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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- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- -1 precipitates Chemical compound 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 13
- ISIQAMHROGZHOV-UHFFFAOYSA-N 3,5-dichloropyridin-4-amine Chemical compound NC1=C(Cl)C=NC=C1Cl ISIQAMHROGZHOV-UHFFFAOYSA-N 0.000 abstract description 5
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- 239000011230 binding agent Substances 0.000 abstract description 2
- IGFDIFLMMLWKKY-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid Chemical class OC(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 IGFDIFLMMLWKKY-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002798 polar solvent Substances 0.000 abstract 1
- LBLBOIFGYPHXGS-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride Chemical compound FC(F)OC1=CC=C(C(Cl)=O)C=C1OCC1CC1 LBLBOIFGYPHXGS-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- OCWBGKZFOYMCCN-UHFFFAOYSA-N 3,5-dichloropyridin-2-amine Chemical compound NC1=NC=C(Cl)C=C1Cl OCWBGKZFOYMCCN-UHFFFAOYSA-N 0.000 description 1
- GLKVMXXYMNTCJX-UHFFFAOYSA-N Cc(cncc1Cl)c1N Chemical compound Cc(cncc1Cl)c1N GLKVMXXYMNTCJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ABBGQGWAIHSSNW-UHFFFAOYSA-N N-cyclopropyl-4-hydroxy-2-methoxybenzamide Chemical compound COc1cc(O)ccc1C(=O)NC1CC1 ABBGQGWAIHSSNW-UHFFFAOYSA-N 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000012492 regenerant Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- 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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| 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 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 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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