CN104513196B - The synthetic method of roflumilast - Google Patents

The synthetic method of roflumilast Download PDF

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CN104513196B
CN104513196B CN201510021736.1A CN201510021736A CN104513196B CN 104513196 B CN104513196 B CN 104513196B CN 201510021736 A CN201510021736 A CN 201510021736A CN 104513196 B CN104513196 B CN 104513196B
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roflumilast
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synthetic method
chloride
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CN104513196A (en
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洪健
刘国斌
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An Run Pharmaceutical Technology (suzhou) Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

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Abstract

The invention provides a kind of synthetic method of roflumilast, comprise the following steps：（a）In organic solvent, compound（I）There is exchange reaction generation intermediate under reflux with magnesium or RMgBr, the intermediate occurs slotting carbonyl reaction at 0 ~ 50 DEG C, obtains compound with carbon dioxide（II）；Or in organic solvent, compound（I）Reacted at 90 ~ 70 DEG C generation intermediate with n-BuLi, the intermediate occurs slotting carbonyl at 90 ~ 70 DEG C and reacts with carbon dioxide, obtains compound（II）；（b）In organic solvent, step（a）In the compound that obtains（II）With pivaloyl chloride or sulfonic acid chloride at 0 ~ 50 DEG C, generation mixed acid anhydride intermediate is reacted in the presence of alkali, the mixed acid anhydride intermediate and 3,5 dichloro-4,4 aminopyridines react at 0 ~ 70 DEG C and obtain compound（III）Roflumilast.Method of the present invention process route is short, it is to avoid raw material and reagent cost are cheap, and total recovery is high, and reaction condition is gentle, is adapted to industrialized production.The synthetic route of the method is as follows：

Description

The synthetic method of roflumilast
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to a kind of synthetic method of roflumilast.
Background technology
Roflumilast (roflumilast), chemical entitled N- (3,5- dichloropyridine -4- bases) the third methoxyl group of -3- rings -4- two Fluorine methoxy benzamide, is researched and developed by German Anda (Altana) company, Metrizamide company of Switzerland (Nycomed Pharma GmbH phosphodiesterase 4 (PDE4) inhibitor of III clinical trial phases) is completed, and is got the Green Light in Europe in July, 2010, Then in the listing of Germany, Britain and Spain, its trade name Daxas.In March, 2011 obtains U.S. FDA approval again, in the U.S. Listing.Roflumilast is 4 type phosphodiesterase (PDE-4) long-acting inhibitor of selectivity, there is antiinflammatory action.Roflumilast is phosphoric acid Diesterase -4 (PDE-4) inhibitor, is novel C OPD medicines.It is coughed for treating serious COPD patient bronchitis correlation Cough the symptom excessive with mucus.Phosphodiesterase is one group at least includes 11 kinds of enzyme races of hypotype enzyme, with catalytic decomposition courier The effect of molecule cyclic adenosine monophosphate and (or) cyclic guanylic acid.Phosphodiesterase-4 is a kind of main ring gland in inflammation and immunocyte Nucleotide metabolism enzyme, and inhibitors of phosphodiesterase-4 then has including suppressing inflammatory mediator release and suppressing including immune cell activation Extensive anti-inflammatory activity.Also display has had response to treatment to inhibitors of phosphodiesterase-4 in animal airway inflammatory model.Should Medicine is the medicine of the first treatment chronic obstructive pulmonary disease (COPD) for getting the Green Light during the last ten years.This product can be subtracted by suppressing PDE4 The release of few inflammatory mediator, and then reduce the damage that the breathing problems such as COPD and asthma are caused to lung tissue.
So far, the synthetic method of roflumilast mainly has following several：
1st, the use of catechol is initiation material, is reacted by with Cyclopropylmetyl bromide, and and CHF2Cl reactions obtain ether Class；By Pd (OAc)2Then and SOCl catalysis CO intercalation reactions, obtain correspondence carboxylic acid,2Reaction, obtains corresponding acyl chlorides.Acyl chlorides and Aminopyridine reacts and obtains final product roflumilast (WO2004033430,2004).
The reaction scheme of the method is as follows：
2nd, the use of 3,4- 4-dihydroxy benzaldehydes is initiation material, is reacted with Cyclopropylmetyl bromide；Then, CHF2Cl carries out alkane Glycosylation reaction, oxidation reaction obtains corresponding carboxylic acid；Carboxylic acid is in N- methylmorpholines (NMM) and the 2- (nitrogen of 7- azos benzo three Azoles)-N, N, N ', reacted with aminopyridine in the presence of N '-tetramethylurea hexafluorophosphoric acid ester (HATU), obtain final product sieve fluorine department Special (CN102336703,2012).
3rd, the use of para hydroxybenzene cyanogen is initiation material and CHF2Cl is reacted, and reduction obtains amino benzenes compounds；Through Phenol compound is obtained by diazo-reaction, then after hydrolyzing；Then, then with Cyclopropylmetyl bromide react, obtain ether, then exist H2O2In the presence of, hydrolysis obtains corresponding benzamide, then carries out metal catalyzed coupling reaction with haloperidid and obtain final product sieve Fluorine department spy (CN102351787,2012).
Used expensive palladium, Pd/C catalyst and dehydrating agent HATU in the above method, production cost compared with It is high；In addition, synthesis needs special installation, it is difficult to amplify production.
The content of the invention
To overcome above mentioned problem of the prior art, the invention provides a kind of synthetic method of roflumilast, the method Synthetic route it is shorter, the cost of raw material and reagent is relatively low, and yield and product purity are higher, are suitable for industrialized production.
The technical solution adopted by the present invention is：A kind of synthetic method of roflumilast, comprises the following steps：
A () in organic solvent, compound (I) occurs in the middle of exchange reaction generation under reflux with magnesium or RMgBr There is slotting carbonyl reaction in body, the intermediate, obtain compound (II) with carbon dioxide at 0~50 DEG C；Or
In organic solvent, compound (I) and n-BuLi react generation intermediate at -90~-70 DEG C, in this There is slotting carbonyl reaction in mesosome, obtain compound (II) with carbon dioxide at -90~-70 DEG C；
B () in organic solvent, the compound (II) obtained in step (a) is with pivaloyl chloride or sulfonic acid chloride at 0~50 DEG C Under, generation mixed acid anhydride intermediate is reacted in the presence of alkali, the mixed acid anhydride intermediate and the chloro- 4-aminopyridine of 3,5- bis- exist Reaction obtains compound (III) roflumilast at 0~70 DEG C；
Synthetic route is as follows：
Further, in step (a), compound (I) is selected from four with magnesium or RMgBr reaction organic solvent used In hydrogen furans, ether, glycol dimethyl ether, 2- methyltetrahydrofurans, 1,4- dioxane, n-butyl ether and methyl tertiary butyl ether(MTBE) One or more.
Further, compound (I) organic solvent used with n-BuLi reaction is selected from tetrahydrochysene furan in step (a) Mutter, in ether, glycol dimethyl ether, 2- methyltetrahydrofurans, 1,4- dioxane, n-butyl ether and methyl tertiary butyl ether(MTBE) one Plant or several.
Further, in step (a), RMgBr is methyl-magnesium-chloride, ethylmagnesium chloride or isopropylmagnesium chloride.
Further, in step (a), carbon dioxide is carbon dioxide, or solid carbon dioxide, i.e. dry ice.
Preferably, in step (a), the time of exchange reaction is 1-4 hours.
Preferably, in step (a), compound (I) is 1-4 hours with the time of n-BuLi (n-BuLi) reaction, and The time that gained intermediate carries out inserting carbonyl reaction with carbon dioxide after their reactions is 2-5 hours.
Further, in step (b), organic solvent be selected from tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, One or more in ether, n-butyl ether, methyl tertiary butyl ether(MTBE), acetonitrile or ethyl acetate.
Preferably, in step (b), alkali be selected from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, two (isopropyl) ethamine, One or more in pyridine or carbon -7- alkene (DBU) of 1,8- diazabicylos 11.
Preferably, in step (b), compound (II) is 1-10 hours with the time of acyl chloride reaction, in the middle of mixed acid anhydride Body is 2-8 hours with the time of the chloro- 4-aminopyridine carbonyl reactions of 3,5- bis-.
In the present invention, with magnesium or RMgBr there is the intermediate of exchange reaction generation, and compound in compound (I) (I) react the intermediate of generation with n-BuLi, it is not necessary to separates, directly in reaction dissolvent with carbon dioxide reaction, Obtain compound (II).That is, exchange reaction can use identical solvent with the reaction of slotting carbonyl.Compound (I) is sent out with n-BuLi Raw reaction, and the intermediate that the reaction is generated reacts with the slotting carbonyl of carbon dioxide generation, it is possible to use identical solvent.
Compared with prior art, the present invention has advantages below：The present invention is initiation material using compound (I), is passed through Grignard or n-BuLi/CO2Reaction, obtains correspondence carboxylic acid, then dexterously uses sulfonic acid chloride (RSO2) or pivaloyl chloride is carried out Cl Reaction obtains mixed anhydride, then obtains final product roflumilast with aminopyridine reaction.By using above-mentioned technical proposal, this hair The process route of bright description roflumilast synthetic method is short, generally speaking, only 2 steps reaction, it is to avoid using in conventional art Expensive catalyst, strong acid, highly basic etc., raw material and reagent cost are cheap, and total recovery is high, product purity (purity high> 99%), reaction condition is gentle, is adapted to industrialized production.
Specific embodiment
With reference to specific embodiment, the present invention will be described in further detail.
Embodiment 1
Synthesis compound (II)
Example 1-1：Metal magnesium rod (0.12mol, 2.88g) adds anhydrous THF (50ml) in 250ml there-necked flasks, a small amount of iodine, It is heated to 40 DEG C.Then THF (100ml) solution of compound (I) (0.1mol, 29.3g) is added dropwise.After completion of dropping, continue to add Heat backflow 2 hours, is then passed through CO at 50 DEG C2Gas.Watery hydrochloric acid is added to adjust to acidity after reaction terminates, in reaction solution, EtOAc (60ml × 3) is extracted, anhydrous Na2SO4Dry, filter, be concentrated to give carboxylic acid compound (II) (white solid, 23.5g, Yield 91%).
1H-NMR(CDCl3,400MHz,δppm):0.32-0.36(m,2H),0.60-0.68(m,2H),1.20-1.24(m, 1H), 3.90 (d, J=6.6Hz, 2H), 6.70 (t, J=76Hz, 1H, CHF2), 7.16 (d, J=7.2Hz, 1H), 7.60-7.66 (m,2H)。
Example 1-2：Metal magnesium rod (0.12mol, 2.88g) adds anhydrous 2- methyltetrahydrofurans in 250ml there-necked flasks (50ml), a small amount of iodine is heated to 40 DEG C.Then THF (100ml) solution of compound (I) (0.1mol, 29.3g) is added dropwise.It is added dropwise After finishing, continue to be heated to reflux 2 hours, then in 40 DEG C of broken dry ice (10g) of input.After reaction terminates, added in reaction solution Watery hydrochloric acid is adjusted to acidity, EtOAc (70ml × 3) extractions, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (23.8g, yield 92.2%).
Example 1-3：At room temperature, compound (I) (0.1mol, 29.3g) is dissolved in Isosorbide-5-Nitrae-dioxy six in 250ml there-necked flasks Ring (100ml), is then added dropwise the THF solution of methyl-magnesium-chloride (MeMgCl, 0.11mol).After completion of dropping, 1 is heated to reflux small When, then in 30 DEG C of broken dry ice of input.Watery hydrochloric acid is added to adjust to acidity after reaction terminates, in reaction solution, EtOAc (80ml × 3) extract, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (24.9g, yield 96.6%).
Example 1-4：At room temperature, compound (I) (0.1mol, 29.3g) is dissolved into glycol dimethyl ether in 250ml there-necked flasks (100ml), is then added dropwise the THF solution of ethylmagnesium chloride (EtMgCl, 0.11mol).After completion of dropping, it is heated to reflux 1 hour, 20 DEG C are subsequently cooled to, broken dry ice is put into.Watery hydrochloric acid is added to adjust to acidity, EtOAc (80ml after reaction terminates, in reaction solution × 3) extract, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (24.5g, yield 95%).
Example 1-5：At room temperature, compound (I) (0.1mol, 29.3g) is dissolved in THF in 250ml there-necked flasks (100ml), is cooled to -78 DEG C.Then slowly be added dropwise n-BuLi (n-BuLi) (hexane solution of 2.5M) (0.12mol, 48ml).After completion of dropping, stir 2 hours, then pass to CO2Gas, at -78 DEG C, stirs 3 hours.After reaction terminates, add Watery hydrochloric acid is adjusted to acidity, EtOAc (60ml × 3) extractions, anhydrous Na2SO4Dry, filter, be concentrated to give carboxylic acid compound (II) (24.0g, yield 92.7%).
Example 1-6：At room temperature, in 250ml there-necked flasks, compound (I) (0.1mol, 29.3g) dissolves ether (100ml), cold But -90 DEG C are arrived.Then n-BuLi (hexane solution of 2.5M) (0.12mol, 48ml) is slowly added dropwise.After completion of dropping, stirring 3 Hour, it is subsequently adding broken dry ice (10g).At -90 DEG C, stir 4 hours.Watery hydrochloric acid adjustment is added after reaction terminates, in reaction solution To acid, EtOAc (60mlx3) extractions, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (23.6g, Yield 91.2%).
Example 1-7：At room temperature, compound (I) (0.1mol, 29.3g) is dissolved in glycol dinitrate in 250ml there-necked flasks Ether (100ml), is then added dropwise the THF solution of methyl-magnesium-chloride (MeMgCl, 0.11mol).After completion of dropping, 1 is heated to reflux small When.10 DEG C are subsequently cooled to, broken dry ice is put into.After reaction terminates, watery hydrochloric acid is added to adjust to acidity, EtOAc (80ml × 3) extractions Take, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (23.0g, yield 89%)
Example 1-8：At room temperature, compound (I) (0.1mol, 29.3g) is dissolved in n-butyl ether in 250ml there-necked flasks (100ml), is then added dropwise the THF solution of isopropyl base magnesium chloride (MeMgCl, 0.11mol).After completion of dropping, 1 is heated to reflux Hour.0 DEG C is subsequently cooled to, broken dry ice is put into.After reaction terminates, watery hydrochloric acid is added to adjust to acidity, EtOAc (80ml × 3) Extraction, anhydrous Na2SO4Dry, then filter, be concentrated to give carboxylic acid compound (II) (23.5g, yield 90.9%).
Embodiment 2
Synthesis compound (III)
Example 2-1：At 25 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in THF (100ml) In, it is subsequently adding pivaloyl chloride (0.11mol, 13.3g) and Na2CO3(0.12mol, 12.7g), after stirring 2 hours, is slowly added dropwise THF (50ml) solution of 3,5- bis- chloro- 4-aminopyridines (0.1mol, 16.3g).After completion of dropping, 50 DEG C are heated to, continue to stir Mix 4 hours to raw material 3, the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings), washed after adding ethyl acetate dilution, water phase is again It is extracted with ethyl acetate 2 times.Merge organic phase, obtaining off-white color after anhydrous sodium sulfate drying, after filtering, concentration and recrystallization consolidates Body roflumilast (25.6g, yield 64%, HPLC purity：99.5%), mp 156-158 DEG C (document mp 157-158 DEG C).
1H-NMR(CDCl3,400MHz,δppm):0.36-0.40(m,2H),0.64-0.70(m,2H),1.20-1.36(m, 1H), 3.96 (d, J=6.8Hz, 2H), 6.72 (t, J=74.8Hz, 1H, CHF2), 7.30 (d, J=8.2Hz, 1H), 7.46- 7.50(m,2H)。
Example 2-2：At 10 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in CH2Cl2(120ml) In, it is subsequently adding pivaloyl chloride (0.11mol, 13.3g), K2CO3(0.11mol, 15.2g) is stirred 3 hours.At a temperature of this, then The CH of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is slowly added dropwise2Cl2(60ml) solution.After completion of dropping, it is heated to 40 DEG C are continued to stir 5 hours to the chloro- 4-aminopyridines of raw material 3,5- bis- disappearance (HPLC monitorings).Add water after ethyl acetate dilution Wash, water is mutually extracted with ethyl acetate 2 times again.Merge organic phase, after anhydrous sodium sulfate drying, filtering, concentration and post are obtained after purification To off-white powder roflumilast (24.6g, yield 61%, HPLC purity：99.2%).
Example 2-3：At 5 DEG C, in 250ml there-necked flasks, compound II (0.1mol, 25.8g) is dissolved in EtOA (100ml), so Pivaloyl chloride (0.11mol, 13.3g), Et are added afterwards3N (0.11mol, 11.2g) is stirred 4 hours.At a temperature of this, then slowly EtOAc (70ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is added dropwise.After completion of dropping, 70 DEG C are heated to Continue to stir 6 hours to raw material 3, the chloro- 4-aminopyridines of 5- bis- disappear, washed after adding ethyl acetate dilution, water mutually uses second again Acetoacetic ester is extracted 2 times.Merge organic phase, after anhydrous sodium sulfate drying, off-white powder sieve is obtained after filtering, concentration and recrystallization Fluorine department spy (22.6g, yield 56%, HPLC purity：99.0%).
Example 2-4：At 0 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in ether (100ml) In, it is subsequently adding pivaloyl chloride (0.11mol, 13.3g), Na2CO3(0.12mol, 12.7g) is stirred 5 hours.At a temperature of this, so Ether (50ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is slowly added dropwise afterwards.After completion of dropping, 0 DEG C after It is continuous to stir 5 hours to the chloro- 4-aminopyridines of raw material 3,5- bis- disappearance (HPLC monitorings).Washed after adding ethyl acetate dilution, water Mutually it is extracted with ethyl acetate again 2 times, organic phase obtains crude product, isopropyl after anhydrous sodium sulfate drying after filtering, concentration Alcohol is recrystallized to give off-white powder roflumilast (22.6g, yield 58.5%, HPLC purity：99.0%).
Example 2-5：At 50 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in MeCN (100ml) In, it is subsequently adding paratoluensulfonyl chloride (0.12mol, 22.8g), Na2CO3(0.12mol, 12.7g) is stirred 5 hours.This temperature Under, MeCN (60ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is then slowly added dropwise.After completion of dropping, 25 DEG C are continued to stir 5 hours to the chloro- 4-aminopyridines of raw material 3,5- bis- disappearance (HPLC monitorings).Add water after ethyl acetate dilution Wash, water is mutually extracted with ethyl acetate 2 times again, organic phase obtains slightly being produced after anhydrous sodium sulfate drying after filtering, concentration Thing, recrystallisation from isopropanol obtains off-white powder roflumilast (21.6g, yield 56%, HPLC purity：99.2%).
Example 2-6：At 50 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in 1,2- dichloroethanes In (100ml), paratoluensulfonyl chloride (0.12mol, 22.8g) is subsequently adding, triethylamine (0.12mol, 12.1g) is stirred 5 hours. At a temperature of this, 1, the 2- dichloroethanes (80ml) that the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- are then slowly added dropwise is molten Liquid.After completion of dropping, 50 DEG C are continued to stir 6 hours to raw material 3, and the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings).Add second Acetoacetic ester dilution after wash, water mutually be extracted with ethyl acetate again 2 times, organic phase after anhydrous sodium sulfate drying, filtering, concentration after Crude product is obtained, recrystallisation from isopropanol obtains off-white powder roflumilast (22.0g, yield 57%, HPLC purity： 99.0%).
Example 2-7：At 35 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in chloroform (100ml) In, it is subsequently adding to benzene sulfonyl chloride (0.12mol, 21.1g), two (isopropyl) ethamine (0.12mol, 15.5g) are stirred 4 hours. At a temperature of this, chloroform (80ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is then slowly added dropwise.Drip Bi Hou, 50 DEG C are continued to stir 6 hours to raw material 3, and the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings).Add ethyl acetate dilute Washed after releasing, water is mutually extracted with ethyl acetate 2 times again, organic phase is obtained after anhydrous sodium sulfate drying after filtering, concentration Crude product, recrystallisation from isopropanol obtains off-white powder roflumilast (23.5g, yield 61%, HPLC purity：99.2%).
Example 2-8：At 45 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in ethyl acetate In (100ml), mesyl chloride (0.12mol, 13.7g), two (isopropyl) ethamine (0.12mol, 15.5g) stirring 5 are subsequently adding Hour.At a temperature of this, the ethyl acetate (80ml) that the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- are then slowly added dropwise is molten Liquid.After completion of dropping, 60 DEG C are continued to stir 6 hours to raw material 3, and the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings).Add second Acetoacetic ester dilution after wash, water mutually be extracted with ethyl acetate again 2 times, organic phase after anhydrous sodium sulfate drying, filtering, concentration after Crude product is obtained, recrystallisation from isopropanol obtains off-white powder roflumilast (22.5g, yield 58.6%, HPLC purity： 99.6%).
Example 2-9：At 30 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in acetonitrile (100ml) In, ethyl sulfonic chloride (0.12mol, 14.4g) is subsequently adding, pyridine (0.12mol, 9.5g) is stirred 6 hours.At a temperature of this, then Acetonitrile (80ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is slowly added dropwise.After completion of dropping, 70 DEG C of continuation Stir 6 hours to the chloro- 4-aminopyridines of raw material 3,5- bis- disappearance (HPLC monitorings).Washed after adding ethyl acetate dilution, water phase It is extracted with ethyl acetate again 2 times, organic phase obtains crude product, isopropanol after anhydrous sodium sulfate drying after filtering, concentration It is recrystallized to give off-white powder roflumilast (23g, yield 59.3%, HPLC purity：99.1%)
Example 2-10：At 20 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in acetonitrile (100ml) In, it is subsequently adding isopropyl sulphonyl chloride (0.12mol, 16.1g), carbon -7- alkene (DBU) of 1,8- diazabicylo 11 (0.12mol, 18.3g) is stirred 8 hours.At a temperature of this, be then slowly added dropwise the chloro- 4-aminopyridines of 3,5- bis- (0.1mol, Acetonitrile (70ml) solution 16.3g).After completion of dropping, 60 DEG C are continued to stir 5 hours to raw material 3, the chloro- 4-aminopyridines of 5- bis- Disappear (HPLC monitorings).Washed after adding ethyl acetate dilution, water is mutually extracted with ethyl acetate 2 times again, and organic phase is through anhydrous sulphur After sour sodium is dried, crude product is obtained after filtering, concentration, recrystallisation from isopropanol obtains off-white powder roflumilast (22.2g, yield 57%, HPLC purity：99.2%)
Example 2-11：At 25 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in ethyl acetate In (100ml), tert-butyl group sulfonic acid chloride (0.12mol, 17.8g), carbon -7- alkene (DBU) of 1,8- diazabicylo 11 are subsequently adding (0.12mol, 18.3g) is stirred 6 hours.At a temperature of this, be then slowly added dropwise the chloro- 4-aminopyridines of 3,5- bis- (0.1mol, Ethyl acetate (90ml) solution 16.3g).After completion of dropping, 40 DEG C are continued to stir 6 hours to raw material 3, the chloro- 4- amino of 5- bis- Pyridine disappears (HPLC monitorings).Washed after adding ethyl acetate dilution, water is mutually extracted with ethyl acetate 2 times again, and organic phase is through nothing After aqueous sodium persulfate is dried, crude product is obtained after filtering, concentration, recrystallisation from isopropanol obtains off-white powder roflumilast (23.3g, yield 59.9%, HPLC purity：99.4%)
Example 2-12：At 20 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in n-butyl ether In (100ml), trifluoromethanesulfchloride chloride (0.12mol, 20.2g) is subsequently adding, triethylamine (0.12mol, 12.1g) is stirred 4 hours. At a temperature of this, n-butyl ether (100ml) solution of the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- is then slowly added dropwise. After completion of dropping, 40 DEG C are continued to stir 6 hours to raw material 3, and the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings).Add acetic acid Ethyl ester is washed after diluting, and water is mutually extracted with ethyl acetate 2 times again, and organic phase is obtained after anhydrous sodium sulfate drying after filtering, concentration To crude product is obtained, recrystallisation from isopropanol obtains off-white powder roflumilast (23.6g, yield 60.7%, HPLC purity： 99.1%).
Example 2-13：At 35 DEG C, in 250ml there-necked flasks, compound (II) (0.1mol, 25.8g) is dissolved in methyl tertbutyl In ether (100ml), trifluoro-acetyl chloride (0.12mol, 15.9g) is subsequently adding, triethylamine (0.12mol, 12.1g) is stirred 4 hours. At a temperature of this, the methyl tertiary butyl ether(MTBE) (120ml) that the chloro- 4-aminopyridines (0.1mol, 16.3g) of 3,5- bis- are then slowly added dropwise is molten Liquid.After completion of dropping, 35 DEG C are continued to stir 6 hours to raw material 3, and the chloro- 4-aminopyridines of 5- bis- disappear (HPLC monitorings).Add second Acetoacetic ester dilution after wash, water mutually be extracted with ethyl acetate again 2 times, organic phase after anhydrous sodium sulfate drying, filtering, concentration after Crude product is obtained, recrystallisation from isopropanol obtains off-white powder roflumilast (22.6g, yield 58.2%, HPLC purity： 99.3%).
The particular embodiment of the present invention is illustrated above, but protection content of the invention is not only limited to the above Embodiment, in art of the invention, the usual knowledge of a GPRS, it is possible to carried out in the range of its technology main idea Diversified change.

Claims (6)

1. a kind of synthetic method of roflumilast, it is characterised in that comprise the following steps：
A () in organic solvent, there is exchange reaction generation intermediate in compound (I), should under reflux with magnesium or RMgBr There is slotting carbonyl reaction in intermediate, obtain compound (II) with carbon dioxide at 0~50 DEG C；
(b) in organic solvent, the compound (II) that is obtained in step (a) with sulfonic acid chloride at 0~50 DEG C, in the presence of alkali Reaction generation mixed acid anhydride intermediate, the mixed acid anhydride intermediate and the chloro- 4-aminopyridine of 3,5- bis- react at 0~70 DEG C To compound (III) roflumilast；
2. the synthetic method of roflumilast according to claim 1, it is characterised in that：In step (a), the compound (I) tetrahydrofuran, ether, glycol dimethyl ether, 2- methyl tetrahydrochysenes are selected from magnesium or RMgBr reaction organic solvent used One or more in furans, 1,4- dioxane, n-butyl ether and methyl tertiary butyl ether(MTBE).
3. the synthetic method of roflumilast according to claim 1, it is characterised in that：In step (a), the grignard examination Agent is methyl-magnesium-chloride, ethylmagnesium chloride or isopropylmagnesium chloride.
4. the synthetic method of roflumilast according to claim 1, it is characterised in that：In step (a), carbon dioxide is Carbon dioxide or solid carbon dioxide.
5. the synthetic method of roflumilast according to claim 1, it is characterised in that：It is described organic molten in step (b) Agent is selected from tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, ether, methyl tertiary butyl ether(MTBE), n-butyl ether, acetonitrile or second One or more in acetoacetic ester.
6. the synthetic method of roflumilast according to claim 1, it is characterised in that：In step (b), the alkali is selected from In sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, two (isopropyl) ethamine, pyridine and the carbon -7- alkene of 1,8- diazabicylos 11 One or more.
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