CN102093194A - New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid - Google Patents

New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid Download PDF

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CN102093194A
CN102093194A CN2010106030958A CN201010603095A CN102093194A CN 102093194 A CN102093194 A CN 102093194A CN 2010106030958 A CN2010106030958 A CN 2010106030958A CN 201010603095 A CN201010603095 A CN 201010603095A CN 102093194 A CN102093194 A CN 102093194A
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CN102093194B (en
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廖明毅
李�瑞
杨少宁
张连第
丁磊
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Jiangsu Pre Medical Diagnosis Co Ltd
Nanjing Pioneer Medical Laboratory Co Ltd
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Jiangsu Simcere Pharmaceutical R&D Co Ltd
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Abstract

The invention relates to a new method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid. The method is characterized by taking 3-nitro-4-hydroxybenzoic acid ester as the raw material to obtain the 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid through alkylation, reduction, diazotization, hydrolysis, alkylation, deprotection and the like. The 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid is a key intermediate for synthesizing the drug roflumilast.

Description

The new synthetic method of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid
Technical field
The present invention relates to the novel method of a kind of synthetic 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is the key intermediate of synthetic drugs roflumilast.
Background technology
(roflumilast Daxas) is developed by Switzerland Nycomed company and the U.S. Forest company roflumilast jointly, obtains European Union's approval listing on July 6th, 2010, is used for the treatment of chronic obstructive pulmonary disease (COPD).Roflumilast is selectivity phosphodiesterase 4 (PDE4) inhibitor, is the new class COPD medicine that obtains European Union's approval during the last ten years first.Roflumilast is the oral tablet of 1 medication on the one, must share with other bronchodilator, is applicable to the treatment of keeping of the relevant serious COPD (FEV1 is less than 50% of predicated value after the diastole) of the adult patient chronic bronchitis that frequently increases the weight of medical history.At first Shang Shi country is Germany and Britain.
3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is the intermediate of a key in roflumilast synthetic.From present document, 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid synthetic mainly contains following several method:
(1) synthetic route among the WO2005026095, from 3,4-resorcylic acid ester sets out, and through two step alkylated reactions, hydrolysis obtains 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid again.There is optionally problem in the first step reaction, and reaction can obtain mixture 3 or 4 generations, and yield is low, is difficult to separate, and needs to be difficult to carry out industry's enlarging production by the column chromatography purifying.
Figure BDA0000040331230000011
(2) synthetic route among the CN101490004, from 3, the 4-Dihydroxy benzaldehyde sets out, and through two step alkylated reactions, reoxidizes and obtains 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid.There is optionally problem equally in the first step reaction, and yield is low, is difficult to separate, and needs to be difficult to carry out industry's enlarging production by the column chromatography purifying.
Figure BDA0000040331230000021
(3) synthetic route among the WO2004033430, from pyrocatechol, through alkylation, bromination, alkylation again, carbonylation, last hydrolysis obtains 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid.Contain two alkylates of part and unreacted raw material in the first step reacting coarse product, need be by repeatedly distilling the purpose that just can reach purifying; The second step reaction needed is carried out under-60 ℃; Four-step reaction has been used hypertoxic carbon monoxide.Be difficult to carry out industry's enlarging production.
Figure BDA0000040331230000022
Summary of the invention
The invention provides the novel method of a kind of synthetic 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, comprise that step is as follows:
(1) 3-of formula 2 nitro-4-hydroxybenzoate alkylation obtains the compound of formula 3;
(2) reduction of the compound of formula 3 obtains the compound of formula 4;
(3) compound of formula 4 through diazotization again hydrolysis obtain the compound of formula 5;
(4) alkylation of formula 5 obtains the compound of formula 6;
(5) the compound deprotection of formula 6 obtains the 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid of formula 1;
Wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
Figure BDA0000040331230000031
The compound of its Chinese style 2 can be bought and obtain, also can be from p-Hydroxybenzoate (SyntheticCommunications, 2003,33,961.Journal?of?Organic?Chemistry,2005,70,9071。) and 3-nitro-4-hydroxy-benzoic acid by synthetic (Journal of Organic Chemistry, 2006,71,6374 of obtaining of simple method.Bioorganic&Medicinal?Chemistry,2006,14,8219。)。
Each goes on foot reaction conditions:
(1) compound of formula 2 under the effect of alkali B, with the difluoromethyl reagent react, obtains the compound of formula 3 in solvent orange 2 A;
(2) compound of formula 3 is reduced agent D reduction in solvent C, obtains the compound of formula 4, and temperature of reaction is 0-80 ℃, and the reaction times is 1-15h;
(3) compound of formula 4 diazotization in dilution heat of sulfuric acid, hydrolysis obtains the compound of formula 5 again, and temperature of reaction is 0-90 ℃, and the reaction times is 1-10h;
(4) compound of formula 5 under the effect of alkali F, with the reaction of ring third methylating reagent, obtains the compound of formula 6 in solvent E, and temperature of reaction is 0-100 ℃, and the reaction times is 3-16h;
(5) compound of formula 6 is in solvent G, and under the effect of alkali H, deprotection obtains the 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid of formula 1, and temperature of reaction is 10-100 ℃, and the reaction times is 1-10h.
Concrete reaction conditions is described below:
(1) in the step (1), solvent orange 2 A is selected from one or more in acetone, ethyl acetate, DMF (N, dinethylformamide), DMSO (methyl-sulphoxide base), NMP (N-Methyl pyrrolidone), tetrahydrofuran (THF), dioxane, toluene, the acetonitrile; Preferred solvent orange 2 A is selected from one or more in DMF, DMSO, NMP, dioxane or the toluene; Preferred solvent orange 2 A is selected from DMF, dioxane or toluene.Alkali B is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or cesium carbonate; Preferred alkali B is selected from sodium hydroxide, potassium hydroxide, salt of wormwood or cesium carbonate, and preferred alkali B is selected from sodium hydroxide or salt of wormwood.Described difluoromethyl reagent is selected from CHF 2Cl, CHF 2Br, 1-chloro-1,1-difluoroacetic acid sodium or 1-chloro-1,1-ethyl difluoro; Be preferably CHF 2Cl.
(2) in the step (2), solvent C is selected from one or more in ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, acetate, the water; Preferred solvent C is selected from one or more in methyl alcohol, ethanol, Virahol or the acetate, and preferred solvent C is selected from methyl alcohol or acetate.Reductive agent D is selected from one or more in tindichloride, tin tetrachloride, reduced iron powder, zinc powder, vat powder, sodium sulphite, palladium carbon or the nickel; Preferred reductive agent D is selected from tindichloride, reduced iron powder, palladium carbon or nickel, and preferred reductive agent D is selected from reduced iron powder or palladium carbon.Preferred temperature of reaction is 10-60 ℃, and preferred temperature of reaction is 20-50 ℃; The preferred reaction times is 2-12h, and the preferred reaction times is 3-10h.
(3) in the step (3), the concentration of dilute sulphuric acid is 10-70%; Preferred concentration is 15-40%, and preferred concentration is 20-30%.Preferred temperature of reaction is 0-70 ℃, and preferred temperature of reaction is 0-50 ℃; The preferred reaction times is 2-8h, and the preferred reaction times is 3-6h.
(4) in the step (4), solvent E is selected from one or more in acetone, ethyl acetate, DMF, DMSO, NMP, tetrahydrofuran (THF), dioxane, toluene, the acetonitrile; Preferred solvent E is one or more among DMF, DMSO or the NMP, and preferred solvent E is selected from DMF or NMP.Alkali F is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or the cesium carbonate; Preferred alkali F is one or more in sodium hydroxide, potassium hydroxide, salt of wormwood or the cesium carbonate, and preferred alkali F is selected from salt of wormwood or cesium carbonate.Encircle the compound that third methylating reagent is a formula 7, wherein X is a leavings group, as Cl, Br, OMs (mesyloxy) or OTs (tolysulfonyl oxygen base).Preferred temperature of reaction is 20-80 ℃, and preferred temperature of reaction is 60-75 ℃.The preferred reaction times is 5-15h, and the preferred reaction times is 9-13h.
Figure BDA0000040331230000041
(5) in the step (5), solvent G is selected from one or more in ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, acetate, the water; Preferred solvent G is selected from one or more in methyl alcohol, ethanol or the Virahol, and it is methyl alcohol or ethanol that preferred solvent G is selected from.Alkali H is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, yellow soda ash, salt of wormwood or the cesium carbonate; Preferred alkali H is one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide or the salt of wormwood; Preferred alkali H is sodium hydroxide, potassium hydroxide or salt of wormwood.Preferred temperature of reaction is 20-80 ℃, and preferred temperature of reaction is 60-75 ℃.The preferred reaction times is 2-5h, and the preferred reaction times is 2-3h.
The invention has the beneficial effects as follows easy and simple to handlely, it is all very high that each goes on foot intermediate purity.Method of the present invention can react fully and carry out, and side reaction is few, and each goes on foot the high and easy purifying of product yield.In addition, great advantage of the present invention is to can be used for suitability for industrialized production.
The invention will be further described in the mode of embodiment more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
The specific embodiment mode
Embodiment 1:3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid
Step (1): the preparation of 3-nitro-4-difluoro-methoxy-benzoic acid methyl esters
3-nitro-4-methyl hydroxybenzoate 26.0g, phenmethyl trimethyl ammonium chloride 0.67g, 50% sodium hydroxide 31.4g and dioxane 200mL are joined in the reactor, under violent stirring, in system, feed chlorodifluoromethane.After having reacted, add frozen water, use ethyl acetate extraction, anhydrous magnesium sulfate drying, remove solvent under reduced pressure after, obtain 3-nitro-4-difluoro-methoxy-benzoic acid methyl esters 28.4g, yield 87%.
Step (2): the preparation of 3-amino-4-difluoro-methoxy-benzoic acid methyl esters
3-nitro-4-difluoro-methoxy-benzoic acid methyl esters 28.0g is dissolved in the 500mL methyl alcohol, adds 10% palladium charcoal (containing 50% water) 2.8g, normal pressure hydrogenation 10h.Remove by filter the palladium charcoal, filtrate concentrating obtains 3-amino-4-difluoro-methoxy-benzoic acid methyl esters 24.2g, yield 98%.Crude product is directly used in next step without being further purified.
Step (3): the preparation of 3-hydroxyl-4-difluoro-methoxy-benzoic acid methyl esters
Under agitation, in the 210mL pure water, slowly add the 35mL vitriol oil, add 3-amino-4-difluoro-methoxy-benzoic acid methyl esters 24.0g, stir and make its dissolving.Ice-water bath is cooled to system temperature less than 5 ℃, slowly drips NaNO 2The aqueous solution (7.78g NaNO 2Be dissolved in the 30mL pure water), keep system temperature less than 5 ℃, restir 30min.Heating makes system temperature rise to 50 ℃, stirs 2h.System temperature is reduced to room temperature, stirs 1h.Filter washing, vacuum-drying.Re-crystallizing in ethyl acetate obtains 3-hydroxyl-4-difluoro-methoxy-benzoic acid methyl esters 20.2g, yield 84%.Step (4): the preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid methyl esters
Add 3-hydroxyl-4-difluoro-methoxy-benzoic acid methyl esters 20.0g, brooethyl cyclopropane 17mL, salt of wormwood 25.3g and DMF 100mL, 70 ℃ are stirred 12h down.Reaction system is told organic phase, washing, anhydrous magnesium sulfate drying with ethyl acetate and water dilution.After removing solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid methyl esters 22.5g, yield 90%.
Step (5): the preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid
Add 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid methyl esters 22.3g, methyl alcohol 600mL and 10% aqueous sodium hydroxide solution 1200mL, be heated to 70-75 ℃, stir 2h.Steam the methyl alcohol in the system of removing, with the normal heptane washing, water to pH<3, is used ethyl acetate extraction, anhydrous magnesium sulfate drying with hcl acidifying then.After removing solvent under reduced pressure, obtain crude product, use acetonitrile and sherwood oil recrystallization again, obtain white solid 18.0g, be 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, yield 85%.
Embodiment 2:3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid
Step (1): the preparation of 3-nitro-4-difluoro-methoxy-benzoic acid ethyl ester
3-nitro-4-nipagin A 35.0g, Tetrabutyl amonium bromide 3.5g, 35% sodium hydroxide 65mL and toluene 250mL are joined in the reactor, under violent stirring, in system, feed chlorodifluoromethane.After having reacted, add frozen water, tell organic phase, anhydrous magnesium sulfate drying, remove solvent under reduced pressure after, obtain 3-nitro-4-difluoro-methoxy-benzoic acid ethyl ester 36.8g, yield 85%.
Step (2): the preparation of 3-amino-4-difluoro-methoxy-benzoic acid ethyl ester
3-nitro-4-difluoro-methoxy-benzoic acid ethyl ester 36.0g is dissolved in the 500mL Glacial acetic acid, adds iron powder 63.0g, restir 3h under the room temperature in batches.Add 500mL toluene, diatomite filtration, filtrate concentrates.Resistates is dissolved in the ethyl acetate, saturated sodium bicarbonate solution washing, anhydrous magnesium sulfate drying.Filtrate concentrating obtains 3-amino-4-difluoro-methoxy-benzoic acid ethyl ester 26.4g, yield 83%.
Step (3): the preparation of 3-hydroxyl-4-difluoro-methoxy-benzoic acid ethyl ester
Under agitation, in the 210mL pure water, slowly add the 35mL vitriol oil, add 3-amino-4-difluoro-methoxy-benzoic acid ethyl ester 25.5g, stir and make its dissolving.Ice-water bath is cooled to system temperature less than 5 ℃, slowly drips NaNO 2The aqueous solution (7.78g NaNO 2Be dissolved in the 30mL pure water), keep system temperature less than 5 ℃, restir 30min.Heating makes system temperature rise to 50 ℃, stirs 3h.System temperature is reduced to room temperature, stirs 1h.Filter washing, vacuum-drying.Re-crystallizing in ethyl acetate obtains 3-hydroxyl-4-difluoro-methoxy-benzoic acid ethyl ester 21.8g, yield 85%.Step (4): the preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid ethyl ester
Add 3-hydroxyl-4-difluoro-methoxy-benzoic acid ethyl ester 21.3g, brooethyl cyclopropane 18mL, cesium carbonate 55.0g and DMF 120mL, 70 ℃ are stirred 10h down.Reaction system is told organic phase, washing, anhydrous magnesium sulfate drying with ethyl acetate and water dilution.After removing solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid ethyl ester 23.8g, yield 91%.
Step (5): the preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid
Add 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid ethyl ester 23.4g, methyl alcohol 600mL and 10% potassium hydroxide aqueous solution 1200mL, be heated to 60-65 ℃, stir 3h.Steam the methyl alcohol in the system of removing, with the normal heptane washing, water to pH<3, is used ethyl acetate extraction, anhydrous magnesium sulfate drying with hcl acidifying then.After removing solvent under reduced pressure, obtain crude product, use acetonitrile and sherwood oil recrystallization again, obtain white solid 17.8g, be 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, yield 84%.

Claims (10)

1. a method for preparing 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid is characterized in that comprising the steps: (a) formula 5Alkylation obtain formula 6Compound; (b) formula 6The compound deprotection obtain formula 13-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid; Wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
Figure 2010106030958100001DEST_PATH_IMAGE002
2. the preparation method described in the claim 1 is characterized in that:
(a) formula 5Compound in solvent E, under the effect of alkali F,, obtain formula with ring third methylating reagent reaction 6Compound, temperature of reaction is 0-100 ℃, the reaction times is 3-16 h; Solvent E be selected from acetone, ethyl acetate, DMF ( N, N-dimethyl formamide), DMSO (methyl-sulphoxide base), NMP ( N-methyl-2-pyrrolidone), one or more in tetrahydrofuran (THF), dioxane, toluene, the acetonitrile; Alkali F is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or the cesium carbonate; Encircling third methylating reagent is formula 7Compound, wherein X is a leavings group, is selected from Cl, Br, OMs (mesyloxy) or OTs (tolysulfonyl oxygen base);
Figure 2010106030958100001DEST_PATH_IMAGE004
(b) formula 6Compound in solvent G, under the effect of alkali H, deprotection obtains formula 13-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid, temperature of reaction is 10-100 ℃, the reaction times is 1-10 h; Solvent G is selected from one or more in ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, acetate, the water; Alkali H is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, yellow soda ash, salt of wormwood or the cesium carbonate.
3. the preparation method described in the claim 2 is characterized in that solvent E is selected from DMF or NMP; Alkali F is selected from salt of wormwood or cesium carbonate; Step (a) temperature of reaction is 60-75 ℃; Step (a) reaction times is 9-13 h; Solvent G is selected from methyl alcohol or ethanol; Alkali H is selected from sodium hydroxide, potassium hydroxide, salt of wormwood; Step (b) temperature of reaction is 60-75 ℃; Step (b) reaction times is 2-3 h.
4. the preparation method described in the claim 1 is characterized in that described formula 5Compound by formula 4Compound diazotization in sulphuric acid soln, hydrolysis obtains again, temperature of reaction is 0-90 ℃, the reaction times is 1-10 h; Wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
5. the preparation method described in the claim 4, the concentration that it is characterized in that dilute sulphuric acid is 20-30%; Temperature of reaction is 0-50 ℃; Reaction times is 3-6 h.
6. the preparation method described in the claim 4 is characterized in that described formula 4Compound by formula 3Compound in solvent C, be reduced agent D reduction and obtain, temperature of reaction is 0-80 ℃, the reaction times is 1-15 h; Solvent C is selected from one or more in ethyl acetate, acetonitrile, methyl alcohol, ethanol, Virahol, acetate, the water; Reductive agent D is selected from one or more in tindichloride, tin tetrachloride, reduced iron powder, zinc powder, vat powder, sodium sulphite, palladium carbon or the nickel; Wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
Figure 2010106030958100001DEST_PATH_IMAGE008
7. the preparation method described in the claim 6 is characterized in that solvent C is selected from methyl alcohol or acetate; Reductive agent D is selected from reduced iron powder or palladium carbon; Temperature of reaction is 20-50 ℃; Reaction times is 3-10 h.
8. the preparation method described in the claim 6 is characterized in that described formula 3Compound by formula 23-nitro-4-hydroxybenzoate in solvent orange 2 A, under the effect of alkali B, obtain with the difluoromethyl reagent react; Solvent orange 2 A is selected from one or more in acetone, ethyl acetate, DMF, DMSO, NMP, tetrahydrofuran (THF), dioxane, toluene, the acetonitrile; Alkali B is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium ethylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or the cesium carbonate; Difluoromethyl reagent is selected from CHF 2Cl, CHF 2Br, 1-chloro-1,1-difluoroacetic acid sodium or 1-chloro-1, one or more in the 1-ethyl difluoro; Wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
Figure 2010106030958100001DEST_PATH_IMAGE010
9. the preparation method described in the claim 8 is characterized in that solvent orange 2 A is selected from DMF, dioxane or toluene; Alkali B is selected from sodium hydroxide or salt of wormwood; Difluoromethyl reagent is selected from CHF 2Cl.
10. formula 5Compound, wherein R is C 1-6Alkyl, benzyl, substituted benzyl.
Figure 2010106030958100001DEST_PATH_IMAGE012
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CN102336703A (en) * 2011-07-20 2012-02-01 北京赛科药业有限责任公司 Method for preparing roflumilast
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CN102336705A (en) * 2011-10-28 2012-02-01 成都苑东药业有限公司 Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine
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CN115417766A (en) * 2022-08-31 2022-12-02 天津药明康德新药开发有限公司 Synthesis method of 3-hydroxy-4, 5-dimethoxy benzoic acid tert-butyl ester

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CN102336703A (en) * 2011-07-20 2012-02-01 北京赛科药业有限责任公司 Method for preparing roflumilast
CN102336703B (en) * 2011-07-20 2013-09-25 华润赛科药业有限责任公司 Method for preparing roflumilast
CN102336704A (en) * 2011-10-19 2012-02-01 丁克 Method for preparing Roflumilast
CN102336704B (en) * 2011-10-19 2013-04-17 丁克 Method for preparing Roflumilast
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