbaxy Laboratories Limited | Process for the preparation of roflumilast |
| WO2006040645A1 (en) * | 2004-10-11 | 2006-04-20 | Ranbaxy Laboratories Limited | N-(3,5-dichloropyridin-4-yl)-2,4,5-alkoxy and 2,3,4-alkoxy benzamide derivatives as pde-iv (phophodiesterase type-iv) inhibitors for the treatment of inflammatory diseases such as asthma |
Non-Patent Citations (1)
| Title |
|---|
| Toshinbu Suzuki等.Acylation of heteroaromatic amine，II dibenzoylation of aminopyridines.《J.heterocyclic chem》.1979,第16卷全文. * |
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