CN102351787A - High-bioavailability roflumilast compound - Google Patents
High-bioavailability roflumilast compound Download PDFInfo
- Publication number
- CN102351787A CN102351787A CN201110237138XA CN201110237138A CN102351787A CN 102351787 A CN102351787 A CN 102351787A CN 201110237138X A CN201110237138X A CN 201110237138XA CN 201110237138 A CN201110237138 A CN 201110237138A CN 102351787 A CN102351787 A CN 102351787A
- Authority
- CN
- China
- Prior art keywords
- compound
- roflumilast
- solvent
- temperature
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a roflumilast compound shown in formula I and a preparation method thereof. Roflumilast is a new crystal form, and has the advantages that the chemical purity is high, the highest purity content is smaller than 1 per mill, the optical purity is high, roflumilast is soluble in water, and a preparation prepared from roflumilast has good stability, particularly wet stability, and high bioavailability. The compound provided by the invention has low production cost and stable quality, and is suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to roflumilast compound and preparation method thereof.
Background technology
Nearly forty-two million asthma patient in the whole world and 2,800 ten thousand COPD (chronic obstructive pulmonary disease) patients.Over past ten years, along with atmospheric pollution in the global range and environmental degradation, the M & M of asthma is in rising trend, has every year 180000 people of surpassing to die from asthma.Other has the demonstration of analysis, and to the year two thousand twenty, COPD will rise to the 3rd from the 6th of the present global cause of the death.Conservative estimation, the annual number because of COPD death in the whole world will reach more than 3,500,000 till that time.At home, an epidemiology survey result who is presided over by Zhong Nanshan academician shows that the overall morbidity of present Chinese COPD is 8.2%, and wherein the male sicken rate is 12.4%, and women's morbidity is 5.1%.COPD patient surpasses 4,000 ten thousand in China, estimates that China will have 6,500 ten thousand people and die from COPD during 2003～2033 years.
Huge patient crowd has achieved the pharmaceutical market that has a high potential.2005, the market sales revenue of global treating asthma medicine was up to 17,000,000,000 dollars.Wherein the Advair of GlaxoSmithKline PLC company is first ICS/LABA class medicine, and it is bellwether's the status in occupation of market always just in U.S. listing back first from 1999.2005, this product was created 54.65 hundred million dollars sale good result with 21.4% rate of increase, was sure to occupy the position of the world's three big best-selling drugses., and in the whole world sales volume of seven big main medical markets also above 4,900,000,000 dollars.After 2 years, AstraZeneca has been released combination therapy medicine Symbicort, and this product goes on the market in Europe in calendar year 2001 first.Occupy global best-selling drugs with 10.06 hundred million dollars global marketing volume in 2005 and be ranked first 00.The combination therapy medicine of the 3rd listing in the whole world is that the beclometasone+formoterol of Chiesi company goes on the market in Germany in September, 2007 first.Its global marketing volume was expected to reach 3,300 hundred million dollars in 2015 according to estimates.Although COPD treatment market will be doubled above from 2004 by 2014; But with regard to the drug development merchant; Because the medicament research and development scale of treatment COPD is smaller; And the method that lacks some real innovations solves outstanding demand; Improving curative effect of medication and the effective anti-inflammatory agent of exploitation, so the medicine that presses for the new treatment COPD of research and development is to satisfy market to dissimilar and different demands of treating machine-processed medicine to disease.
Roflumilast
English name: Roflumilast;
Chemical name: N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoro-methoxy benzamide;
Structural formula:
Molecular formula: C
17H
14C
L2F
2N
2O
3
Molecular weight: 403.21;
Physico-chemical property: these article be white to the off-white color crystalline powder, be soluble in acetone, slightly soluble in methyl alcohol and ethanol, almost insoluble in water.
Pharmacology type: phosphodiesterase 4 (PDE-4) suppressor factor.
Mechanism of action: process-N-oxidation generates roflumilast-N-oxide compound.Roflumilast and roflumilast-N-oxide compound optionally effectively suppresses the PDE4 activity.Leukotriene B4, interleukin (IL-2, IL-4, IL-5), Interferon, rabbit and tumour necrosis factor synthetic, and the formation of active oxygen in the human leucocyte all reduce because of two kinds of compounds.Except anti-inflammatory activity, roflumilast can also make the CBF in near-end and the far-end air flue increase external, shows that it has the latent effect that promotes lung mucociliary clearance rate.Roflumilast also can significantly reduce neutrophil leucocyte, eosinophilic granulocyte, reach the absolute quantity that whole cell migrations get into air flue, thereby reduces the stimulation to respiratory tract.
Indication: be used to follow the chronic bronchitis history of frequent outbreak severe chronic obstructive pulmonary disease (COPD) (give after the bronchodilator the not enough desired value of FEV1 50%) adult patient keep treatment.
Usage and dosage: oral.Once a day, each a slice.
The former producer of grinding of roflumilast is a German company Nycomed GmbH (trade(brand)name: Daxas; Specification: 500 μ g; Formulation: tablet).In July, 2010 European Union's approval listing.Be the PDE-4 suppressor factor, its effect is extremely strong, have characteristics of high selectivity, oral administration.It can be used for the treatment of asthma, COPD and chronic obstructive bronchitis.Clinically, the research of selectivity PDE-4 inhibitor for treating asthma and COPD is carried out for many years.Got into the clinical study stage the 1st generation selectivity PDE-4 suppressor factor such as rolipram (rolipram) interrupt research owing to tangible gastrointestinal side effect.The 2nd generation selectivity PDE-4 suppressor factor, like cilomilast (cilomilast), roflumilast (roflumilast), but cilomilast part test result all occur aspect curative effect of medication and the security with the expection different, cause this medicine to stop further research and development.And several clinical test results of roflumilast are managed aspect curative effect of medication, security and tolerance.So in April, 2010 its list marketing of European Union's approval.Test in the model in experiment, after PDE-4 receives the roflumilast inhibition, cause cAMP level rising in the cell, alleviated the white corpuscle relevant, air flue and pulmonary vascular smooth muscle cell, endothelium and airway epithelia cell and fibroblastic dysfunction with COPD.In human neutrophil, monocyte, scavenger cell or the test of lymphocytic stimulated in vitro, roflumilast and roflumilast-N-oxide compound has suppressed the release of inflammatory mediator (for example leukotriene B4, active oxygen, tumor necrosis factor alpha, interferon-gamma and granzyme B).In the patient of suffering from copd, roflumilast has also reduced the neutrophil leucocyte quantity in the sputum.In addition, in the healthy volunteer that intracellular toxin excites, it has reduced neutrophil leucocyte and eosinophilic granulocyte converging in air flue, thereby alleviates dyspnoea.
Because treatment COPD pharmacological agent lacks breakthrough at present always, have no medicine to be proved now and can stop progression of disease or reduce mortality.Roflumilast is as a kind of anti-inflammatory drug; Severe COPD patient's pulmonary function in can effectively improving; It is as the supplement therapy of bronchodilator; Be used to follow frequent outbreak the chronic bronchitis history the COPD adult patient keep treatment; Can improve patient's quality of life to a certain extent, clinical safety is effective.Roflumilast provides new selection for the COPD patient of doctor and different ill characteristics, farthest satisfies the needs to asthma and chronic obstructive pulmonary disease treatment.
WO9501338 has introduced the synthesis method of the substituted benzamide of dialkoxy (comprising roflumilast) and his purposes.WO2005026095, WO2004033430, CN101490004, the preparation method of WO9402465 roflumilast.
Among the preparation method of the roflumilast that WO9501338 describes, the tetrahydrofuran (THF) drop of 3-cyclo propyl methoxy-4-difluoro-methoxy benzoyl chloride is added to 4-amino-3, in the tetrahydrofuran (THF) suspension-s of 5-dichloropyridine and sodium hydrogen, yield is 58.6%.But explanation is not done in the source to key intermediate 3-cyclo propyl methoxy-4 hydroxy benzaldehyde, and the intermediate steps purifying need adopt silica gel to cross column purification, is not suitable for industry and goes up the highly purified roflumilast of preparation.
WO2005026095; CN101490004 is in the preparation method of the roflumilast of describing; All adopting substituted pyrocatechol is raw material; Carry out alkylation; But alkylating product all need carry out post to be handled, last and 4-amino-3, and the reaction of 5-dichloropyridine makes roflumilast; But, make it be difficult to realize upward scale operation of industry because its intermediate needed column purification.
WO2004033430 is raw material with the pyrocatechol, at first carries out alkylation, bromination, alkylation again, inserts carbonylation step and obtain roflumilast.At first contain the intact raw material of unreacted and two alkylation products in the first step reaction product, need be through repeatedly distilling the purpose that just can reach purifying.Bromination reaction carries out under-60 ℃, inserts the carbon monoxide that carbonyl needs severe toxicity.This makes it be difficult in industry and goes up scale operation.
WO9402465 is a raw material with 4-methoxyl group-3-nipagin A, and through alkylation, hydrolysis, acidylate, amino-3 with 4-, the coupling of 5-dichloropyridine forms acid amides, obtains roflumilast with the reaction of two fluoro xenons.Though its front yield is all very considerable and convenient processing, two expensive fluoro xenons are adopted in its final step, and purifying is at first crossed the thick mistake of silicagel column, then purifying obtains qualified product on HPLC, and this makes it be difficult in industry and goes up scale operation.
In research process, repeat the method for above-mentioned patent documentation, obtain various crystal formations or noncrystalline form roflumilast, total impurities is higher, optical purity is low, bioavailability is low.The roflumilast that the present invention obtains is a kind of new crystal formation, the advantage that has: chemical purity is high, and maximum contaminant is less than 1 ‰, and optical purity is high, soluble in water in, be prepared into better stability of preparation, especially to wet good stability, bioavailability is high.
Summary of the invention
One object of the present invention discloses a kind of roflumilast compound.
Another object of the present invention discloses the preparation method of the optimization of roflumilast compound.
Another purpose of the present invention discloses the pharmaceutical composition that comprises the roflumilast compound.
Combine the object of the invention that content of the present invention is specifically described at present.
The invention provides a kind of roflumilast compound (shown in the formula I),
（Ⅰ）
Reaction process:
1. the alkylation of compound (2) para hydroxybenzene formonitrile HCN obtains compound (3);
2. the nitrated compound (4) that obtains of compound (3) 4-difluoro-methoxy cyanobenzene;
3. compound (4) 3-nitro-4-difluoro-methoxy cyanobenzene reduction obtains (5);
4. compound (5) 3-amido-4-difluoro-methoxy cyanobenzene diazotization, hydrolysis obtain compound (6);
5. compound (6) 3-hydroxyl-4-difluoro-methoxy cyanobenzene alkylation obtains compound (7);
6. compound (7) 3-cyclo propyl methoxy-4-difluoro-methoxy cyanobenzene hydrolysis obtains compound (8);
7. compound (8) 3-cyclo propyl methoxy-4-difluoro-methoxy benzamide generation coupled reaction obtains roflumilast;
Wherein R is chlorine, bromine, trifluoro-methanesulfonyl oxy.
Specifically comprise the following steps:
1. take by weighing compound (2): the mol ratio of mineral alkali=1: (1-10); Compound (2), mineral alkali are joined in the solvent, under agitation, in system, feed the halo methylene fluoride.After reacting completely, add frozen water, use ethyl acetate extraction, the salt washing, dried over sodium sulfate is filtered, and revolves the dried compound (3) that obtains, and above-mentioned used solvent is acetone, tetrahydrofuran (THF), DMF, DMSO, dioxan etc.; Selected alkali is mineral alkali like salt of wormwood, yellow soda ash, sodium hydroxide etc.; Temperature of reaction is between 40-100 ℃; Said difluoromethyl reagent is CHF
2Cl, CHF
2Br etc.;
2. take by weighing compound (3): the mol ratio of mineral acid=1: (1-30); Mineral acid and 4-difluoro-methoxy cyanobenzene are mixed, at a certain temperature reaction.Reaction solution is poured in the frozen water, uses ethyl acetate extraction, sodium hydrogencarbonate washing, salt washing; Dried over sodium sulfate is filtered, and revolves the dried compound (4) that obtains; Above-mentioned used acid is the mixture of mixture, sulfuric acid, nitric acid and the glacial acetic acid of nitric acid, sulfuric acid and nitric acid, and temperature is 10 ℃-60 ℃;
3. take by weighing mol ratio=1 of compound (4) and catalyzer: (0.1-30); Compound (4), catalyzer and methyl alcohol are joined in the reaction flask successively, take a breath the room temperature synthesis under normal pressure 3 times.Reacted and filter out catalyzer, filtrating concentrating obtains compound (5), and above-mentioned used solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) etc.; Reductive agent is inorganic salt and metals such as palladium carbon, nickel such as iron powder, tin chloride, vat powder, and temperature is 20 ℃-100 ℃;
4. take by weighing compound (5): vitriolic mol ratio=1: (1-50); Under agitation, in the water of certain volume, add a certain amount of vitriol oil, add compound (5), ice bath is cooled to below 5 ℃, slowly drips the aqueous solution of SODIUMNITRATE, keeps system temperature less than 5 ℃, after dripping, stirs the regular hour.Be heated to 45 ℃ of reactions.Cool the temperature to room temperature, stir.Filtration, washing, drying obtain compound (6), and above-mentioned used vitriolic concentration is 15-50%, and temperature is 0-20 ℃;
5. take by weighing compound (6): encircle third methylating reagent: the mol ratio of mineral alkali=1: (1-5): (1-10); Compound (6) is joined in the suspension-s of ring third methylating reagent, mineral alkali and solvent, react 10h down, filter at 60 ℃.Add 20% sodium hydroxide solution in the filtrating; Use ethyl acetate extraction; Organic phase is washed with salt; Dried over sodium sulfate; Concentrate and obtain compound (7); Above-mentioned used solvent is acetone, tetrahydrofuran (THF), DMF, DMSO, dioxan etc., selected alkali be mineral alkali as: salt of wormwood, yellow soda ash, sodium hydroxide etc., temperature of reaction is between 40-100 ℃.Encircle shown in the third methylating reagent formula 10, wherein X is chlorine, bromine, iodine, OMs (mesyloxy), OTs (to Methyl benzenesulfonyl oxygen base) etc.;
6. take by weighing compound (7): ydrogen peroxide 50: the mol ratio of mineral alkali=1: (1-10): (1-10); Then compound (7) is dissolved in the solvent, then adds mineral alkali; Stirring to pulp, heating then drips ydrogen peroxide 50, up to reacting completely, is cooled to room temperature, filter, washing, oven dry obtains compound (8), and above-mentioned mineral alkali is salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide etc.; Solvent is for DMSO, ethanol etc.; Temperature of reaction is 40 ℃-100 ℃;
7. take by weighing compound (9): compound (8): alkali: catalyzer: the mol ratio of part is 1: (1-5): (1-7): (0.01-0.1): (0.015-0.3).With compound (8), part, alkali, catalyzer joins in the autoclave, takes a breath 3 times, makes it under protection of nitrogen gas, adds compound (9) and solvent, and heating is after reaction finishes.Be cooled to room temperature, add solvent cut, filter.Filtrating concentrates,, extract with alkali lye.Water transfers to pH < 3 with acid; Filter; Filter cake is with washing; The Virahol recrystallization obtains roflumilast; Above-mentioned alkali is cesium carbonate; Potassiumphosphate; Mineral alkali and Potassium ethanoates such as salt of wormwood; Organic basess such as potassium tert.-butoxide; Part is: 1; Two (diphenylphosphine) ferrocene of 1'-; 4; Two (diphenylphosphine)-9 of 5-, 9-dimethyl oxa-anthracene; Phosphine parts such as tri-tert phosphorus, catalyzer is: three (two benzylidene-acetone) two palladiums (0); Palladium; Palladium reagents such as two benzylidene-acetone two palladiums; Solvent is: dioxan; Tetrahydrofuran (THF); Toluene; Chloroform; DMF; R is a chlorine among the DMSO etc., compound (9); Bromine; Trifluoro-methanesulfonyl oxy.
Among the above-mentioned preparation method, roflumilast is soluble in water, and good stability can guarantee the quality of pharmaceutical preparation.
The chemical structure of used roflumilast proves that through determination of elemental analysis chemical structure is correct.
Another purpose of the present invention provides the roflumilast compound compositions that comprises roflumilast compound crystal and one or more pharmaceutically acceptable carrier compositions.
Preparation of pharmaceutical compositions of the present invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Said composition is used to prepare oral preparations, injection, Liposomal formulation.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis; The amount of used compound or concentration are regulated in the scope of a broad, and the weight range of active compound is 1%～50% (weight) of composition.
The advantage of the design's route:
1) the invention has the beneficial effects as follows easy and simple to handlely, it is all very high that each goes on foot intermediate purity;
2) method of the present invention makes and reacts carry out abundant, and side reaction is few, and easy purifying;
3) the present invention is easy to realize suitability for industrialized production;
4) the present invention has avoided the selective problems in the alkylated reaction in the former patent, in addition the realization through buchwald amidation higher yields roflumilast synthetic.
Stability test
The contriver studies the stability of crystal formation of the present invention, and the investigation condition is a high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance, content and related substance to high humidity to strong illumination.
The result: under high light, high temperature, super-humid conditions from 0-15 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, the manufacturing and the standing storage of suitable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in the roflumilast compound crystal:
The result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is fit to the manufacturing and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1, the roflumilast compound synthesizes route map.
Embodiment:
Below in conjunction with embodiment the present invention is done further explanation, make this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits scope of the present invention by any way.
With 50g para hydroxybenzene formonitrile HCN, 1.2g phenmethyl trimethyl ammonium chloride, 99g salt of wormwood and 500 mL acetone join in the reaction flask, under agitation, in system, feed chlorodifluoromethane.After reacting completely, add frozen water, use ethyl acetate extraction, the salt washing, dried over sodium sulfate is filtered, and revolves dried 67.5 g 4-difluoro-methoxy cyanobenzenes, the yield 95% of obtaining.
Step 2
Nitric acid and the 67 g 4-difluoro-methoxy cyanobenzenes of 20 m 40% are mixed, react 0.5 h down at 40 ℃.Reaction solution is poured in the frozen water, uses ethyl acetate extraction, sodium hydrogencarbonate washing, salt washing, and dried over sodium sulfate is filtered, and revolves dried 76.4 g 3-nitros-4-difluoro-methoxy cyanobenzene, the yield 90% of obtaining.
Step 3
With 6 g 10%Pd/C (containing 50% water), 76 g 3-nitro 4-difluoro-methoxy cyanobenzenes, 500 mL methyl alcohol join in the reaction flask successively, take a breath room temperature synthesis under normal pressure 8h 3 times.Filter out palladium carbon, filtrating concentrating obtains 62.7g 3-amido-4-difluoro-methoxy cyanobenzene, yield 96%.
Step 4
Under agitation, in 150 mL water, add the 70 mL vitriol oils, add 50 g 3-amidos-4-difluoro-methoxy cyanobenzene; Ice bath is cooled to below 5 ℃, slowly drips the aqueous solution (16g is dissolved in the 60 mL water) of SODIUMNITRATE, keeps system temperature less than 5 ℃; After dripping, stirring 1h.Be heated to 45 ℃ of reaction 1h.Cool the temperature to room temperature, stir.Filtration, washing, drying obtain 44g 3-hydroxyl-4-difluoro-methoxy cyanobenzene, yield 88%.
Step 5
40 g 3-hydroxyls-4-difluoro-methoxy cyanobenzene is joined in the suspension-s of 60 g salt of wormwood, 38 g brooethyl cyclopropane and 400 mL tetrahydrofuran (THF)s, react 10h down, filter at 60 ℃.Add 20% sodium hydroxide solution in the filtrating, use ethyl acetate extraction, organic phase is washed with salt, dried over sodium sulfate, concentrated 50.1 g 3-cyclo propyl methoxies-4-difluoro-methoxy cyanobenzene, the yield 97% of obtaining.
Step 6
45g 3-cyclopropyl methoxy hydroxyl-4-difluoro-methoxy cyanobenzene is dissolved in the 100 mL dimethyl sulfoxide (DMSO), is warming up to 50 ℃, slowly drip 30% ydrogen peroxide 50, keep system temperature less than 60 ℃.React 0.5 h, filter, washing, oven dry obtains 43 g 3-cyclo propyl methoxies-4-difluoro-methoxy benzamide, yield 88.9%.
Step 7
35 g 3-cyclo propyl methoxies-4-difluoro-methoxy benzamide is suspended in the toluene, is heated to backflow, add potassium tert.-butoxide and 3,4 successively, 5-trichloropyridine, backflow 10h.System cool to room temperature, filtration.Concentrated filtrate is with the sodium hydroxide solution extraction of 2 M.Water with acetate transfer to pH 3, filter, filter cake is with washing, the Virahol recrystallization obtains 16.3 g roflumilasts, yield 48%.
Step 7
With 35 g 3-cyclo propyl methoxies-4-difluoro-methoxy benzamide; 1.0 g 4, two (diphenylphosphine)-9 of 5-, 9-dimethyl oxa-anthracene; 0.26g palladium; 55.5 the g cesium carbonate joins in the autoclave, takes a breath 3 times; Make it under protection of nitrogen gas; Add 25.8 g 3, the solution of 5-two chloro-4-bromopyridines and 400 mL dioxan reacted 30 hours down at 80 ℃.Be cooled to room temperature, add the methylene dichloride dilution, filter.Filtrating concentrates,, with the sodium hydroxide solution extraction of 2 M.Water with acetate transfer to pH 3, filter, filter cake is with washing, the Virahol recrystallization obtains 36 g roflumilasts, yield 78.6% (with 3,5-two chloro-4-bromopyridine meters).
Embodiment 2
Get embodiment 1 roflumilast raw material, use medicinal composite film packaging, in 40 ℃ ± 2 ℃ relative humidity, 75% ± 5% fixed temperature and humidity condition held, respectively at 0,1,2,3, the sampling in June detects, detected result is seen table
Above result shows: the roflumilast steady quality.
Claims (5)
1. roflumilast compound shown in the formula I,
（Ⅰ）。
2. according to the preparation method of the said roflumilast compound crystal of claim 1, comprise the steps:
1) takes by weighing compound (2): the mol ratio of mineral alkali=1: (1-10); Compound (2), mineral alkali are joined in the solvent, under agitation, in system, feed the halo methylene fluoride.After reacting completely, add frozen water, use ethyl acetate extraction, the salt washing, dried over sodium sulfate is filtered, and revolves the dried compound (3) that obtains, and above-mentioned used solvent is acetone, tetrahydrofuran (THF), DMF, DMSO, dioxan etc.; Selected alkali is mineral alkali like salt of wormwood, yellow soda ash, sodium hydroxide etc.; Temperature of reaction is between 40-100 ℃; Said difluoromethyl reagent is CHF
2Cl, CHF
2Br etc.;
2) take by weighing compound (3): the mol ratio of mineral acid=1: (1-30); Mineral acid and 4-difluoro-methoxy cyanobenzene are mixed, at a certain temperature reaction.Reaction solution is poured in the frozen water, uses ethyl acetate extraction, sodium hydrogencarbonate washing, salt washing; Dried over sodium sulfate is filtered, and revolves the dried compound (4) that obtains; Above-mentioned used acid is the mixture of mixture, sulfuric acid, nitric acid and the glacial acetic acid of nitric acid, sulfuric acid and nitric acid, and temperature is 10 ℃-60 ℃;
3) take by weighing mol ratio=1 of compound (4) and catalyzer: (0.1-30); Compound (4), catalyzer and methyl alcohol are joined in the reaction flask successively, take a breath the room temperature synthesis under normal pressure 3 times.Reacted and filter out catalyzer, filtrating concentrating obtains compound (5), and above-mentioned used solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) etc.; Reductive agent is inorganic salt and metals such as palladium carbon, nickel such as iron powder, tin chloride, vat powder, and temperature is 20 ℃-100 ℃.
4) take by weighing compound (5): vitriolic mol ratio=1: (1-50); Under agitation, in the water of certain volume, add a certain amount of vitriol oil, add compound (5), ice bath is cooled to below 5 ℃, slowly drips the aqueous solution of SODIUMNITRATE, keeps system temperature less than 5 ℃, after dripping, stirs the regular hour.Be heated to 45 ℃ of reactions.Cool the temperature to room temperature, stir.Filtration, washing, drying obtain compound (6), and above-mentioned used vitriolic concentration is 15-50%, and temperature is 0-20 ℃;
5) take by weighing compound (6): encircle third methylating reagent: the mol ratio of mineral alkali=1: (1-5): (1-10); Compound (6) is joined in the suspension-s of ring third methylating reagent, mineral alkali and solvent, react 10h down, filter at 60 ℃.Add 20% sodium hydroxide solution in the filtrating; Use ethyl acetate extraction; Organic phase is washed with salt; Dried over sodium sulfate; Concentrate and obtain compound (7); Above-mentioned used solvent is acetone, tetrahydrofuran (THF), DMF, DMSO, dioxan etc., selected alkali be mineral alkali as: salt of wormwood, yellow soda ash, sodium hydroxide etc., temperature of reaction is between 40-100 ℃.Encircle shown in the third methylating reagent formula 10, wherein X is chlorine, bromine, iodine, OMs (mesyloxy), OTs (to Methyl benzenesulfonyl oxygen base) etc.;
6) take by weighing compound (7): ydrogen peroxide 50: the mol ratio of mineral alkali=1: (1-10): (1-10); Then compound (7) is dissolved in the solvent, then adds mineral alkali; Stirring to pulp, heating then drips ydrogen peroxide 50, up to reacting completely, is cooled to room temperature, filter, washing, oven dry obtains compound (8), and above-mentioned mineral alkali is salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide etc.; Solvent is for DMSO, ethanol etc.; Temperature of reaction is 40 ℃-100 ℃;
7) take by weighing compound (9): compound (8): alkali: catalyzer: the mol ratio of part is 1: (1-5): (1-7): (0.01-0.1): (0.015-0.3).With compound (8), part, alkali, catalyzer joins in the autoclave, takes a breath 3 times, makes it under protection of nitrogen gas, adds compound (9) and solvent, and heating is after reaction finishes.Be cooled to room temperature, add solvent cut, filter.Filtrating concentrates,, extract with alkali lye.The aqueous phase was adjusted with acid pH <3, filtered, and the filter cake washed with water and recrystallized from isopropanol to obtain roflumilast, the base is cesium carbonate, potassium phosphate, inorganic bases such as potassium carbonate and potassium acetate, potassium tert-butoxide and organic bases such ligands are: 1,1 '- bis (diphenylphosphino) ferrocene, 4,5 - bis (diphenylphosphino) -9,9 - dimethyl xanthene, tri-tert- phosphorus-based phosphine ligand catalyst is: tris (dibenzylideneacetone) dipalladium (0), palladium acetate, bis-benzylidene acetone dipalladium palladium reagent such as, solvent: dioxane, tetrahydrofuran, toluene, chloroform , DMF, DMSO, etc., the compound (9)
in which R is chlorine, bromine, trifluoromethanesulfonyloxy group.
3. according to the said roflumilast compound crystal of claim 1, it is characterized in that its moisture is less than 2%.
4. the roflumilast compound compositions of forming according to the pharmaceutically acceptable carrier of the said roflumilast compound crystal of claim 1 and one or more.
5. composition according to claim 4 is characterized in that said composition is used to prepare solid preparation, injection, Liposomal formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110237138.XA CN102351787B (en) | 2011-08-18 | 2011-08-18 | High-bioavailability roflumilast compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110237138.XA CN102351787B (en) | 2011-08-18 | 2011-08-18 | High-bioavailability roflumilast compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102351787A true CN102351787A (en) | 2012-02-15 |
| CN102351787B CN102351787B (en) | 2014-08-13 |
Family
ID=45575458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110237138.XA Active CN102351787B (en) | 2011-08-18 | 2011-08-18 | High-bioavailability roflumilast compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351787B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012147098A2 (en) * | 2011-04-28 | 2012-11-01 | Glenmark Generics Limited | Novel process for the preparation of 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide |
| CN103232390A (en) * | 2013-05-10 | 2013-08-07 | 成都合迅医药技术有限公司 | Refining method for high-purity roflumilast |
| WO2013131255A1 (en) * | 2012-03-07 | 2013-09-12 | Scinopharm (Changshu) Pharmaceutical, Ltd. | Preparation method of roflumilast |
| WO2014060464A1 (en) | 2012-10-17 | 2014-04-24 | Interquim, S.A. | Process for preparing roflumilast |
| EP3538076A4 (en) * | 2016-11-08 | 2019-11-13 | University of Louisville Research Foundation, Inc. | Encapsulation of phosphodiesterase inhibitors to treat alcoholic liver disease |
| CN112142615A (en) * | 2020-10-29 | 2020-12-29 | 山东兴强化工产业技术研究院有限公司 | Preparation method of isophthalimide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1701062A (en) * | 2003-03-10 | 2005-11-23 | 奥坦纳医药公司 | Novel process for the preparation of roflumilast |
-
2011
- 2011-08-18 CN CN201110237138.XA patent/CN102351787B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1701062A (en) * | 2003-03-10 | 2005-11-23 | 奥坦纳医药公司 | Novel process for the preparation of roflumilast |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012147098A2 (en) * | 2011-04-28 | 2012-11-01 | Glenmark Generics Limited | Novel process for the preparation of 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide |
| WO2012147098A3 (en) * | 2011-04-28 | 2013-03-21 | Glenmark Generics Limited | Novel process for preparation of 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide |
| WO2013131255A1 (en) * | 2012-03-07 | 2013-09-12 | Scinopharm (Changshu) Pharmaceutical, Ltd. | Preparation method of roflumilast |
| US9233925B2 (en) | 2012-03-07 | 2016-01-12 | Scinopharm (Changshu) Pharmaceuticals, Ltd. | Process for preparation of roflumilast |
| WO2014060464A1 (en) | 2012-10-17 | 2014-04-24 | Interquim, S.A. | Process for preparing roflumilast |
| CN103232390A (en) * | 2013-05-10 | 2013-08-07 | 成都合迅医药技术有限公司 | Refining method for high-purity roflumilast |
| CN103232390B (en) * | 2013-05-10 | 2014-06-11 | 成都合迅医药技术有限公司 | Refining method for high-purity roflumilast |
| EP3538076A4 (en) * | 2016-11-08 | 2019-11-13 | University of Louisville Research Foundation, Inc. | Encapsulation of phosphodiesterase inhibitors to treat alcoholic liver disease |
| CN112142615A (en) * | 2020-10-29 | 2020-12-29 | 山东兴强化工产业技术研究院有限公司 | Preparation method of isophthalimide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102351787B (en) | 2014-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102351787B (en) | High-bioavailability roflumilast compound | |
| CN111448189A (en) | Biaryl derivative, preparation method and pharmaceutical application thereof | |
| CN102361855A (en) | Process for making modulators of cystic fibrosis transmembrane conductance regulator | |
| Alam et al. | Novel Bis-Schiff’s base derivatives of 4-nitroacetophenone as potent α-glucosidase agents: Design, synthesis and in silico approach | |
| Shiohara et al. | Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia | |
| JP6310612B2 (en) | Filigenin ibuprofen ester, its preparation method and its application | |
| JP2019500322A (en) | Compound having agonistic effect on GPR84, method for producing the same, and use | |
| CN103694176B (en) | Preparation method of nilotinib intermediate | |
| CN101817761A (en) | Benzoate derivatives, preparation method and application | |
| EP0036637A1 (en) | Use of 3,3'-azo-bis-(6-hydroxy benzoic acid) as a drug and pharmaceutical compositions containing the same | |
| CN105085396B (en) | For preparing shellfish up to intermediate of quinoline and its preparation method and application | |
| CN102579462A (en) | Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs | |
| CN103204808B (en) | A kind of pair of quinoline and preparation method thereof and preparing the application in cancer therapy drug | |
| Shamle et al. | Synthesis, characterization, antioxidant and antidiabetic studies of Cu (II) and Zn (II) complexes of tolfenamic acid/mefenamic acid with 1-methylimidazole | |
| CN105037325A (en) | Preparation method of alogliptin or pharmaceutically acceptable salt of alogliptin | |
| CN101899004A (en) | Sinomenine derivatives and preparation method and medical application thereof | |
| US20080267866A1 (en) | Novel Antiviral Macrocycle Derivatives and Metal Complexes, Incorporating Bridged Macrocycles | |
| TW416957B (en) | Novel purine derivatives and pharmaceutically acceptable salt thereof | |
| CN103483158B (en) | A kind of diphenyl ethane derivative and application thereof | |
| TW203606B (en) | ||
| Barlow et al. | Synthesis and evaluation of 4-amino-3, 4-dihydro-2H-naphthalen-1-one derivatives as mast cell stabilising and anti-inflammatory compounds | |
| Nnabuike et al. | Cobalt (II) complexes containing mefenamic acid with imidazole and pyridine based auxiliary ligands: Synthesis, structural investigation and cytotoxic evaluation | |
| Mohamad et al. | Synthesis, biological evaluation of ortho-carboxamidostilbenes as potential inhibitors of hyperglycemic enzymes, and molecular docking study | |
| CN104151295B (en) | A kind of synthetic method of 2-[(4-chloro-phenyl-) (4-piperidyl oxygen base) methyl] pyridine | |
| CN103804366B (en) | Lafutidine crystal compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |