CN102775345A - Preparation method of roflumilast and intermediates - Google Patents
Preparation method of roflumilast and intermediates Download PDFInfo
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- CN102775345A CN102775345A CN2011101247525A CN201110124752A CN102775345A CN 102775345 A CN102775345 A CN 102775345A CN 2011101247525 A CN2011101247525 A CN 2011101247525A CN 201110124752 A CN201110124752 A CN 201110124752A CN 102775345 A CN102775345 A CN 102775345A
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Abstract
The invention relates to a method for preparation of 3-(cyclopropylmethoxy)-N-(3, 5-dichloropyridine-4-yl)-4-(difluoromethoxy)benzamide as shown in formula I, its N-oxides, and pharmaceutically acceptable acid addition salts, and also discloses intermediates involved in the preparation process. The preparation method provided in the invention has the advantages of simple and convenient process, high yield, and low cost, thus being suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field; More specifically; Relate to the midbody that relates among preparation method and the above-mentioned preparation method thereof of 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, its N-oxide compound or pharmaceutically acceptable acid additive salt.
Background technology
Roflumilast (roflumilast) is first selectivity phosphodiesterase 4 (PDE4) suppressor factor that secures permission and be used for chronic obstructive pulmonary disease (COPD) clinical treatment of Altana Pharma company research and development, successively obtains European Union in July, 2010 and in March, 2011 and ratifies with FDA (Food and Drug Adminstration).Its chemistry 3-(cyclo propyl methoxy) by name-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, structural formula is suc as formula shown in the I:
Described 3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenylformic acid and sulfur oxychloride in the International Patent Application WO 95/01338 and obtained acyl chlorides in reflux in toluene; Again with 4-amino-3; The condensation in sodium hydrogen/THF of 5-dichloropyridine obtains formula I compound, shown in reaction formula 1:
Reaction formula 1:
Among the above-mentioned disclosed preparation method, because 3, the amino in the 5-two chloro-4-aminopyridines active relatively poor; Need with highly basic such as sodium hydrogen pull out hydrogen later on again with acyl chloride reaction, make reaction conditions violent relatively, therefore be prone to produce by product 3-cyclo propyl methoxy-N-(3 in process of production; 5-dichloropyridine-4-yl)-the 4-hydroxybenzamide; The amount of this by product even repeatedly all not reducing behind the recrystallization has not only reduced the total recovery of route, has also increased production cost indirectly.
Therefore, seek a suitability for industrialized production route that technology is easy, yield is high, cost is low and prepare roflumilast, that is, 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM just seems particularly urgent.
Summary of the invention
An object of the present invention is to provide the method for preparation 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt.
Another object of the present invention provides the midbody that relates in the above-mentioned preparation process.
For realizing above-mentioned purpose; The invention provides 3-(cyclo propyl methoxy)-N-(3 shown in the preparation formula I; 5-dichloropyridine-4-yl)-method of 4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt; Said method comprises: shown in reaction formula 2, formula II compound and the reaction of formula III compound obtain formula IV midbody, obtain formula I compound with difluoromethyl reagent (V) reaction again; Perhaps, shown in reaction formula 3, formula II compound and difluoromethyl reagent (V) reaction obtain formula VI midbody compound, obtain formula I compound with the reaction of formula III compound again.
Reaction formula 2:
Reaction formula 3:
In reaction formula 2 or 3, LG representation hydroxy or leavings group, said leavings group are selected from halogen, mesyloxy, trifluoro-methanesulfonyl oxy and the Methyl benzenesulfonyl oxygen base, and wherein, LG is preferably halogen or hydroxyl;
Said difluoromethyl reagent is selected from difluorochloromethane, difluorobromomethane, ethyl bromide difluoride, difluoro chloracetate and the 2-chloro-2-difluoro acetophenone, and wherein, said difluoro chloracetate is preferably difluoro methyl chloroacetate or difluoro ethyl chloroacetate.
More specifically, formula II compound and formula III compound in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula IV midbody under suitable solvent, suitable temperature; Formula IV midbody and difluoromethyl reagent equally in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula I compound under suitable solvent, suitable temperature; Perhaps, formula II compound and difluoromethyl reagent in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula VI midbody under suitable solvent, suitable temperature; Formula VI midbody and formula III compound equally in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula I compound under suitable solvent, suitable temperature;
Said alkali comprises organic bases and mineral alkali; Said organic bases is sodium hydrogen, sodium alkoxide, potassium alcoholate, triethylamine, Trimethylamine 99, TBuA, triisopropylamine, diisopropylethylamine, DBU (1; 8-diazabicyclo (5; 4,0)-the 7-hendecene), DBN (1,5-diazabicyclo [4.3.0]-5-nonene), dimethylamino pyridine or its mixture; Said mineral alkali is alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide or its mixture; Said alkaline carbonate is Quilonum Retard, yellow soda ash, salt of wormwood or cesium carbonate; Said alkali metal hydrocarbonate is sodium hydrogencarbonate or saleratus; Said alkali metal hydroxide is Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide.
Said phase-transfer catalyst be quaternary ammonium salt or season phosphonium salt, said quaternary ammonium salt is selected from Tetramethylammonium iodide, tetrabutylammonium iodide, 1-picoline iodide, benzyl tributyl brometo de amonio, Tetrabutyl amonium bromide (TBAB), tetraethylammonium bromide, hexadecyl tributyl phosphonium ammonium, tertiary butyl ethyl dimethyl-brometo de amonio, tetrabutylammonium chloride, tetramethyl--2-butyl ammonium chloride, tri-n-octyl methyl ammonium chloride, trimethylammonium cyclopropyl ammonium chloride, benzyltriethylammoinium chloride (TEBA), DTAC and the tetradecyl trimethyl ammonium chloride; Said season, phosphonium salt was selected from tributyl-methyl phosphonium phosphonium iodide, triethyl methyl phosphonium iodide, tetrabutyl phosphonium bromide phosphine, benzyl triphenyl bromide phosphine, tetraphenylphosphonium chloride and the tetrabutylphosphonium chloride.
Said suitable solvent comprises: ethers, like dioxane, THF, ether, propyl ether, isopropyl ether or glycol dimethyl ether; Nitrile is like acetonitrile or cyanobenzene; Alcohols is like methyl alcohol, ethanol, Virahol or butanols; Ketone is like acetone, MIBK or methyl-sulphoxide; The ester class is like ETHYLE ACETATE or isopropyl acetate; Varsol is like benzene, YLENE, toluene, methylene dichloride, tetracol phenixin, trichloromethane, hexanaphthene or normal hexane; Amides, like N, dinethylformamide, N, N-DEF, DMAC N,N or N-Methyl pyrrolidone; And the mixture of above-mentioned solvent.
Said suitable reaction temperature is 10 ℃～150 ℃; Preferred 20 ℃～120 ℃.
3-(cyclo propyl methoxy)-N-(3 shown in the said preparation formula I; 5-dichloropyridine-4-yl)-method of 4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt; Further comprise the steps: shown in reaction formula 4; To 3, the hydroxyl protection of 4-resorcylic acid (VII) obtains compound VIII, and the formula VIII compound reactive derivative that first activation obtains in the presence of the carboxylic acid activating agent is again with 3; 5-two chloro-4-aminopyridines (IX) or its acid salt are at reacting generating compound X in the presence of the alkali, under appropriate organic solvent, suitable temperature, and compounds X dehydroxylation protection base again obtains compound I I; Perhaps, the esterification of formula VIII compound elder generation obtains formula XI compound, or, the hydroxyl protection of the ester (3,4-resorcylic acid ester) of compound VI I is obtained formula XI compound; Formula XI compound and 3,5-two chloro-4-aminopyridines (IX) or its acid salt carry out amidate action and obtain compounds X, and compounds X dehydroxylation protection base again obtains compound I I;
Reaction formula 4
Wherein, PG is a phenolic hydroxyl group protection base, and PG can form ether or ester group with phenolic hydroxyl group;
PG can be selected from ethanoyl, benzoyl-, valeryl, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based, trimethyl silicon based, triisopropylsilyl, triethyl are silica-based, benzyl, in methoxy-benzyl, methyl, allyl group, trityl group, methoxymethyl, methylthiomethyl, benzyloxymethyl and the tert.-butoxy methyl;
R is C
1-8The straight or branched alkyl is preferably C
1-4The straight or branched alkyl most preferably is methyl or ethyl;
More specifically, described carboxylic acid activating agent is selected from any one in sulfur oxychloride, oxalyl chloride, thionyl bromide, POCl3, pivaloyl chloride, chloro-formic ester, mixed acid anhydride, the carbodiimide like NSC 57182 (DCC), 4-Dimethylamino pyridine (DMAP) and the phosphinylidyne diimidazole (CDI);
Said alkali is selected from any one in sodium hydride, potassium hydride KH, lithium alkylide (n-Butyl Lithium or tert-butyl lithium), Lithamide, sodium amide, potassium amide, lithium diisopropylamine (LDA), hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS), sodium ethylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine and the Trimethylamine 99;
Described organic solvent comprises: hydro carbons, like benzene, YLENE, toluene, methylene dichloride or chloroform; Ethers is like THF, ether, propyl ether or 1,4-dioxane; Amides, like N, dinethylformamide, N, N-DEF or DMAC N,N; Nitrile is like acetonitrile; Methyl-sulphoxide; And the mixture of above-mentioned solvent, wherein, preferred organic is THF, N, dinethylformamide or methyl-sulphoxide;
Temperature of reaction is 0 ℃～150 ℃.
Described esterification is 3 of a hydroxyl protection, 4-resorcylic acid (VIII) and alcohol reaction under sulfur oxychloride or small amount of acid catalysis; Said alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and is fit in other alcohol of the present invention; Said acid is optional in sulfuric acid, hydrochloric acid and its mixture;
Be well known to those skilled in the art for the method for the protection of hydroxyl and deprotection, the method for protection and deprotection is referring to " the protection base in the organic synthesis ", and 2007, the 4 editions, T.W.Greene and P.G.M.Wuts, John Wiley & Sons.
The present invention also provides 3-(cyclo propyl methoxy)-N-(3 shown in other a kind of preparation formula I; 5-dichloropyridine-4-yl)-method of 4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt; Shown in reaction formula 5; Said method comprises that formula XII compound and the reaction of formula XIII compound obtain formula XIV midbody, obtain formula I through chlorination again:
Reaction formula 5:
More specifically; The first activation in the presence of the carboxylic acid activating agent of formula XII compound obtains 3-(cyclo propyl methoxy)-benzoic reactive derivative of 4-(difluoro-methoxy); Again with formula XIII compound at reacting generating compound XIV in the presence of the alkali, under appropriate organic solvent, suitable temperature, obtain formula I compound through chlorination again;
Described carboxylic acid activating agent is selected from any one in sulfur oxychloride, oxalyl chloride, thionyl bromide, POCl3, pivaloyl chloride, chloro-formic ester, mixed acid anhydride, the carbodiimide like NSC 57182 (DCC), 4-Dimethylamino pyridine (DMAP) and the phosphinylidyne diimidazole (CDI);
Said alkali is selected from any one in sodium hydride, potassium hydride KH, lithium alkylide (n-Butyl Lithium or tert-butyl lithium), Lithamide, sodium amide, potassium amide, lithium diisopropylamine (LDA), hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS), sodium ethylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine and the Trimethylamine 99;
Described organic solvent comprises: hydro carbons, like benzene, YLENE, toluene, methylene dichloride or chloroform; Ethers is like THF, ether, propyl ether or 1,4-dioxane; Amides, like N, dinethylformamide, N, N-DEF or DMAC N,N; Nitrile is like acetonitrile; Methyl-sulphoxide; And the mixture of above-mentioned solvent, wherein, preferred organic is THF, N, dinethylformamide or methyl-sulphoxide;
Temperature of reaction is 0 ℃～150 ℃.
Described chlorination reagent is POCl3, phosphorus pentachloride or phosphorus trichloride;
3-(cyclo propyl methoxy)-benzoic reactive derivative of 4-(difluoro-methoxy) is that the method for knowing by one of skill in the art prepares.For example, 3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenylformic acid and sulfur oxychloride in the presence of the N of catalytic amount, the corresponding acyl chlorides of prepared in reaction in inert solvent.
The present invention also provides following midbody compound:
3,4-dihydroxyl-N-(3,5-dichloropyridine-4-yl) BM
3-hydroxy-n-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM
3-(cyclo propyl methoxy)-N-(3,5-dihydroxy-pyridine-4-yl)-4-(difluoro-methoxy) BM
Embodiment
Further specify the present invention through following examples, following examples only are used for the preferred embodiments of the invention more specifically are described, are not used in technical scheme of the present invention is limited.
Among the following embodiment, nucleus magnetic resonance is by Bruker AMX-300 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; Mass spectrum is measured by MAT-711 type and MAT-95 type mass spectrograph; Column chromatography is with silica gel 200-300 order, and Haiyang Chemical Plant, Qingdao produces; The HSGF-254 type thin-layer chromatography precoated plate that the TLC silica-gel plate is produced for the chemical plant, Yantai; The sherwood oil boiling range is 60-90 ℃; Adopt uv lamp, the colour developing of iodine cylinder.If do not particularly point out working method, said concentrated finger steams with the solvent that Rotary Evaporators will prepare in the compound solution among the embodiment; Said drying refers to will prepare the compound oven dry with the DHG-9240A thermostatic drying chamber at 60 ℃.
Preparation example 3, the benzoic preparation of 4-diacetoxy
3,4-resorcylic acid (7.81g) is dissolved in the 2N KOH aqueous solution (76ml), and the ice-water bath cooling slowly drips aceticanhydride (13ml); Finish, continued stirring reaction 30 minutes, reaction solution is acidified to pH1～2 with concentrated hydrochloric acid, filters the solid of separating out; Oven dry gets 3,4-diacetoxy phenylformic acid 9.3g.
Embodiment 1 N-(3,5-dichloropyridine-4-yl)-3, the preparation of 4-diacetoxy BM
3, (4.8g 0.02mol) is dissolved in the methylene dichloride (25ml) 4-diacetoxy phenylformic acid, the ice-water bath cooling; Slowly drip the DMF of oxalyl chloride (4ml) and catalytic amount, finish, room temperature reaction 2 hours, excessive oxalyl chloride and solvent are removed in decompression; Residue is dissolved in the chloroform (25ml), adds triethylamine (2.3ml), is cooled to 4 ℃ with ice-water bath, adds 4-amino-3 in batches; (3.4g 0.021mol), finishes stirred overnight at room temperature to the 5-dichloropyridine.Add entry (50ml) in the reaction solution,, separate organic phase with chloroform (25ml * 3) extraction, anhydrous sodium sulfate drying, concentrate product 6.8g, yield: 89%.
Embodiment 2 N-(3,5-dichloropyridine-4-yl)-3, the preparation of 4-dihydroxy benzoyl amine (II)
N-(3,5-dichloropyridine-4-yl)-3, (5.7g 0.015mol) is dissolved in the methylene dichloride (25ml) 4-diacetoxy BM; Add 2NHCl (5ml), stirring at room reaction 1 hour adds entry (50ml); Separate organic phase, water merges organic phase with methylene dichloride (15ml * 2) extraction; Saturated common salt washing, anhydrous sodium sulfate drying, concentrate product 4.4g.
Embodiment 3 N-(3,5-dichloropyridine-4-yl)-3, the preparation of 4-diacetoxy BM
3, (2.38g 0.01mol) is dissolved in the anhydrous methanol (20ml) 4-diacetoxy phenylformic acid, and low temperature adds sulfur oxychloride (1.5ml) catalysis down; 70～80 ℃ were refluxed 3 hours, naturally cooled to room temperature, added 4-amino-3 in the reaction solution, 5-dichloropyridine (1.63g; 0.01mol), 35 ℃～40 ℃ were reacted 3 hours, steamed and removed methyl alcohol, added entry (50ml); With chloroform (25ml * 3) extraction, separate organic phase, anhydrous sodium sulfate drying, concentrate product 3.8g.
The preparation of embodiment 4 3-hydroxy-ns-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM (VI)
N-(3,5-dichloropyridine-4-yl)-3, and the 4-dihydroxy benzoyl amine (4.4g, 0.015mol); Difluorochloromethane (1.3g, 0.015mol), 30% aqueous sodium hydroxide solution (25ml); Tetrabutyl amonium bromide (3g) and toluene (50ml) mix, and 20 ℃～35 ℃ reactions, reaction is finished; Separate organic phase, anhydrous sodium sulfate drying, concentrate target compound 3.2g.
The preparation of embodiment 53-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM (I)
3-hydroxy-n-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM (3.2g, 9mmol), cyclopropyl monobromomethane (1.24g; 9mmol), salt of wormwood (1.25g, 9mmol) and acetone (50ml) mix; 40 ℃ were reacted 18 hours, solids filtered, and concentrated filtrate gets target compound 3.4g.
The preparation of embodiment 6 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-hydroxybenzamide (IV)
N-(3,5-dichloropyridine-4-yl)-3, and the 4-dihydroxy benzoyl amine (4.4g, 0.015mol); The cyclopropyl monobromomethane (2.0g, 0.016mol), salt of wormwood (2.03g, 0.016mol) and acetone (50ml) mix; 40 ℃ were reacted 12 hours, and filtering solid, concentrated filtrate get target compound 4.1g.
The preparation of embodiment 73-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM (I)
3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-hydroxybenzamide (4.1g, 0.012mol); Difluorochloromethane (1.1g, 0.013mol), 30% aqueous sodium hydroxide solution (30ml); Tetrabutyl amonium bromide (2.5g) and toluene (50ml) mix, and 20 ℃～35 ℃ reactions, reaction is finished; Separate organic phase, anhydrous sodium sulfate drying, concentrate target compound 3.8g.
Claims (10)
1. method for preparing 3-shown in the formula I (cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt:
Said method comprises: shown in reaction formula 2, formula II compound and the reaction of formula III compound obtain formula IV midbody, obtain formula I compound with difluoromethyl reagent V reaction again; Perhaps, shown in reaction formula 3, formula II compound and difluoromethyl reagent V reaction obtain formula VI midbody, obtain formula I compound with the reaction of formula III compound again;
Reaction formula 2:
Reaction formula 3:
In reaction formula 2 or 3, LG representation hydroxy or leavings group, said leavings group are selected from halogen, mesyloxy, trifluoro-methanesulfonyl oxy and the Methyl benzenesulfonyl oxygen base;
Said difluoromethyl reagent is selected from difluorochloromethane, difluorobromomethane, ethyl bromide difluoride, difluoro chloracetate and the 2-chloro-2-difluoro acetophenone.
2. preparation method according to claim 1, wherein, LG is halogen or hydroxyl; Said difluoro chloracetate is difluoro methyl chloroacetate or difluoro ethyl chloroacetate.
3. preparation method according to claim 1, formula II compound and formula III compound in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula IV midbody in solvent, under 10 ℃～150 ℃ the temperature; Formula IV midbody and difluoromethyl reagent equally in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula I compound in solvent, under 10 ℃～150 ℃ the temperature; Perhaps, formula II compound and difluoromethyl reagent in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula VI midbody in solvent, under 10 ℃～150 ℃ the temperature; Formula VI midbody and formula III compound equally in the presence of alkali, be with or without in the presence of the phase-transfer catalyst, reaction obtains formula I compound in solvent, under 10 ℃～150 ℃ the temperature.
4. preparation method according to claim 3; Said alkali is organic bases or mineral alkali; Said organic bases is sodium hydrogen, sodium alkoxide, potassium alcoholate, triethylamine, Trimethylamine 99, TBuA, triisopropylamine, diisopropylethylamine, 1,8-diazabicyclo (5,4; 0)-and 7-hendecene, 1,5-diazabicyclo [4.3.0]-5-nonene, dimethylamino pyridine or its mixture; Said mineral alkali is alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide or its mixture; Said alkaline carbonate is Quilonum Retard, yellow soda ash, salt of wormwood or cesium carbonate; Said alkali metal hydrocarbonate is sodium hydrogencarbonate or saleratus; Said alkali metal hydroxide is Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide;
Said phase-transfer catalyst be quaternary ammonium salt or season phosphonium salt, said quaternary ammonium salt is selected from Tetramethylammonium iodide, tetrabutylammonium iodide, 1-picoline iodide, benzyl tributyl brometo de amonio, Tetrabutyl amonium bromide, tetraethylammonium bromide, hexadecyl tributyl phosphonium ammonium, tertiary butyl ethyl dimethyl-brometo de amonio, tetrabutylammonium chloride, tetramethyl--2-butyl ammonium chloride, tri-n-octyl methyl ammonium chloride, trimethylammonium cyclopropyl ammonium chloride, benzyltriethylammoinium chloride, DTAC and the tetradecyl trimethyl ammonium chloride; Said season, phosphonium salt was selected from tributyl-methyl phosphonium phosphonium iodide, triethyl methyl phosphonium iodide, tetrabutyl phosphonium bromide phosphine, benzyl triphenyl bromide phosphine, tetraphenylphosphonium chloride and the tetrabutylphosphonium chloride;
Said solvent is selected from: be the ethers of dioxane, THF, ether, propyl ether, isopropyl ether or glycol dimethyl ether; Nitrile for acetonitrile or cyanobenzene; Alcohols for methyl alcohol, ethanol, Virahol or butanols; Ketone for acetone, MIBK or methyl-sulphoxide; Ester class for ETHYLE ACETATE or isopropyl acetate; Varsol for benzene, YLENE, toluene, methylene dichloride, tetracol phenixin, trichloromethane, hexanaphthene or normal hexane; Be N, dinethylformamide, N, the amide solvent of N-DEF, DMAC N,N or N-Methyl pyrrolidone; And in the mixture of above-mentioned solvent;
Said temperature is 20 ℃～120 ℃.
5. preparation method according to claim 1; Further comprise the preparation of formula II compound; Shown in reaction formula 4; To 3, the hydroxyl protection of 4-resorcylic acid VII obtains compound VIII, and the formula VIII compound reactive derivative that first activation obtains in the presence of the carboxylic acid activating agent is again with 3; 5-two chloro-4-aminopyridine IX or its acid salt are at reacting generating compound X in the presence of the alkali, in organic solvent, under 0 ℃～150 ℃ the temperature, and compounds X dehydroxylation protection base again obtains compound I I; Perhaps; The esterification of formula VIII compound elder generation obtains formula XI compound; Or to the ester 3 of compound VI I, the hydroxyl protection of 4-resorcylic acid ester obtains formula XI compound, formula XI compound and 3; 5-two chloro-4-aminopyridine IX or its acid salt carry out amidate action and obtain compounds X, and compounds X dehydroxylation protection base again obtains compound I I;
Reaction formula 4:
In reaction formula 4, PG is a phenolic hydroxyl group protection base, and PG and phenolic hydroxyl group form ether or ester group;
R is C
1-8The straight or branched alkyl.
6. preparation method according to claim 5, PG are selected from ethanoyl, benzoyl-, valeryl, tertiary butyl dimethyl-is silica-based, tert-butyl diphenyl is silica-based, trimethyl silicon based, triisopropylsilyl, triethyl are silica-based, benzyl, in methoxy-benzyl, methyl, allyl group, trityl group, methoxymethyl, methylthiomethyl, benzyloxymethyl and the tert.-butoxy methyl;
R is C
1-4The straight or branched alkyl;
Described carboxylic acid activating agent is selected from sulfur oxychloride, oxalyl chloride, thionyl bromide, POCl3, pivaloyl chloride, chloro-formic ester, mixed acid anhydride, is in the carbodiimide of NSC 57182,4-Dimethylamino pyridine and the phosphinylidyne diimidazole any one;
Said alkali is selected from any one in sodium hydride, potassium hydride KH, n-Butyl Lithium, tert-butyl lithium, Lithamide, sodium amide, potassium amide, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, sodium ethylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine and the Trimethylamine 99;
Said organic solvent is selected from: be the hydro carbons of benzene, YLENE, toluene, methylene dichloride or chloroform; Be THF, ether, propyl ether or 1, the ethers of 4-dioxane; Be N, dinethylformamide, N, the amides of N-DEF or DMAC N,N; Nitrile for acetonitrile; Methyl-sulphoxide; And in the mixture of above-mentioned solvent;
Described esterification is 3 of a hydroxyl protection, and 4-resorcylic acid VIII reacts under sulfur oxychloride or acid catalysis with alcohol.
7. preparation method according to claim 6, wherein,
R is methyl or ethyl;
Said organic solvent is THF, N, dinethylformamide or methyl-sulphoxide;
Alcohol in the described esterification is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol and the isopropylcarbinol, and the acid in the described esterification is selected from sulfuric acid, hydrochloric acid and its mixture.
8. one kind prepares 3-shown in the formula I (cyclo propyl methoxy)-N-(3; 5-dichloropyridine-4-yl)-method of 4-(difluoro-methoxy) BM, its N-oxide compound, pharmaceutically acceptable acid additive salt; Shown in reaction formula 5; This method comprises: the first activation in the presence of the carboxylic acid activating agent of formula XII compound obtains 3-(cyclo propyl methoxy)-benzoic reactive derivative of 4-(difluoro-methoxy); Again with formula XIII compound at reacting generating compound XIV in the presence of the alkali, in organic solvent, under 0 ℃～150 ℃ the temperature, obtain formula I compound through chlorination again:
Reaction formula 5:
9. preparation method according to claim 8, wherein,
Described carboxylic acid activating agent is selected from sulfur oxychloride, oxalyl chloride, thionyl bromide, POCl3, pivaloyl chloride, chloro-formic ester, mixed acid anhydride, is in the carbodiimide of NSC 57182,4-Dimethylamino pyridine and the phosphinylidyne diimidazole any one;
Said alkali is selected from any one in sodium hydride, potassium hydride KH, n-Butyl Lithium, tert-butyl lithium, Lithamide, sodium amide, potassium amide, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, sodium ethylate, potassium tert.-butoxide, sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine and the Trimethylamine 99;
Described organic solvent is selected from: be the hydro carbons of benzene, YLENE, toluene, methylene dichloride or chloroform; Be THF, ether, propyl ether or 1, the ethers of 4-dioxane; Be N, dinethylformamide, N, the amides of N-DEF or DMAC N,N; Nitrile for acetonitrile; Methyl-sulphoxide; And in the mixture of above-mentioned solvent;
The reagent that said chlorination uses is POCl3, phosphorus pentachloride or phosphorus trichloride.
10. the midbody compound that has following structure:
3-(cyclo propyl methoxy)-N-(3,5-dihydroxy-pyridine-4-yl)-4-(difluoro-methoxy) BM.
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| CN102942521A (en) * | 2012-11-27 | 2013-02-27 | 四川科伦药物研究有限公司 | Preparation method of roflumilast |
| CN109748780A (en) * | 2017-11-02 | 2019-05-14 | 中国医学科学院药物研究所 | The synthetic method of a kind of four poly- benzyl compounds |
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| MX2018002575A (en) * | 2015-09-04 | 2018-07-06 | Shin Poong Pharmaceutical Co Ltd | Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same. |
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| PL2125736T3 (en) * | 2006-12-22 | 2011-09-30 | Leo Pharma As | Substituted acetophenones useful as pde4 inhibitors |
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| CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
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| CN102942521A (en) * | 2012-11-27 | 2013-02-27 | 四川科伦药物研究有限公司 | Preparation method of roflumilast |
| CN102942521B (en) * | 2012-11-27 | 2015-08-05 | 四川科伦药物研究有限公司 | The preparation method of roflumilast |
| CN109748780A (en) * | 2017-11-02 | 2019-05-14 | 中国医学科学院药物研究所 | The synthetic method of a kind of four poly- benzyl compounds |
| CN109748780B (en) * | 2017-11-02 | 2021-09-14 | 中国医学科学院药物研究所 | Synthetic method of tetrapolybenzyl compounds |
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