CN102603623A - Method for preparing high-purity roflumilast - Google Patents
Method for preparing high-purity roflumilast Download PDFInfo
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Abstract
The invention discloses a method for preparing high-purity roflumilast which is a compound as shown in the formula (I). The compound is an orally taken selective phosphodiesterase 4 (PDE4) inhibitor and is proven to be capable of inhibiting inflammation related to a chronic obstructive pulmonary disease (COPD).
Description
Technical field
The present invention relates to the organic synthesis field, relate in particular to a kind of method for preparing the high purity roflumilast.
Background technology
Roflumilast (Roflumilast), chemical name: 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, structural formula is following:
Roflumilast is the new oral medicine that Nycomed company developed, was used to treat asthma and chronic obstructive pulmonary disease.Roflumilast was ratified to be used for serious chronic obstructive pulmonary disease (COPD) and chronic bronchitis by European Union in June, 2010, and in European Union member countries, its commodity are called Daxas.On February 28th, 2011, it is used for serious COPD treatment drugs approved by FDA, at the commodity of U.S. Daliresp by name.
Roflumilast is a kind of oral selectivity phosphodiesterase 4 (PDE4) suppressor factor.Verified, this medicine can suppress and the relevant inflammation of chronic obstructive pulmonary disease (COPD).Roflumilast is not only first kind of medicine in the serious COPD new therapy, and is first kind of oral pharmaceutical towards COPD patient.The character that it is unique; Help to manage better patients with chronic obstructive pulmonary diseases: when treating severe chronic obstructive pulmonary patient with the bronchodilator drug combination; Roflumilast can provide the additional benefit of further minimizing symptom and disease progression rate, becomes target particular phenotype chronic obstructive pulmonary disease thus and promptly has serious flow limitation relevant with many phlegm with long-term cough and tool first medicine of disease progression history patient repeatedly.
Relevant analyst's prediction, in the European Union area, roflumilast listing sales volume then was 7,000,000, can rise to 1.50 hundred million by 2015.
For synthesizing of roflumilast, the method summary of relevant bibliographical information is following:
(1) one Chinese patent application has been reported the synthetic of roflumilast key intermediate for No. 201010603095.8; This method is a starting raw material with 3-nitro-4-hydroxybenzoate, and alkylation, reduction nitro, diazotization, hydrolysis are passed through by elder generation, the last hydrolysis of alkylation obtains the key intermediate that carboxylic acid is a roflumilast again.
Starting raw material is difficult for obtaining in this route, needs self-control, and has used diazotization reaction, and hazardous is difficult to realize suitability for industrialized production.
(2) document WO 2005026095 has been reported with 3, and 4-resorcylic acid ester is a kind of compound method of starting raw material, and through two step alkylations, hydrolysis obtains the carboxylic acid midbody then earlier, and last with 2,6-two chloro-4-aminopyridine condensations obtain target product.
There is selective problems in the first step reaction in this route, and reaction can take place on two hydroxyls, and what obtain is mixture, is difficult in aftertreatment, separate, and needs through column chromatography purification, and yield is low, is difficult to realize suitability for industrialized production.
(3) document CN101490004 has reported with 3, and the 4-Dihydroxy benzaldehyde is a kind of compound method of starting raw material, and through two step alkylations, oxidation obtains the carboxylic acid midbody then earlier, and last with 2,6-two chloro-4-aminopyridine condensations obtain target product.
There is selective problems equally in the first step reaction in this route, and reaction can take place on two hydroxyls, and what obtain is mixture, is difficult in aftertreatment, separate, and needs through column chromatography purification, and yield is low, is difficult to realize suitability for industrialized production.
(4) document WO 2004033430 has reported that the use o-phenol is raw material in fact, once obtains the carboxylic acid midbody through alkylation, bromination, alkylation again, carboxylated and hydrolysis.
Use low-temp reaction in this route, and used bromine, also used expensive palladium catalyzed reaction, complicated operation, cost is high, is not suitable for suitability for industrialized production.
Summary of the invention
Variety of issue in view of aforesaid method exists is necessary to invent a kind of low cost, operates simple and easy, as to be fit to suitability for industrialized production method.
Therefore, the method that relates in one aspect to preparation I compound of the present invention,
Said method comprising the steps of:
(b) make compound 3 demethylating in the presence of demethylation reagent, obtain compound 4:
(c) make compound 4 in the presence of alkali with monochlorodifluoromethane generation alkylated reaction, obtain compound 5:
(d) compound 5 is oxidized to corresponding carboxylic acid compound 6:
(e) compound 6 usefulness chloride reagents are converted into corresponding chloride compounds 7:
(f) make compound 7 and 3,5-two chloro-4-aminopyridines react in the presence of alkali, obtain formula (I) compound:
Another aspect of the present invention relates to the midbody compound 3 that is used for preparation formula (I) compound:
Embodiment
Summary of the invention part like preceding text is said, the method that relates in one aspect to preparation I compound of the present invention,
In an embodiment of method of the present invention, used demethylation reagent is selected from the step (b), but is not limited to: thiophenol sodium, sulfur alcohol sodium, boron trichloride, boron tribromide or their combination are preferably thiophenol sodium; Solvent used in the reaction is selected from, but is not limited to: DMF, DMSO, NMP, dioxane, toluene, acetonitrile or their combination are preferably DMF or NMP.Temperature of reaction can be for example 0-190 ℃, is preferably 80-140 ℃.Reaction times can be preferably 2-12 hour for for example 1-24 hour.
In an embodiment of method of the present invention; Used alkali is selected from the step (c); But be not limited to: sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination are preferably salt of wormwood; Solvent used in the reaction is selected from, but is not limited to acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination, is preferably DMF.Temperature of reaction can be for example 0-100 ℃, is preferably 20-40 ℃.Reaction times can be preferably 8-12 hour for for example 3-24 hour.
In an embodiment of method of the present invention, used oxygenant is selected from the step (d), but is not limited to: hydrogen peroxide, Youxiaolin, VAL-DROP, potassium hypochlorite, Potcrate, potassium permanganate or their combination are preferably hydrogen peroxide or VAL-DROP; Solvent used in the reaction is selected from, but is not limited to: water, acetic acid, methyl alcohol, ethanol or their combination.Temperature of reaction can be for example 0-100 ℃, is preferably 10-40 ℃.Reaction times is preferably for example 3-24 hour, is preferably 3-10 hour.
In an embodiment of method of the present invention, used chloride reagent is selected from the step (e), but is not limited to: sulfur oxychloride, oxalyl chloride, phosphorus trichloride or their combination are preferably sulfur oxychloride or oxalyl chloride.
In an embodiment of method of the present invention; Used alkali is selected from the step (f); But be not limited to sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, hexamethyldisilazane lithium, hmds base potassium, sodium hydride or their combination, be preferably potassium tert.-butoxide.
In an embodiment of method of the present invention, method of the present invention is further comprising the steps of:
(a) make compound 1 and compound 2 in the presence of alkali, carry out alkylated reaction, obtain compound 3:
Wherein X is a leavings group, is selected from Cl, Br, I, OMs and OTs.
In an embodiment of method of the present invention; Alkali used in the step (a) can be selected from; But be not limited to: sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination are preferably salt of wormwood; Solvent used in the reaction is selected from, but is not limited to: acetone, N, dinethylformamide (DMF), DMSO 99.8MIN. (DMSO), N-Methyl pyrrolidone (NMP), THF (THF), dioxane, toluene, acetonitrile or their combination are preferably DMF.Temperature of reaction can be for example 0-100 ℃, is preferably 20-40 ℃.Reaction times can be preferably 8-12 hour for for example 3-24 hour.
In an embodiment of method of the present invention, said method also comprises the step of the formula of being further purified (I) compound, comprising: with the thick product of formula (I) compound with the acidic aqueous solution processing of pulling an oar; With the slurry suction filtration that obtains, and with the mixed solvent recrystallization of filter cake with alcohol and water.
In an embodiment of method of the present invention, comprise in the described acidic aqueous solution, but be not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or their combination are preferably hydrochloric acid; The concentration of described acidic aqueous solution is 0-90%, is preferably 5-20%.In an embodiment of method of the present invention, alcohol used in the recrystallization is selected from, but is not limited to: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol or their combination are preferably Virahol; The content of water can be preferably 10-30% for for example 0-80% in the mixed solvent.
Another aspect of the present invention relates to the midbody compound 3 that is used for preparation formula (I) compound:
Embodiment
Below will combine embodiment that preparation method of the present invention is described in more detail.Yet art technology person should be appreciated that following examples only are for illustrative purposes, but not to qualification of the present invention.Protection scope of the present invention should be limited appending claims.
The preparation of embodiment 1:3-(cyclo propyl methoxy)-4-methoxybenzaldehyde (compound 3)
In reaction flask, add 3-hydroxyl-4-methoxybenzaldehyde (compound 1,15.2g, 0.1mol), the brooethyl Trimetylene (compound 2, wherein X is Br, 16.2g, 0.12mol), salt of wormwood (41.4g, 0.36mol) and DMF (200mL).Make this mixture room temperature reaction 8 hours, complete through the TLC detection reaction.In reaction solution, add ETHYLE ACETATE (200mL), use distilled water wash.Water phase separated and organic phase are used ethyl acetate extraction with water.Merge organic phase, use anhydrous sodium sulfate drying.Boil off solvent under the decompression, obtain compound 3, be off-white color solid 20.2g, yield is 98%.
1H?NMR(CDCl
3)：δ9.84(1H，s)，7.47-7.44(1H，d，J＝2.0Hz)，7.39(1H，s)，6.98-7.00(1H，d，J＝8.4Hz)，3.97(3H，s)，3.97-3.92(2H，d，J＝22Hz)，1.30-1.32(1H，m)，0.69-0.66(2H，m)，0.39-0.38(2H，m)。
The preparation of embodiment 2:3-(cyclo propyl methoxy)-4-hydroxy benzaldehyde (compound 4)
With compound 3 (10.3g 50mmol) is dissolved among the NMP (150mL), and add the thiophenol sodium water solution (～36.7%w/w, 0.1mol).The mixing solutions that obtains in 190～200 ℃ of stirring reactions 1 hour, is cooled to room temperature then.Reaction mixture is poured in the zero(ppm) water (500mL), with ethyl acetate extraction (2 * 100mL).Water is regulated pH to 1～2 with hydrochloric acid (6.0M), with ethyl acetate extraction (3 * 100mL).Merge organic phase, use anhydrous sodium sulfate drying.Boil off solvent under the decompression, obtain compound 4, be off-white color solid 7.68g, yield is 80%.
1H?NMR(CDCl
3)：δ9.81(1H，s)，7.43-7.40(1H，d，J＝2.0Hz)，7.38(1H，s)，7.06-7.04(1H，d，J＝4.0Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.33-1.29(1H，m)，0.70-0.66(2H，m)，0.39-0.36(2H，m)。
The preparation of embodiment 3:3-(cyclo propyl methoxy)-4-difluoro-methoxy phenyl aldehyde (compound 5)
With compound 4 (5.77g, 30mmol), K
2CO
3(12.42g, 90mmol) and DMF (100mL) be mixed in the there-necked flask, feed Freon gas then, 45 ℃ the reaction 6 hours.The TLC demonstration reacts completely.Reaction solution is poured in the zero(ppm) water, with twice of ethyl acetate extraction.Organic phase is washed with saturated sodium-chloride, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains compound 5, is yellow oily liquid 7.05g, and yield is 97%.
1H?NMR(CDCl
3)：δ9.92(1H，s)，7.47-7.44(1H，d，J＝2.0Hz)，7.43(1H，s)，7.32-7.30(1H，d，J＝4.0Hz)，6.94-6.57(1H，d，J＝150Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.65(2H，m)，0.39-0.36(2H，m)。
The preparation of embodiment 4:3-(cyclo propyl methoxy)-4-difluoro-methoxy-benzoic acid (compound 6)
In reaction flask, add compound 5 (0.5g, 2.1mmol) and aqueous sodium hydroxide solution (30%, 10mL).Under vigorous stirring, (30%, 50mL), and control reaction temperature is about 45 ℃ to drip ydrogen peroxide 50.After dropwising, continue under this temperature and reacted 5 hours.After reacting completely, add sodium sulfite solution, use ethyl acetate extraction.Tell organic phase, wash organic phase, and use anhydrous sodium sulfate drying with Hydrogen chloride.The pressure reducing and steaming solvent obtains compound 6, is faint yellow solid 0.82g, and yield is 80%.
1H?NMR(CDCl
3)：δ7.74-7.73(1H，d，J＝2.0Hz)，7.71(1H，s)，7.26-7.23(1H，d，J＝14.0Hz)，6.93-6.56(1H，d，J＝150Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.66(2H，m)，0.39-0.37(2H，m)。
Embodiment 5: the preparation of roflumilast (formula (I) compound)
In reaction flask, add compound 6 (15g, 0.058mol), a small amount of DMF and sulfur oxychloride (300mL).Made the said mixture back flow reaction 4 hours.Pressure reducing and steaming sulfur oxychloride, resistates are treated and directly be used for next step reaction.
With 3,5-two chloro-4-aminopyridines (19g 0.12mol) is dissolved among the DMF (400mL), and the adding potassium tert.-butoxide (17g, 0.15mol).With the mixture that obtains in 0 ℃ of following stirring reaction 0.5 hour.Add the above-mentioned acyl chlorides midbody that obtains.With the mixture that obtains stirring reaction 6 hours under room temperature.After reaction finishes, reaction solution is poured in the zero(ppm) water, with ethyl acetate extraction three times.Merge organic phase, use the saturated common salt water washing, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains the off-white color solid, is roflumilast bullion 19.5g, and yield is 82%.
1H?NMR(CDCl
3)：δ8.58(2H，s)，7.69(2H，br)，7.49(1H，s)，7.47-7.46(1H，d，J＝2.0Hz)，7.30-7.26(1H，d，J＝14.0Hz)，6.94-6.56(1H，d，J＝150Hz)，3.98-3.96(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.66(2H，m)，0.39-0.36(2H，m)。
Embodiment 6: the purifying of roflumilast (formula (I) compound)
(19.5g 0.048mol) joins in 10% hydrochloric acid (200mL) stirring at room 0.5 hour with the thick product of the roflumilast that obtains among the embodiment 5.Filter, add the mixed solution of Virahol (300mL) and zero(ppm) water (30mL) in the filter cake.Be warming up to backflow, add small amount of activated decolouring 0.5 hour.Suction filtration makes the filter cake naturally cooling separate out crystal while hot.Filter, obtain white solid 15.5g, yield is 79.5%.HPLC purity is 99.5%, and fusing point is 157-158 ℃.
Claims (9)
1. the method for preparing formula (I) compound,
Said method comprising the steps of:
(b) make compound 3 demethylating in the presence of demethylation reagent, obtain compound 4:
(c) make compound 4 in the presence of alkali with monochlorodifluoromethane generation alkylated reaction, obtain compound 5:
(d) compound 5 is oxidized to corresponding carboxylic acid compound 6:
(e) compound 6 usefulness chloride reagents are converted into corresponding chloride compounds 7:
(f) make compound 7 and 3,5-two chloro-4-aminopyridines react in the presence of alkali, obtain formula (I) compound:
2. method according to claim 1, wherein in step (b), described demethylation reagent is selected from thiophenol sodium, sulfur alcohol sodium, boron trichloride, boron tribromide or their combination, is preferably thiophenol sodium; Used solvent is selected from DMF, DMSO, NMP, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF or NMP.
3. method according to claim 1 and 2; Wherein in step (c); Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination, is preferably salt of wormwood; Used solvent is selected from acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF.
4. according to the described method of aforementioned arbitrary claim, wherein in step (d), described oxygenant is selected from hydrogen peroxide, Youxiaolin, VAL-DROP, potassium hypochlorite, Potcrate, potassium permanganate or their combination, is preferably hydrogen peroxide or VAL-DROP.
5. according to the described method of aforementioned arbitrary claim, wherein in step (e), described chloride reagent is selected from sulfur oxychloride, oxalyl chloride, phosphorus trichloride or their combination, is preferably sulfur oxychloride or oxalyl chloride.
6. according to the described method of aforementioned arbitrary claim; Wherein in step (f); Used alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, hexamethyldisilazane lithium, hmds base potassium, sodium hydride or their combination in the reaction, is preferably potassium tert.-butoxide.
7. according to the described method of aforementioned arbitrary claim, it is further comprising the steps of:
(a) make compound 1 and compound 2 in the presence of alkali, carry out alkylated reaction, obtain compound 3:
Wherein X is a leavings group, is selected from Cl, Br, I, OMs and OTs.
8. method according to claim 7; Wherein in step (a); Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination, is preferably salt of wormwood; Used solvent is selected from acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF.
9. compound 3:
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850266A (en) * | 2012-08-24 | 2013-01-02 | 郑州明泽医药科技有限公司 | Preparation method of Roflumilast |
| CN102964297A (en) * | 2012-11-27 | 2013-03-13 | 贵州信邦制药股份有限公司 | Preparation method and detection method of roflumilast material |
| CN103012256A (en) * | 2012-12-11 | 2013-04-03 | 四川科伦药物研究有限公司 | Method for synthesizing roflumilast |
| CN103214360A (en) * | 2013-05-17 | 2013-07-24 | 毛志英 | Synthetic method of (4-chlorphenyl)-[4-(1-methyl ethyoxyl) phenyl] ketone |
| CN104447244A (en) * | 2014-10-29 | 2015-03-25 | 成都森科制药有限公司 | Roflumilast intermediates and preparation method of roflumilast |
| CN105017011A (en) * | 2015-06-03 | 2015-11-04 | 青岛辰达生物科技有限公司 | Preparation method of intermediate of roflumilast for treatment of chronic obstructive pulmonary disease |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850266A (en) * | 2012-08-24 | 2013-01-02 | 郑州明泽医药科技有限公司 | Preparation method of Roflumilast |
| CN102850266B (en) * | 2012-08-24 | 2015-01-14 | 郑州明泽医药科技有限公司 | Preparation method of Roflumilast |
| CN102964297A (en) * | 2012-11-27 | 2013-03-13 | 贵州信邦制药股份有限公司 | Preparation method and detection method of roflumilast material |
| CN102964297B (en) * | 2012-11-27 | 2018-05-04 | 贵州信邦制药股份有限公司 | The preparation method and detection method of a kind of Roflumilast raw material |
| CN103012256A (en) * | 2012-12-11 | 2013-04-03 | 四川科伦药物研究有限公司 | Method for synthesizing roflumilast |
| CN103012256B (en) * | 2012-12-11 | 2015-03-25 | 四川科伦药物研究有限公司 | Method for synthesizing roflumilast |
| CN103214360A (en) * | 2013-05-17 | 2013-07-24 | 毛志英 | Synthetic method of (4-chlorphenyl)-[4-(1-methyl ethyoxyl) phenyl] ketone |
| CN104447244A (en) * | 2014-10-29 | 2015-03-25 | 成都森科制药有限公司 | Roflumilast intermediates and preparation method of roflumilast |
| CN105017011A (en) * | 2015-06-03 | 2015-11-04 | 青岛辰达生物科技有限公司 | Preparation method of intermediate of roflumilast for treatment of chronic obstructive pulmonary disease |
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Application publication date: 20120725 |