CN104513196A - Synthetic method for roflumilast - Google Patents

Synthetic method for roflumilast Download PDF

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CN104513196A
CN104513196A CN201510021736.1A CN201510021736A CN104513196A CN 104513196 A CN104513196 A CN 104513196A CN 201510021736 A CN201510021736 A CN 201510021736A CN 104513196 A CN104513196 A CN 104513196A
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compound
roflumilast
organic solvent
synthetic method
ether
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CN104513196B (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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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

Abstract

The invention provides a synthetic method for roflumilast. The method comprises the following steps: (a), in an organic solvent, producing an exchange reaction of a compound (I) and magnesium or a Grignard reagent under the backflow condition to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 0-50 DEG C to obtain a compound (II); or in the organic solvent, reacting the compound (I) with n-butyl lithium at 90 DEG C below zero to 70 DEG C below zero to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 90 DEG C below zero to 70 DEG C below zero to obtain a compound (II); (b) in the organic solvent, reacting the compound (II) obtained in the step (a) with pivaloyl chloride or sulfonyl chloride at 0-50 DEG C in the presence of alkali to generate a mixed anhydride intermediate, and reacting the mixed anhydride intermediate with 3,5-dichloro-4-aminopyridine at 0-70 DEG C to obtain a compound (III) which is roflumilast. The method is short in process route, low in raw material and reagent costs, high in total yield, mild in reaction condition and suitable for industrialized production. The synthetic route of the method is as shown in the descriptions.

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), chemistry N-(3 by name, 5-dichloropyridine-4-base)-3-ring third methoxyl group-4-difluoromethoxybenzoamine amine, researched and developed by German Anda (Altana) company, Metrizamide company of Switzerland (Nycomed Pharma GmbH) completes phosphodiesterase 4 (PDE4) inhibitor of III clinical trial phase, and get the Green Light in July, 2010 in Europe, subsequently in Germany, Britain and Spain's listing, its commodity are called Daxas.Obtain again U.S. FDA approval in March, 2011, go on the market in the U.S..Roflumilast is selectivity 4 type phosphodiesterase (PDE-4) long-acting inhibitor, has anti-inflammatory action.Roflumilast is phosphodiesterase-4 (PDE-4) inhibitor, is novel C OPD medicine.It is used for the treatment of serious COPD patient bronchitis and is correlated with cough and the too much symptom of mucus.Phosphodiesterase is one group of enzyme race at least comprising 11 kinds of hypotype enzymes, has the effect of catalytic decomposition messenger molecule cyclic amp and (or) cyclic guanosine monophosphate.Phosphodiesterase-4 is the main cyclic amp metabolic enzyme of one in inflammation and immunocyte, and inhibitors of phosphodiesterase-4 then has the extensive anti-inflammatory activity comprising the release of inflammation-inhibiting medium and Immunosuppression cell-stimulating.Inhibitors of phosphodiesterase-4 also in animal airway inflammatory model display there is response to treatment.This medicine is the medicine of the first treatment chronic obstructive pulmonary disease (COPD) got the Green Light during the last ten years.The release of this product by suppressing PDE4 to reduce inflammatory mediator, and then the damage that respiratory tract disease such as reduction COPD and asthma etc. causes lung tissue.
So far, the synthetic method of roflumilast mainly contains following several:
1, catechol is used to be starting raw material, through reacting with Cyclopropylmetyl bromide, and and CHF 2cl is obtained by reacting ethers; Through Pd (OAc) 2then and SOCl catalysis CO insertion reaction, obtains corresponding carboxylic acid, 2reaction, obtains corresponding acyl chlorides.Acyl chlorides and aminopyridine react and obtain final product roflumilast (WO2004033430,2004).
The reaction scheme of the method is as follows:
2, use 3,4-Dihydroxy benzaldehyde to be starting raw material, react with Cyclopropylmetyl bromide; Then, CHF 2cl carries out alkylated reaction, and oxidizing reaction obtains corresponding carboxylic acid; Carboxylic acid is at N-methylmorpholine (NMM) and 2-(7-azo benzotriazole)-N, N, N ', there is lower and aminopyridine reaction in N '-tetramethyl-urea phosphofluoric acid ester (HATU), obtain final product roflumilast (CN102336703,2012).
3, para hydroxybenzene cyanogen is used to be starting raw material and CHF 2cl reacts, and reduction obtains amino benzenes compounds; Via diazotization reaction, then obtain phenol compound after hydrolysis; Then, then react with Cyclopropylmetyl bromide, obtain ether, then at H 2o 2under existence, hydrolysis obtains corresponding benzamide, then carries out metal catalyzed coupling reaction with haloperidid and obtain final product roflumilast (CN102351787,2012).
Employ expensive palladium, Pd/C catalyzer and dewatering agent HATU in aforesaid method, production cost is higher; In addition, synthesis needs specific installation, not easily amplifies production.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of synthetic method of roflumilast, the synthetic route of the method is shorter, and the cost of raw material and reagent is lower, yield and product purity higher, be suitable for suitability for industrialized production.
The technical solution used in the present invention is: a kind of synthetic method of roflumilast, comprises the following steps:
A () in organic solvent, there is permutoid reaction with magnesium or Grignard reagent and generate intermediate in compound (I) under reflux, this intermediate and carbonic acid gas occur to insert carbonyl and react at 0 ~ 50 DEG C, obtain compound (II); Or
In organic solvent, compound (I) and n-Butyl Lithium react generation intermediate at-90 ~-70 DEG C, and this intermediate and carbonic acid gas slotting carbonyl occur at-90 ~-70 DEG C and react, and obtain compound (II);
B () in organic solvent, the compound (II) obtained in step (a) and pivaloyl chloride or SULPHURYL CHLORIDE are at 0 ~ 50 DEG C, under the effect of alkali, reaction generates mixed acid anhydride intermediate, this mixed acid anhydride intermediate and the chloro-4-aminopyridine of 3,5-bis-are obtained by reacting compound (III) roflumilast at 0 ~ 70 DEG C;
Synthetic route is as follows:
Further, in step (a), the organic solvent that compound (I) and magnesium or Grignard reagent react used is selected from one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n-butyl ether and methyl tertiary butyl ether.
Further, the organic solvent that compound (I) and n-Butyl Lithium react used in step (a) is selected from one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n-butyl ether and methyl tertiary butyl ether.
Further, in step (a), Grignard reagent is methylmagnesium-chloride, ethylmagnesium chloride or isopropylmagnesium chloride.
Further, in step (a), carbonic acid gas is carbon dioxide, or solid carbon dioxide, i.e. dry ice.
Preferably, in step (a), the time of permutoid reaction is 1-4 hour.
Preferably, in step (a), the time that compound (I) and n-Butyl Lithium (n-BuLi) react is 1-4 hour, and the time that the rear gained intermediate of their reactions and carbonic acid gas carry out slotting carbonyl reaction is 2-5 hour.
Further, in step (b), organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, ether, n-butyl ether, methyl tertiary butyl ether, one or more in acetonitrile or ethyl acetate.
Preferably, in step (b), alkali is selected from one or more in sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, two (sec.-propyl) ethamine, pyridine or 1,8-diazabicylo 11 carbon-7-alkene (DBU).
Preferably, in step (b), compound (II) is 1-10 hour with the time of acyl chloride reaction, and the time that mixed acid anhydride intermediate and the chloro-4-aminopyridine carbonyl of 3,5-bis-react is 2-8 hour.
In the present invention, the intermediate that compound (I) generates with magnesium or Grignard reagent generation permutoid reaction, and compound (I) and n-Butyl Lithium react the intermediate generated, do not need to be separated, directly in reaction solvent with carbon dioxide reaction, obtain compound (II).That is, permutoid reaction is reacted with slotting carbonyl and can be used identical solvent.The reaction that compound (I) and n-Butyl Lithium occur, and the slotting carbonyl that the intermediate that generates of this reaction and carbonic acid gas occur reacts, and can use identical solvent.
Compared with prior art, the present invention has the following advantages: the present invention uses compound (I) to be starting raw material, through Grignard or n-BuLi/CO 2reaction, obtains corresponding carboxylic acid, then uses SULPHURYL CHLORIDE (RSO dexterously 2cl) or pivaloyl chloride carry out being obtained by reacting mixed anhydride, be then obtained by reacting final product roflumilast with aminopyridine.By utilizing technique scheme, the operational path that the present invention describes roflumilast synthetic method is short, generally speaking, only 2 steps reactions, avoid using the expensive catalyzer, strong acid, highly basic etc. in conventional art, raw material and reagent cost cheap, total recovery is high, product purity high (purity >99%), reaction conditions is gentle, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
Synthetic compound (II)
Example 1-1: metal magnesium rod (0.12mol, 2.88g), in 250ml there-necked flask, adds anhydrous THF (50ml), a small amount of iodine, is heated to 40 DEG C.Then THF (100ml) solution of compound (I) (0.1mol, 29.3g) is dripped.After dropwising, continue reflux 2 hours, then pass into CO at 50 DEG C 2gas.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity in reaction solution, EtOAc (60ml × 3) extracts, anhydrous Na 2sO 4drying, filters, concentrated obtains carboxylic acid cpd (II) (white solid, 23.5g, productive rate 91%).
1H-NMR(CDCl 3,400MHz,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,CHF 2),7.16(d,J＝7.2Hz,1H),7.60-7.66(m,2H)。
Example 1-2: metal magnesium rod (0.12mol, 2.88g) is in 250ml there-necked flask, and add anhydrous 2-methyltetrahydrofuran (50ml), a small amount of iodine, is heated to 40 DEG C.Then THF (100ml) solution of compound (I) (0.1mol, 29.3g) is dripped.After dropwising, continue reflux 2 hours, then drop into broken dry ice (10g) at 40 DEG C.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity in reaction solution, EtOAc (70ml × 3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (23.8g, productive rate 92.2%).
Example 1-3: under room temperature, in 250ml there-necked flask, compound (I) (0.1mol, 29.3g) is dissolved in Isosorbide-5-Nitrae-dioxane (100ml), then the THF solution of methylmagnesium-chloride (MeMgCl, 0.11mol) is dripped.After dropwising, reflux 1 hour, then drops into broken dry ice at 30 DEG C.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity in reaction solution, EtOAc (80ml × 3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (24.9g, productive rate 96.6%).
Example 1-4: under room temperature, in 250ml there-necked flask, compound (I) (0.1mol, 29.3g) is dissolved glycol dimethyl ether (100ml), then drip the THF solution of ethylmagnesium chloride (EtMgCl, 0.11mol).After dropwising, reflux 1 hour, is then cooled to 20 DEG C, drops into broken dry ice.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity in reaction solution, EtOAc (80ml × 3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (24.5g, productive rate 95%).
Example 1-5: under room temperature, in 250ml there-necked flask, compound (I) (0.1mol, 29.3g) is dissolved in THF (100ml), is cooled to-78 DEG C.Then n-Butyl Lithium (n-BuLi) (hexane solution of 2.5M) (0.12mol, 48ml) is slowly dripped.After dropwising, stir 2 hours, then pass into CO 2gas, at-78 DEG C, stirs 3 hours.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity, EtOAc (60ml × 3) extracts, anhydrous Na 2sO 4drying, filters, concentrated obtains carboxylic acid cpd (II) (24.0g, productive rate 92.7%).
Example 1-6: under room temperature, in 250ml there-necked flask, compound (I) (0.1mol, 29.3g) dissolves ether (100ml), is cooled to-90 DEG C.Then n-BuLi (hexane solution of 2.5M) (0.12mol, 48ml) is slowly dripped.After dropwising, stir 3 hours, then add broken dry ice (10g).At-90 DEG C, stir 4 hours.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity in reaction solution, EtOAc (60mlx3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (23.6g, productive rate 91.2%).
Example 1-7: under room temperature, by compound (I) (0.1mol in 250ml there-necked flask, 29.3g) be dissolved in glycol dimethyl ether (100ml), then drip the THF solution of methylmagnesium-chloride (MeMgCl, 0.11mol).After dropwising, reflux 1 hour.Then be cooled to 10 DEG C, drop into broken dry ice.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity, EtOAc (80ml × 3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (23.0g, productive rate 89%)
Example 1-8: under room temperature, by compound (I) (0.1mol in 250ml there-necked flask, 29.3g) be dissolved in n-butyl ether (100ml), then drip the THF solution of sec.-propyl base magnesium chloride (MeMgCl, 0.11mol).After dropwising, reflux 1 hour.Then be cooled to 0 DEG C, drop into broken dry ice.After reaction terminates, add dilute hydrochloric acid and be adjusted to acidity, EtOAc (80ml × 3) extracts, anhydrous Na 2sO 4drying, then filters, concentrated obtains carboxylic acid cpd (II) (23.5g, productive rate 90.9%).
Embodiment 2
Synthetic compound (III)
At example 2-1:25 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) is dissolved in THF (100ml), then adds pivaloyl chloride (0.11mol, 13.3g) and Na 2cO 3(0.12mol, 12.7g), stirred after 2 hours, slowly dripped THF (50ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, be heated to 50 DEG C, continue stirring 4 little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-, add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again.Merge organic phase, after anhydrous sodium sulfate drying, filter, concentrate and obtain off-white color solid roflumilast (25.6g, productive rate 64%, HPLC purity: 99.5%), mp 156-158 DEG C (document mp 157-158 DEG C) after recrystallization.
1H-NMR(CDCl 3,400MHz,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)。
At example 2-2:10 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) is dissolved in CH 2cl 2(120ml), in, pivaloyl chloride (0.11mol, 13.3g) is then added, K 2cO 3(0.11mol, 15.2g) stirs 3 hours.At this temperature, then slowly drip the CH of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis- 2cl 2(60ml) solution.After dropwising, be heated to 40 DEG C of continuation stirrings 5 little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again.Merge organic phase, after anhydrous sodium sulfate drying, filter, concentrate and obtain off-white color solid roflumilast (24.6g, productive rate 61%, HPLC purity: 99.2%) after column purification.
At example 2-3:5 DEG C, in 250ml there-necked flask, Compound II per (0.1mol, 25.8g) dissolves in EtOA (100ml), then adds pivaloyl chloride (0.11mol, 13.3g), Et 3n (0.11mol, 11.2g) stirs 4 hours.At this temperature, then slowly drip EtOAc (70ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, be heated to 70 DEG C of continuation stirrings 6 little of the chloro-4-aminopyridine disappearance of raw material 3,5-bis-, add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again.Merge organic phase, after anhydrous sodium sulfate drying, filter, concentrate and obtain off-white color solid roflumilast (22.6g, productive rate 56%, HPLC purity: 99.0%) after recrystallization.
At example 2-4:0 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) is dissolved in ether (100ml), then adds pivaloyl chloride (0.11mol, 13.3g), Na 2cO 3(0.12mol, 12.7g) stirs 5 hours.At this temperature, then slowly drip ether (50ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 0 DEG C of continuation stirring 5 is little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (22.6g, productive rate 58.5%, HPLC purity: 99.0%).
At example 2-5:50 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) is dissolved in MeCN (100ml), then adds Tosyl chloride (0.12mol, 22.8g), Na 2cO 3(0.12mol, 12.7g) stirs 5 hours.At this temperature, then slowly drip MeCN (60ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 25 DEG C of continuation stirrings 5 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (21.6g, productive rate 56%, HPLC purity: 99.2%).
At example 2-6:50 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in 1, in 2-ethylene dichloride (100ml), then add Tosyl chloride (0.12mol, 22.8g), triethylamine (0.12mol, 12.1g) stirs 5 hours.At this temperature, then slowly drip 1,2-ethylene dichloride (80ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 50 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (22.0g, productive rate 57%, HPLC purity: 99.0%).
At example 2-7:35 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in chloroform (100ml), then add benzene sulfonyl chloride (0.12mol, 21.1g), two (sec.-propyl) ethamine (0.12mol, 15.5g) stir 4 hours.At this temperature, then slowly drip chloroform (80ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 50 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (23.5g, productive rate 61%, HPLC purity: 99.2%).
At example 2-8:45 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in ethyl acetate (100ml), then methylsulfonyl chloride (0.12mol is added, 13.7g), two (sec.-propyl) ethamine (0.12mol, 15.5g) stir 5 hours.At this temperature, then slowly drip ethyl acetate (80ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 60 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (22.5g, productive rate 58.6%, HPLC purity: 99.6%).
At example 2-9:30 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in acetonitrile (100ml), then add ethyl sulfonyl chloride (0.12mol, 14.4g), pyridine (0.12mol, 9.5g) stirs 6 hours.At this temperature, then slowly drip acetonitrile (80ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 70 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (23g, productive rate 59.3%, HPLC purity: 99.1%)
At example 2-10:20 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in acetonitrile (100ml), then isopropyl sulphonyl chloride (0.12mol, 16.1g) is added, 1,8-diazabicylo 11 carbon-7-alkene (DBU) (0.12mol, 18.3g) stirs 8 hours.At this temperature, then slowly drip acetonitrile (70ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 60 DEG C of continuation stirrings 5 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (22.2g, productive rate 57%, HPLC purity: 99.2%)
At example 2-11:25 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in ethyl acetate (100ml), then tertiary butyl SULPHURYL CHLORIDE (0.12mol, 17.8g) is added, 1,8-diazabicylo 11 carbon-7-alkene (DBU) (0.12mol, 18.3g) stirs 6 hours.At this temperature, then slowly drip ethyl acetate (90ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 40 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (23.3g, productive rate 59.9%, HPLC purity: 99.4%)
At example 2-12:20 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in n-butyl ether (100ml), then trifluoromethanesulfchloride chloride (0.12mol is added, 20.2g), triethylamine (0.12mol, 12.1g) stirs 4 hours.At this temperature, then slowly drip n-butyl ether (100ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 40 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (23.6g, productive rate 60.7%, HPLC purity: 99.1%).
At example 2-13:35 DEG C, in 250ml there-necked flask, compound (II) (0.1mol, 25.8g) be dissolved in methyl tertiary butyl ether (100ml), then trifluoroacetyl chloride (0.12mol is added, 15.9g), triethylamine (0.12mol, 12.1g) stirs 4 hours.At this temperature, then slowly drip methyl tertiary butyl ether (120ml) solution of the chloro-4-aminopyridine (0.1mol, 16.3g) of 3,5-bis-.After dropwising, 35 DEG C of continuation stirrings 6 are little of chloro-4-aminopyridine disappearance (HPLC monitoring) of raw material 3,5-bis-.Add diluted ethyl acetate after washing, aqueous phase is extracted with ethyl acetate 2 times again, and organic phase is after anhydrous sodium sulfate drying, filter, concentrated after obtain crude product, recrystallisation from isopropanol obtains off-white color solid roflumilast (22.6g, productive rate 58.2%, HPLC purity: 99.3%).
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.

Claims (7)

1. a synthetic method for roflumilast, is characterized in that, comprises the following steps:
A () in organic solvent, there is permutoid reaction with magnesium or Grignard reagent and generate intermediate in compound (I) under reflux, this intermediate and carbonic acid gas occur to insert carbonyl and react at 0 ~ 50 DEG C, obtain compound (II); Or
In organic solvent, compound (I) and n-Butyl Lithium react generation intermediate at-90 ~-70 DEG C, and this intermediate and carbonic acid gas slotting carbonyl occur at-90 ~-70 DEG C and react, and obtain compound (II);
B () in organic solvent, the compound (II) obtained in step (a) and pivaloyl chloride or SULPHURYL CHLORIDE are at 0 ~ 50 DEG C, under the effect of alkali, reaction generates mixed acid anhydride intermediate, this mixed acid anhydride intermediate and the chloro-4-aminopyridine of 3,5-bis-are obtained by reacting compound (III) roflumilast at 0 ~ 70 DEG C;
2. the synthetic method of roflumilast according to claim 1, it is characterized in that: in step (a), the organic solvent that described compound (I) and magnesium or Grignard reagent react used is selected from one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n-butyl ether and methyl tertiary butyl ether.
3. the synthetic method of roflumilast according to claim 1, it is characterized in that: in step (a), the organic solvent that compound (I) and n-Butyl Lithium react used is selected from one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n-butyl ether and methyl tertiary butyl ether.
4. the synthetic method of roflumilast according to claim 1, is characterized in that: in step (a), described Grignard reagent is methylmagnesium-chloride, ethylmagnesium chloride or isopropylmagnesium chloride.
5. the synthetic method of roflumilast according to claim 1, is characterized in that: in step (a), carbonic acid gas is carbon dioxide or solid carbon dioxide.
6. the synthetic method of roflumilast according to claim 1, it is characterized in that: in step (b), described organic solvent is selected from one or more in tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, ether, methyl tertiary butyl ether, n-butyl ether, acetonitrile or ethyl acetate.
7. the synthetic method of roflumilast according to claim 1, it is characterized in that: in step (b), described alkali is selected from one or more in sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, two (sec.-propyl) ethamine, pyridine and 1,8-diazabicylo 11 carbon-7-alkene.
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