CN103304475A - Benzoic amide compound as well as preparation method and application thereof - Google Patents
Benzoic amide compound as well as preparation method and application thereof Download PDFInfo
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- CN103304475A CN103304475A CN2013102332134A CN201310233213A CN103304475A CN 103304475 A CN103304475 A CN 103304475A CN 2013102332134 A CN2013102332134 A CN 2013102332134A CN 201310233213 A CN201310233213 A CN 201310233213A CN 103304475 A CN103304475 A CN 103304475A
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Abstract
The invention relates to a preparation method of substances related to bulk drug roflumilast, namely two benzoic amide compounds N-(3,5-dichloropyridine-4-yl)-3,4-di(difluoro methoxyl) benzoic amide (IA) and N-(3,5-dichloropyridine-4-yl)-3-difluoro methoxyl-4-cyprolidol methoxyl benzoic amide (IB), application of the substances in the aspects of controlling or providing mass of roflumilast products, and a method for controlling the mass of roflumilast in a roflumilast preparation technology.
Description
Technical field
The present invention relates to the i.e. two kinds of benzamide compounds N-(3 of the material relevant with the bulk drug roflumilast, 5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide (IA) and N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the preparation method of the third methoxy benzamide (IB), these materials are in control or purposes aspect the quality of roflumilast product is provided, and in the technique of preparation roflumilast the method for the quality of control roflumilast.
Background technology
Roflumilast is a kind of oral selectivity phosphodiesterase-4 (PDE4) inhibitor of Nycomed company exploitation, is used for the treatment of the medicine of a novel chronic obstructive pulmonary disease (COPD) of asthma and chronic obstructive pulmonary disease.Get permission European Union's approval in July, 2010 and be mainly used in treating serious chronic obstructive pulmonary disease (COPD) and chronic bronchitis, commodity are called Daxas; On February 28th, 2011, it is used for serious COPD treatment drugs approved by FDA, and commodity are called Daliresp.Roflumilast is first new oral medicine of getting permission in the world recent decades for the chronic obstructive pulmonary disease treatment.This medicine is mainly expressed the inflammatory cell relevant with asthma, comprises eosinophilic granulocyte, neutrophil leucocyte and mastocyte.This medicine can act on certain enzyme that participates in smooth muscle contraction specifically, can prevent the cAMP degraded, thereby blocking-up proinflammatory signal transmits, and has anti-inflammatory activity.Be mainly used in clinically treating asthma and chronic obstructive pulmonary disease and obtained preferably curative effect.Roflumilast can also obviously delay the deterioration of Respiratory symptoms, greatly improves Quality of Life simultaneously.
In the prior art, usually take 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (II) as starting raw material, allowing it and Cyclopropylmetyl bromide carry out condensation reaction obtains 3-and encircles the third methoxyl group-4-difluoro-methoxy phenyl aldehyde, the condenses of gained oxidized 3-of obtaining under the Textone condition encircles the third methoxyl group-4-difluoro-methoxy-benzoic acid, the chloride and obtain 3-and encircle the third methoxyl group-4-difluoro-methoxy Benzoyl chloride under the thionyl chloride condition of gained oxide compound, last with 3,5-two chloro-4-aminopyridines carry out condensation, and to obtain the finished product roflumilast be that N-(3,5-dichloropyridine-4-yl)-3-encircles the third methoxyl group-4-difluoro-methoxy-benzamide.Yield is generally about 62% [take 3-hydroxyl-4-difluoro-methoxy phenyl aldehydes as the basis].
CN1701062A (200480001216.4) discloses the method for preparing highly purified roflumilast.
CN102093194A (201010603095.8) discloses a kind of novel method of synthetic 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid.Take 3-nitro-4-HBA ester as raw material, obtain the 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid through steps such as alkylation, reduction, diazotization, hydrolysis, alkylation, deprotections.The 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid is the key intermediate of synthetic drugs roflumilast.
CN102617457A (201110031605.3) discloses a kind of short-cut method for preparing roflumilast.3-bromo-4-hydroxyl-phenyl aldehyde (I) according to the present invention; I obtains 4-difluoro-methoxy-3-hydroxy benzaldehyde (II) through etherificate; II obtains 3-through the Liv Ullmann condensation reaction and encircles the third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (III); III further obtains 3-with hypochlorite oxidation and encircles the third methoxyl group-4-difluoro-methoxy-phenylformic acid (IV); IV obtains 3-through chloro and encircles the third methoxyl group-4-difluoro-methoxy-Benzoyl chloride (V); V and 3,5-, two chloro-4-aminopyridine acidylates obtain roflumilast (VI).Do not need selective etherification in the process of this preparation, do not need column chromatography purification, operation is easy, and aftertreatment is simple, and cost is low, and yield is high, and purity is high.
CN102775345A (201110124752.5) discloses method and the intermediate for preparing roflumilast.
CN102276522A (201110160005.7) discloses a kind of midbody compound (I) for preparing roflumilast and has prepared the method for roflumilast by it.
CN102336704A (201110317392.0) discloses a kind of method for preparing roflumilast, wherein methylating through ring third with Isovanillin makes 3-and encircles the third methoxyl group-4-methoxybenzaldehyde, synthesizes the important intermediate 3-for preparing roflumilast through demethylation again and encircles the third methoxyl group-4-hydroxyl-phenyl aldehyde; Then further according to US Patent No. 5712298 synthetic key intermediate formulas (5) and final synthetic roflumilast formula (7).
CN102503815A (201110355750.7) discloses the preparation method of a kind of roflumilast intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (I).
CN102603623A (201110442674.3) discloses the method for preparing the high purity roflumilast.
CN102532011A (201210001306.X) discloses the preparation method of roflumilast raw material and intermediate.
CN102633631A (201210055248.9), CN102617339A (201210055401.8), and CN102617340A (201210055531.1) relates separately to the preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid, 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof and application, and the method for preparing the 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid.
CN102850266A (201210302646.6) discloses the preparation method of roflumilast.
CN102838533A (201210355865.0) discloses a kind of roflumilast preparation method and key intermediate thereof.
In the prior art for the quality that how to improve the roflumilast product that is synthesized, especially reduce the content of some impurity in the product in most economical, the most efficient mode, so that purpose more convenient in suitability for industrialized production, that control the quality of product simply still needs to carry out deep research work.
Summary of the invention
By inference, be N-(3 at roflumilast, 5-dichloropyridine-4-yl)-3-encircles that very likely to produce two kinds of impurity in the building-up process of the third methoxyl group-4-difluoro-methoxy-benzamide (following general formula I) be N-(3,5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide (being called for short compound I A) and N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxy benzamide (be called for short compound I B), therefore, the content of control compound I A and compound I B is the key point of improving the quality of products in the quality standard of bulk drug roflumilast, at present, the synthetic method that does not still have bibliographical information compound I A and compound I B.Seek method or the approach that reduces foreign matter content in the roflumilast product, improves the roflumilast quality product by analysis impurity (or its content) in each step of synthetic roflumilast.
In order to be N-(3 at roflumilast, 5-dichloropyridine-4-yl)-3-encircle more convenient in the synthesis technique of the third methoxyl group-4-difluoro-methoxy-benzamide, detect or the quality of control roflumilast product simply, economically, the invention provides the method for synthetic above-claimed cpd IA and IB itself and the method for synthesizing the intermediate of these compounds, provide simultaneously these compound I A and IB and their intermediate in the building-up process of roflumilast, to detect purposes or method or the approach of the quality of (or control) roflumilast product.
In the synthetic method of the present invention of roflumilast, take 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (II) as starting raw material, allowing it and Cyclopropylmetyl bromide carry out condensation reaction obtains 3-and encircles the third methoxyl group-4-difluoro-methoxy phenyl aldehyde, the condenses of gained oxidized 3-of obtaining under the Textone condition encircles the third methoxyl group-4-difluoro-methoxy-benzoic acid, the chloride and obtain 3-and encircle the third methoxyl group-4-difluoro-methoxy Benzoyl chloride under the thionyl chloride condition of gained oxide compound, last with 3,5-two chloro-4-aminopyridines carry out condensation, and to obtain the finished product roflumilast be that N-(3,5-dichloropyridine-4-yl)-3-encircles the third methoxyl group-4-difluoro-methoxy-benzamide.
The synthetic route of roflumilast (synthetic route 1) is as follows:
[synthetic route 1]
In synthetic route 1, finally obtain N-(3,5-dichloropyridine-4-yl)-3-and encircle the third methoxyl group-4-difluoro-methoxy-benzamide (general formula I).
In addition, for the preparation of starting raw material 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (general formula I I), reported two kinds of methods (two kinds of routes) in the prior art:
First method: take 0412 as starting raw material under alkaline condition and freonll-11-22(difluorochloromethane) react to get 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (general formula I I); Or
Second method: under alkaline condition, react to get 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (general formula I I) with difluoro Monochloro Acetic Acid sodium take 0412 as starting raw material.
Analyze theoretically, no matter produce starting raw material (II) with which kind of method (or route), all can produce as 3 of impurity 4-two (difluoro-methoxy) phenyl aldehyde and 3-difluoro-methoxy-4-hydroxy benzaldehyde.We have confirmed this point by test, and namely 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (starting raw material II) contains impurity: 3-difluoro-methoxy-4-hydroxy benzaldehyde (impurity B) and 3,4-two (difluoro-methoxy) phenyl aldehyde (impurity C).Can in each follow-up step reaction, produce corresponding various impurity thus, and might bring in the finished product, therefore carry out primary study for these the two kinds impurity of being brought into by starting raw material.
In the process of preparation starting raw material II (3-hydroxyl-4-difluoro-methoxy phenyl aldehyde), we are by technical study and liquid matter (liquid chromatography-mass spectrography) combination analysis, find major impurity in prepared starting raw material II be following these:
Annotate: impurity A: 0412
Impurity B: 3-difluoro-methoxy-4-hydroxy benzaldehyde
Impurity C:3,4-two (difluoro-methoxy) phenyl aldehyde
Wherein impurity A is the used reactant of preparation this starting raw material II, and impurity B, impurity C are the by product that this starting raw material of preparation II produces.Impurity A and impurity C can carry out the high performance liquid chromatography positioning analysis by reference substance, and impurity B be owing to can't separate, still with the intermediate III its corresponding product is detected.Above-mentioned impurity A and impurity C all are incorporated into the inner quality standard of starting raw material, strictly control (the HPLC collection of illustrative plates is seen Fig. 5).
In the synthetic route (synthetic route 1) of roflumilast, make 3-by 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde and the condensation of cyclopropylmethyl bromide methane and encircle the third methoxyl group-4-difluoro-methoxy phenyl aldehyde (intermediate III), the main impurity that exists is as follows in the intermediate III of this step:
Annotate: starting raw material: 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Impurity C:3,4-two (difluoro-methoxy) phenyl aldehyde
Impurity D:3-difluoro-methoxy-4-encircles the third methoxybenzaldehyde (positional isomers of intermediate III)
Analyze: wherein impurity C is with impurity by starting raw material; Impurity D is that the impurity B reaction generates by product.Find that also the intermediate III contains a small amount of intermediate IV when many batches of checkings detect, namely 3-encircles the third methoxyl group-4-difluoro-methoxy-benzoic acid, analyzes to should be due to the easy oxidation of aldehyde radical.
Follow the tracks of to detect find by each batch, impurity is due to the impurity reaction that starting raw material brings in the intermediate III.Except a small amount of intermediate IV, do not produce new unknown impuritie.In the inner quality standard of intermediate III, impurity C, D have all been done corresponding control.In finished product, control (each batch HPLC sees Fig. 6) to Cyclopropylmetyl bromide is residual by vapor-phase chromatography.
In the process by above-mentioned intermediate III oxidation synthetic intermediate IV (3-encircles the third methoxyl group-4-difluoro-methoxy-benzoic acid) under the Textone condition, the impurity that may exist in the intermediate compound IV mainly be following these:
Annotate: intermediate III: 3-encircles the third methoxyl group-4-difluoro-methoxy phenyl aldehyde
Impurity E: 3,4-two (difluoro-methoxy) phenylformic acid
Impurity F: 3-difluoro-methoxy-4-encircles the third methoxybenzoic acid
Analyze: wherein impurity E is impurity C due to the oxidizing reaction, and impurity F is impurity D due to the oxidizing reaction, also has the technique of the IV that the crude product IV is obtained making with extra care by second alcohol and water recrystallization in this step reaction, then reacts to obtain roflumilast again.This step reaction is control foreign matter content committed step.By the analysis of each batch assay, we find within the inner quality standard with the content to 0.5% of impurity E and impurity F, can guarantee to make single contaminant less than 0.15% qualified roflumilast.(HPLC sees Fig. 7).
In the whole building-up process of roflumilast, the impurity of each step has following change procedure:
Impurity B → impurity D → impurity F → impurity IB (compound I B),
Impurity C → impurity E → impurity IA (compound I A).
The inventor thinks, the affirmation of impurity B, C, D, E, F, location, synthetic and the affirmation of impurity IA or IB, location, and the analysis of each foreign matter content has important effect for intermediate and roflumilast raw material in the formulation of examination and test of products standard, the control of quality product.
The invention provides the benzamide compounds of following general formula (1):
R wherein
1=R
2=F
2CHO-(that is, compound I A); Or R
1=F
2CHO-, R
2=(CH
2)
2CHCH
2O-(that is, compound I B).
The present invention also provides and prepares wherein R
1=R
2=F
2The method of the compound of the above general formula (1) of CHO-(being compound I A), will be with 3, the 4-Dihydroxy benzaldehyde is that the alkylate that alkylated reaction must mix on the oxygen occurs under alkaline condition for starting raw material and difluorochloromethane (Freon 22), this mixture gets 3 through the post separating-purifying, 4-two (difluoro-methoxy) phenyl aldehyde (impurity C), 3,4-two (difluoro-methoxy) phenyl aldehyde is collectively referred to as oxidation in the technique by roflumilast, chloride and condensation get N-(3,5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide (IA).
More specifically, the present invention also provide prepare R compound IB wherein=R
2=F
2The method of the compound of the above general formula (1) of CHO-(being compound I A), the method comprises:
1) 0412 and difluorochloromethane (being Freon 22) or difluoro one chloroformic acid sodium carry out alkylated reaction in the presence of alkali, obtain 3,4-two (difluoro-methoxy) phenyl aldehyde;
2) above step 1) resulting 3,4-two (difluoro-methoxy) phenyl aldehyde is with oxygenant (NaClO for example
2) carry out oxidation, obtain 3,4-two (difluoro-methoxy) phenylformic acid;
3) above step 2) resulting 3,4-two (difluoro-methoxy) phenylformic acid carries out chloride with acyl chlorinating agent (for example phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dichloride sulfoxide or phosgene), obtain 3,4-two (difluoro-methoxy) Benzoyl chloride;
4) above step 3) resulting 3,4-two (difluoro-methoxy) Benzoyl chloride and 4-amino-3, the 5-dichloropyridine carries out condensation reaction, obtains N-(3,5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide (being compound I A).
Preferably, in the preparation method of above-described compound I A, wherein in step 1) described in the ratio (in molar ratio) of consumption and the consumption of 0412 of alkali be 0.8～3:1, preferred 1.2～2.5:1, more preferably 1.5～2.0:1.Described alkali is the one or two or more in sodium hydroxide, potassium hydroxide, sodium ethylate or the triethylamine.
In aforesaid method, the concrete synthetic route of compound I A is summarized as follows:
In addition, prepare 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde (starting raw material II) with 0412, can obtain theoretically 3-difluoro-methoxy-4-hydroxy benzaldehyde, but find this foreign matter content seldom in the building-up process of reality, can't carry out separating-purifying.Major cause is because the acid difference of two hydroxyls of 0412.The acidity of 4 hydroxyls is greater than the acidity of 3 hydroxyls because the electrophilic conjugative effect of aldehyde radical affects, 4 hydroxyls easily form sodium phenolate when adding the sodium hydroxide of equivalent, the hydroxyl of 4 hydroxyl than 3 more easily forms difluoromethyl, easily generates 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde.In the starting raw material 3-hydroxyl that detects outsourcing-4-difluoro-methoxy phenyl aldehyde, just find this foreign matter content seldom, with accord with theoretical analysis.
But the impurity of considering to be introduced into finished product by 3-difluoro-methoxy-4-hydroxy benzaldehyde is in nature more near roflumilast, be difficult for removing, therefore under study for action, by the synthetic impurity IB of another synthetic route, be N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxy benzamide (seeing accompanying drawing 4), and finally orders the standard into roflumilast.
Therefore, the present invention also provides and prepares wherein R
1=F
2CHO-and R
2=(CH
2)
2CHCH
2The method of the compound of the general formula of O-(1) (being compound I B), the method is with 3, the 4-Dihydroxy benzaldehyde is starting raw material, carrying out on the oxygen alkylated reaction with the brooethyl cyclopropane generates 3-hydroxyl-4-and encircles the third methoxybenzaldehyde, 3-hydroxyl-4-is encircled the third methoxybenzaldehyde and difluorochloromethane (Freon 22) to be got 3-difluoro-methoxy-4-and encircles the third methoxybenzaldehyde (impurity D) alkylated reaction occurs under the alkaline condition on the oxygen, this product is collectively referred to as oxidation in the technique by roflumilast, chloride and condensation get N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxy benzamide (IB).
More specifically, the present invention also provides and prepares wherein R
1=F
2CHO-and R2=(CH
2)
2CHCH
2The method of the compound of the general formula of O-(1) (being compound I B), the method comprises:
1) 0412 and brooethyl cyclopropane carry out alkylated reaction, and obtain 3-hydroxyl-4-and encircle the third methoxybenzaldehyde,
2) above step 1) resulting 3-hydroxyl-4-encircles the third methoxybenzaldehyde and difluorochloromethane (being Freon 22) or difluoro one chloroformic acid sodium carry out alkylated reaction in the presence of alkali, obtains 3-difluoro-methoxy-4-and encircles the third methoxyl group-phenyl aldehyde;
3) above step 2) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-phenyl aldehyde and carries out oxidation with oxygenant (for example NaClO2), obtains 3-difluoro-methoxy-4-and encircles the third methoxyl group-phenylformic acid;
4) above step 3) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-phenylformic acid and carries out chloride with acyl chlorinating agent (for example phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dichloride sulfoxide or phosgene), obtains 3-difluoro-methoxy-4-and encircles the third methoxyl group-Benzoyl chloride; With
5) above step 4) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-Benzoyl chloride and 4-amino-3, the 5-dichloropyridine carries out condensation reaction, obtain N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxyl group-benzamide (being compound I B).
Preferably, in the preparation method of above-described compound I B, wherein in step 2) described in the consumption of alkali be 0.8～3:1 with the ratio (in molar ratio) that 3-hydroxyl-4-encircles the consumption of the third methoxybenzaldehyde, preferred 1.2～2.5:1, more preferably 1.5～2.0:1.Preferably, described alkali is the one or two or more in sodium hydroxide, potassium hydroxide, sodium ethylate or the triethylamine.
In aforesaid method, the concrete synthetic route of compound I B is summarized as follows:
The organic solvent that in preparation compound I A step 1 or compound I B step 2, uses, preferably with an organic solvent.Organic solvent is the organic alcohols compound that is selected from methyl alcohol, ethanol, Virahol or the propyl carbinol, or polyoxyethylene glycol, or any two or three mixture in methyl alcohol, ethanol, Virahol, propyl carbinol or the polyoxyethylene glycol, for example be the mixture of propyl carbinol and polyoxyethylene glycol.Temperature of reaction in each step generally is between 40～80 ℃, preferably between 50～70 ℃.
The present invention also provide compound I A or IB for detection of or improve N-(3,5-dichloropyridine-4-yl)-3-encircles the purposes (especially in the synthetic method of the present invention of above-described roflumilast) of the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast) quality product, wherein adopt ultraviolet visible spectrophotometry, use detects roflumilast product and other related impurities except compound I B take 233nm as detecting wavelength with principal constituent own control product method.Because under the inspection wavelength of 233nm, the response factor of compound I B is 0.74, outside 0.9～1.1 scope, therefore, compound I B is adopted the Self-control method of the correction up factor.
The investigation of compound I B correction factor
Get respectively each about 15mg of roflumilast and compound I B, be diluted to concentration gradient with thinner [acetonitrile-0.005mmol/L ammonium formiate (formic acid is transferred pH3.5)=(70:30)], with different instruments, measure absorption value at 233nm wavelength place according to ultraviolet visible spectrophotometry.
1. UV-1800(Suzhou Shimadzu)
Typical curve:
The different concns roflumilast utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) measures at 233nm wavelength place referring to Fig. 8.
The result shows: roflumilast has good linear relationship in 9.20～21.46 μ g/ml concentration are enclosed.
Different concns compound I B utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) measures at 233nm wavelength place referring to Fig. 9.
The result shows: compound I B has good linear relationship in 9.44～22.02 μ g/ml concentration are enclosed.
2. UV-7501(Wuxi Kodak instrument)
Typical curve:
The different concns roflumilast utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) measures at 233nm wavelength place referring to Figure 10.
The result shows: roflumilast has good linear relationship in 9.13～21.29 μ g/ml concentration are enclosed.
Different concns compound I B utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) measures at 233nm wavelength place referring to Figure 11.
The result shows: compound I B has good linear relationship in 9.19～21.43 μ g/ml concentration are enclosed.
The result: when detecting under the 233nm wavelength, the correction factor of compound I B (f) is 0.7.
Therefore, the detection method of compound I B is the Self-control method of the correction up factor (f=0.7).
In general, adjust N-(3 according to the content of compound I A and IB, 5-dichloropyridine-4-yl)-3-encircles the synthesis technique of the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast), adopt recrystallization method to purify for intermediate compound IV, so that the total content of E and F is reduced to 0.30wt% in the intermediate compound IV, based on the quality of roflumilast product.
The present invention also provides and utilizes the present invention also to provide compound I A or IB to detect N-(3,5-dichloropyridine-4-yl)-3-encircles the method for the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast) quality product, wherein use the detection wavelength of 233nm to carry out UV scanning, detect roflumilast product and other related impurities except compound I B, and when checked for impurities IB, use 0.7 correction factor.
Advantage of the present invention or useful technique effect
The inventor designs the preparation method of above-mentioned two kinds of compound I A and IB, reaction wherein is simple, yield also is relatively high, and therefore, preparing the method for above-mentioned two kinds of compounds and prepared two kinds of compounds provides foundation for formulation and the control of the quality standard of roflumilast.
The present invention is by the preparation of compound I A and compound I B, be very easy to analysis and detection for various impurity in the building-up process of synthetic roflumilast, become quick so that detect, easy, accurately, especially we can understand the character of two kinds of compounds, can improve as far as possible the roflumilast quality product with this, intermediate such as each step in the building-up process of synthetic roflumilast is purified by means re-crystallization, especially at most critical, the most easily remove in the intermediate compound IV synthesis step of impurity by recrystallization method (for example carrying out recrystallization with the second alcohol and water), from intermediate compound IV, remove impurity E and F.
Description of drawings:
The benzoic hydrogen nuclear magnetic resonance spectrogram of Fig. 1: 3,4-two (difluoro-methoxy) (
1H-NMR)
Fig. 2: 3-hydroxyl-4-encircle the third methoxybenzaldehyde the hydrogen nuclear magnetic resonance spectrogram (
1H-NMR)
Fig. 3: N-(3,5-dichloropyridine-4-yl)-3, the hydrogen nuclear magnetic resonance spectrogram of 4-two (difluoro-methoxy) benzamide (compound I A)
Fig. 4: N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the hydrogen nuclear magnetic resonance spectrogram of the third methoxy benzamide (compound I B)
Fig. 5-1: starting raw material, impurity A and impurity C mixing sample introduction HPLC figure
Fig. 5-2: starting raw material II purity test HPLC figure
Fig. 6-1: intermediate III, impurity C, impurity D and starting raw material II are mixed sample introduction HPLC figure
Fig. 6-2 intermediate III (lot number: 20110401) purity test HPLC figure
Fig. 6-3 intermediate III (lot number: 20110422) purity test HPLC figure
Fig. 6-4 intermediate III (lot number: 20110510) purity test HPLC figure
Fig. 7-1 intermediate IV, impurity E and intermediate III are mixed sample introduction HPLC figure
Fig. 7-2 intermediate IV (lot number: 20110405) purity test HPLC figure
Fig. 7-3 intermediate IV (lot number: 20110426) purity test HPLC figure
Fig. 7-4 intermediate IV (lot number: 20110514) purity test HPLC figure
Fig. 7-5 intermediate IV is schemed with impurity F mixing sample introduction HPLC
Fig. 7-6 intermediate IV checked for impurities F(lot number: 20110405) HPLC figure
Fig. 7-7 intermediate IV checked for impurities F(lot number: 20110426) HPLC figure
Fig. 7-8 intermediate IV checked for impurities F(lot number: 20110514) HPLC figure
Fig. 8: the absorption value typical curve that the different concns roflumilast utilizes ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) to measure at 233nm wavelength place.
Fig. 9: the absorption value typical curve that different concns compound I B utilizes ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) to measure at 233nm wavelength place.
Figure 10: the absorption value typical curve that the different concns roflumilast utilizes ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) to measure at 233nm wavelength place.
Figure 11: the absorption value typical curve that different concns compound I B utilizes ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) to measure at 233nm wavelength place.
Figure 12-1: chemical compounds I A, chemical compounds I B and roflumilast mixing sample introduction HPLC figure
Figure 12-2: roflumilast (lot number: the 20110409) HPLC of inspection chemical compounds I A and chemical compounds I B figure
Figure 12-3: roflumilast (lot number: the 20110430) HPLC of inspection chemical compounds I A and chemical compounds I B figure.
Figure 12-4: roflumilast (lot number: the 20110518) HPLC of inspection chemical compounds I A and chemical compounds I B figure.
Concrete embodiment
(1) preparation of compound I A and IB
Embodiment 1-(preparation of compound I A)
1) 3, the preparation of 4-two (difluoro-methoxy) phenyl aldehyde
0412 60g, Virahol 440ml and polyoxyethylene glycol 45ml are joined in the reaction flask, stir; sodium hydroxide 39g is added in nitrogen protection, is heated to 50 ℃; pass into difluorochloromethane (Freon 22) to saturated, keep reaction and spend the night, cooling; thin up; ethyl acetate extraction, drying is concentrated into dried; cross post and get product 3,4-two (difluoro-methoxy) phenyl aldehyde 50g.
2) 3, the benzoic preparation of 4-two (difluoro-methoxy)
With 3,4-two (difluoro-methoxy) phenyl aldehyde 50g, Glacial acetic acid 200ml and thionamic acid 30g, stir, be cooled to about 10 ℃, add the NaClO of 34g
2, water 60ml is about stirring reaction 1h.Add entry 1000ml after reacting completely, have a large amount of solids to produce, filter, the filter cake massive laundering, suction filtration is dry, dry product 3,4-two (difluoro-methoxy) the phenylformic acid 52g of getting.The benzoic sign of 3,4-two (difluoro-methoxy) (1H-NMR) is referring to Fig. 1.
3) N-(3,5-dichloropyridine-4-yl)-3, the preparation of 4-two (difluoro-methoxy) benzamide (compound I A)
With 3,4-two (difluoro-methoxy) phenylformic acid 52g and toluene (300ml), stir, add thionyl chloride 150g, reaction mixture is heated to about backflow 2h, be concentrated into dried yellow oil, for subsequent use.
With 3,5-two chloro-4-amino-pyridine 42g and tetrahydrofuran (THF) 600ml stir, and add at ambient temperature the NaH of 26g, after adding rear stirring at room 30min, drip above-mentioned oily matter and the mixing solutions of tetrahydrofuran (THF) 200ml, after dropwising, continue to stir about 1h, be evaporated to dried, in residuum, add an amount of water, stirring and crystallizing, the dry compound I A76g that gets of suction filtration.N-(3,5-dichloropyridine-4-yl)-3, the sign (1H-NMR) of 4-two (difluoro-methoxy) benzamide (compound I A) is referring to Fig. 3.
Embodiment 2-(preparation of compound I B)
1) 3-hydroxyl-4-encircles the preparation of the third methoxybenzaldehyde
With 0412 50g, sodium hydroxide 15g and DMF500ml, stir 10min, add brooethyl cyclopropane 50g reaction and spend the night to raw material point and disappear.Regulate pH to neutral, use dichloromethane extraction three times, merge organic layer, with saturated NaCl washing secondary, organic layer is dry with anhydrous Na 2SO4.Filter, filtrate decompression is concentrated into dried, and the dry method upper prop gets product 3-hydroxyl-4-and encircles the third methoxybenzaldehyde 35g.
2) 3-difluoro-methoxy-4-encircles the preparation of the third methoxybenzaldehyde
3-hydroxyl-4-is encircled the third methoxybenzaldehyde 30g, Virahol 220ml and polyoxyethylene glycol 25ml joins in the reaction flask, stir nitrogen protection; hydro-oxidation sodium 8g; be heated to 50 ℃, pass into difluorochloromethane (Freon 22) to saturated, keep reaction and spend the night; cooling; thin up, ethyl acetate extraction, drying; be concentrated into driedly, cross post and get product 3-difluoro-methoxy-4-and encircle the third methoxybenzaldehyde 32g.3-difluoro-methoxy-4-encircles the sign (1H-NMR) of the third methoxybenzaldehyde referring to Fig. 2.3) 3-difluoro-methoxy-4-encircles the preparation of the third methoxybenzoic acid
3-difluoro-methoxy-4-is encircled the third methoxybenzaldehyde 32g, Glacial acetic acid 150ml and thionamic acid 20g, stir, be cooled to about 10 ℃, add the NaClO of 22g
2, water 40ml is about stirring reaction 1h.Add entry 800ml after reacting completely, have a large amount of solids to produce, filter, the filter cake massive laundering is drained, the dry product 33g that gets.
4) N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the preparation of the third methoxy benzamide (compound I B)
3-difluoro-methoxy-4-is encircled the third methoxybenzoic acid 33g and toluene 200ml, stir, add thionyl chloride 100g, reaction mixture is heated to about backflow 2h, be concentrated into dried yellow oil, for subsequent use.
With 3,5-two chloro-4-amino-pyridine 27g and tetrahydrofuran (THF) 400ml stir, and add at ambient temperature NaH17g, after adding rear stirring at room 30min, oily matter above dripping and the mixing solutions of tetrahydrofuran (THF) 150ml after dropwising, continue to stir about 1h, be evaporated to dried, in residuum, add an amount of water, stirring and crystallizing, the dry compound I B48g that gets of suction filtration.N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the sign (1H-NMR) of the third methoxy benzamide (compound I B) referring to accompanying drawing 4.
Embodiment 3-(preparation of roflumilast)
1) preparation of 3-cyclo propyl methoxy-4-difluoro-methoxy phenyl aldehyde (III)
Add II 8g, salt of wormwood 35g and tetrahydrofuran (THF) 80ml in reaction flask, stir 10min, cooling and control temperature drip brooethyl cyclopropane 13ml about 0 ℃, tetrahydrofuran (THF) 40ml solution.After dropwising, be heated to and reflux approximately about 14h, TLC detects (ethyl acetate: sherwood oil=1:10) raw material point disappearance.Slightly cooling, suction filtration, filter cake washs secondary with a small amount of tetrahydrofuran (THF), merging filtrate, filtrate decompression is concentrated into dried, and residuum adds 2mol/L sodium hydroxide 80ml, with dichloromethane extraction twice, merges organic layer, with saturated NaCl washing secondary, organic layer anhydrous Na
2SO
4Dry.Filter, filtrate decompression is concentrated into dried, gets tawny oily matter 10g.
2) preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid (IV)
In reaction flask, add III 9.9g, Glacial acetic acid 40ml and thionamic acid 6g, stir, be cooled to about 10 ℃, begin to add NaClO
26.2g with the solution of water 10ml, then about 20～30 ℃ of stirring reaction 1h.Add entry 250ml after reacting completely, have a large amount of solids to produce, stir 15min, filter, the filter cake massive laundering is drained, and the dry product 10g that gets gets product 8.6g with second alcohol and water recrystallization.
3) N-(3,5-dichloropyridine-4-yl)-to encircle the third methoxyl group-4-difluoromethoxybenzoamine amine be the preparation of roflumilast (I) to 3-
In reaction flask, add IV 8.4g and dry toluene 56ml, stir, drip at ambient temperature thionyl chloride 25g, treat that solid dissolves fully, reaction mixture is heated to about backflow 1h, be concentrated into dried yellow oil, for subsequent use.
In reaction flask, add V 6.8g, tetrahydrofuran (THF) 80ml with drying, stir, be cooled to below 10 ℃ and holding temperature adds NaH2.8g in batches, after adding rear holding temperature stirring 30min, the mixing solutions of oily matter above the control temperature adds between 15～20 ℃ and dry tetrahydrofuran (THF) 80ml stirs about 1h, after reacting completely.Be evaporated to driedly, in residuum, add an amount of water, stir, transfer about PH to 2 with 1mol/L HCl, produce a large amount of solids, suction filtration, washing and dry product 12g.
(2) analysis of impurity
The acidity of two hydroxyls of 0412 is different.The acidity of 4 hydroxyls is greater than the acidity of 3 hydroxyls because the electrophilic conjugative effect of aldehyde radical affects, 4 hydroxyls easily form sodium phenolate when adding the sodium hydroxide of equivalent, therefore 4 the hydroxyl of hydroxyl than 3 more easily forms difluoromethyl, the starting raw material 3-hydroxyl of generation roflumilast-4-difluoro-methoxy phenyl aldehyde.But unavoidably produce a small amount of impurity 3-difluoro-methoxy-4-hydroxy benzaldehyde and 3,4-two (difluoro-methoxy) phenyl aldehyde, these two impurity generate compound I A and compound I B by series reaction.The present invention is by the preparation of compound I A and compound I B, be very easy to analysis and detection for various impurity in the process of synthetic roflumilast, especially, we can understand the character of two kinds of compounds, can improve as far as possible the roflumilast quality product with this, such as means re-crystallization.Formulate corresponding quality standard as contrast simultaneously, and these two kinds of compounds are recorded in the quality standard of roflumilast as the impurity reference substance, thereby can greatly improve quality standard (the roflumilast limit of impurities: compound I A: less than 0.1% of roflumilast; Compound I B:0.1%).Concrete roflumilast quality standard research is as follows about compound I A and compound I B research situation:
Compound I A:N-(3,5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide
Compound I B:N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxy benzamide
(1)
UV scanning
Get each impurity (IA or IB) an amount of, with thinner [acetonitrile-0.005mmol/L ammonium formiate (formic acid accent pH3.5)=(70:30)] respectively dissolved dilution become every 1ml approximately to contain the solution of 10 μ g, and carry out UV scanning at 200nm～400nm
1. compound I A: maximum absorption is arranged at 244.2nm, 339.6nm;
2. compound I B: maximum absorption is arranged at 264.2nm, 339.6nm;
The investigation of response factor
To each sample determination response factor, the result is as follows with the maximum absorption wavelength 251nm of roflumilast:
The result shows, majority sample to be investigated all not within 0.9～1.1 scope, can't adopt Self-control method to measure.Find out from the uv-absorbing figure of each sample, each sample is less in 233nm place absorption difference, therefore again measure response factor at 233nm.
Result's demonstration, except compound I B, the response factor of each sample all within 0.9～1.1 scope, can adopt the main ingredient Self-control method to detect.Outside removal of impurity IA and the impurity IB, all the other samples all have larger absorption at the 220nm place, therefore again measure response factor at 220nm.
The result shows, majority sample to be investigated all not within 0.9～1.1 scope, can't adopt Self-control method to measure.And the roflumilast sample is carried out finding when the material inspection is compared under 220nm and 233nm, the quantity of impurity is consistent with content under two conditions.Consider, we intend selecting 233nm as the detection wavelength of roflumilast related substance inspection, compound I B are adopted the Self-control method of the correction up factor.
The investigation of the correction factor of impurity IB
Get respectively each about 15mg of roflumilast and compound I B, be diluted to concentration gradient with thinner, with different instruments, measure absorption value at 233nm wavelength place according to ultraviolet visible spectrophotometry.
1. adopt UV-1800(Suzhou Shimadzu)
Typical curve:
The different concns roflumilast utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) measures at 233nm wavelength place referring to Fig. 8.
The result shows: roflumilast has good linear relationship in 9.20～21.46 μ g/ml concentration are enclosed.
Different concns compound I B utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-1800, Suzhou Shimadzu) measures at 233nm wavelength place referring to Fig. 9.
The result shows: compound I B has good linear relationship in 9.44～22.02 μ g/ml concentration are enclosed.
2. adopt UV-7501(Wuxi Kodak instrument)
Typical curve:
The different concns roflumilast utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) measures at 233nm wavelength place referring to Figure 10.The result shows: roflumilast has good linear relationship in 9.13～21.29 μ g/ml concentration are enclosed.
Different concns compound I B utilizes absorption value typical curve that ultraviolet visible spectrophotometry (UV-7501, Wuxi Kodak instrument) measures at 233nm wavelength place referring to Figure 11.
The result shows: compound I B has good linear relationship in 9.19～21.43 μ g/ml concentration are enclosed.
The result: when detecting under the 233nm wavelength, the correction factor of compound I B is 0.7.
(2) system suitability
Get respectively compound I A, compound I B, roflumilast and intermediate and starting raw material are an amount of, put in the same volumetric flask, be diluted to the solution that every 1ml approximately contains 500 μ g with thinner [acetonitrile-0.005mmol/L ammonium formiate (formic acid is transferred pH3.5)=(70:30)], take 0.005M ammonium phosphate (phosphoric acid is transferred pH=3.5)-acetonitrile=55:45 as mobile phase A, take methyl alcohol as Mobile phase B, detect by following condition.The detection wavelength is 215nm; Flow velocity is 1.5ml/min.
| Time (min) | Mobile phase A | |
| 0 | 95 | 5 |
| 20 | 75 | 25 |
| 55 | 75 | 25 |
Get respectively more above-mentioned each sample and roflumilast oxynitride an amount of, respectively with thinner dissolving, successively sample introduction.The visible starting raw material B of result, starting raw material A, the intermediate IV, the roflumilast oxynitride, compound I A, the intermediate III, compound I B and roflumilast go out the peak successively, and all reach effective separation.Collection of illustrative plates is seen Figure 12.
Each batch of roflumilast impurity analysis result:
| Lot number | Impurity IA | Impurity IB | Oxynitride | Single maximum single assorted | Total impurities |
| 20110409 | Do not detect | 0.02 | Do not detect | 0.06 | 0.16 |
| 20110430 | Do not detect | 0.03 | Do not detect | 0.06 | 0.17 |
| 20110518 | Do not detect | 0.02 | Do not detect | 0.06 | 0.17 |
(3) synthetic for the roflumilast among the embodiment 3, the impurity analysis result of each step is as follows:
(3.1) impurity analysis of starting raw material
Detection method: C18 chromatographic column 250 * 4.6mm (i.d.) 5 μ m; Take acetonitrile-0.005M ammonium formiate=52:48 as moving phase, flow velocity is 1.0ml/min, and the detection wavelength is 247nm.
Starting raw material impurity detection case:
| Title | Content (area normalization method) |
| Impurity A | Do not detect |
| Impurity B | 0.36% |
| Impurity C | 0.29% |
(3.2) impurity analysis of intermediate III
Detection method: C18 chromatographic column 250 * 4.6mm (i.d.) 5 μ m; Take acetonitrile-0.005M ammonium formiate=49:51 as moving phase, flow velocity is 1.0ml/min, and the detection wavelength is 258nm.
Each batch of intermediate III impurity detection case (content: area normalization):
| Lot number | Starting raw material | Impurity C | Impurity D |
| 20110401 | Do not detect | 0.50% | 0.34% |
| 20110422 | Do not detect | 0.51% | 0.33% |
| 20110510 | Do not detect | 0.50% | 0.32% |
(3.3) impurity analysis of intermediate IV
Detection method: C18 chromatographic column 250 * 4.6mm (i.d.) 5 μ m; Take acetonitrile-0.005M ammonium formiate=49:51 as moving phase, flow velocity is 1.0ml/min, and the detection wavelength is 238nm.
Each batch of intermediate IV impurity detection case (content: area normalization):
| Lot number | The intermediate III | Impurity E | Impurity F |
| 20110405 | Do not detect | 0.11% | 0.14% |
| 20110426 | Do not detect | 0.11% | 0.15% |
| 20110514 | Do not detect | 0.11% | 0.11% |
(3.4) roflumilast impurity detection case summary sheet
| The impurity title | The impurity source | The inspection situation |
| Starting raw material | Starting raw material | Do not detect |
| The intermediate III | Intermediate | Do not detect |
| The intermediate IV | Intermediate | Do not detect |
| The impurity I | Starting raw material be with impurity C through the reaction due to | Do not detect |
| The impurity II | Impurity B that starting raw material is with through the reaction due to | ≤0.1% |
| Oxynitride | Reaction and storage | Do not detect |
Claims (9)
1. the benzamide compounds of following general formula 1:
R wherein
1=R
2=F
2CHO-; Or R
1=F
2CHO-, R
2=(CH
2)
2CHCH
2O-.
2. the wherein R for preparing claim 1
1=R
2=F
2The method of the general formula of CHO-(1) compound, the method comprises:
1) 0412 and difluorochloromethane (being Freon 22) or difluoro one chloroformic acid sodium carry out alkylated reaction in the presence of alkali, obtain 3,4-two (difluoro-methoxy) phenyl aldehyde;
2) above step 1) resulting 3,4-two (difluoro-methoxy) phenyl aldehyde carries out oxidation with oxygenant (for example NaClO2), obtains 3,4-two (difluoro-methoxy) phenylformic acid;
3) above step 2) resulting 3,4-two (difluoro-methoxy) phenylformic acid carries out chloride with acyl chlorinating agent (for example phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dichloride sulfoxide or phosgene), obtain 3,4-two (difluoro-methoxy) Benzoyl chloride; With
4) above step 3) resulting 3,4-two (difluoro-methoxy) Benzoyl chloride and 4-amino-3, the 5-dichloropyridine carries out condensation reaction, obtains N-(3,5-dichloropyridine-4-yl)-3,4-two (difluoro-methoxy) benzamide (being compound I A).
3. the wherein R for preparing claim 1
1=F
2CHO-and R
2=(CH
2)
2CHCH
2The method of the general formula of O-(1) compound, the method comprises:
1) 0412 and brooethyl cyclopropane carry out alkylated reaction, and obtain 3-hydroxyl-4-and encircle the third methoxybenzaldehyde,
2) above step 1) resulting 3-hydroxyl-4-encircles the third methoxybenzaldehyde and difluorochloromethane (being Freon 22) or difluoro one chloroformic acid sodium carry out alkylated reaction in the presence of alkali, obtains 3-difluoro-methoxy-4-and encircles the third methoxyl group-phenyl aldehyde;
3) above step 2) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-phenyl aldehyde with oxygenant (NaClO for example
2) carry out oxidation, obtain 3-difluoro-methoxy-4-and encircle the third methoxyl group-phenylformic acid;
4) above step 3) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-phenylformic acid and carries out chloride with acyl chlorinating agent (for example phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dichloride sulfoxide or phosgene), obtains 3-difluoro-methoxy-4-and encircles the third methoxyl group-Benzoyl chloride; With
5) above step 4) resulting 3-difluoro-methoxy-4-encircles the third methoxyl group-Benzoyl chloride and 4-amino-3, the 5-dichloropyridine carries out condensation reaction, obtain N-(3,5-dichloropyridine-4-yl)-3-difluoro-methoxy-4-encircles the third methoxyl group-benzamide (being compound I B).
4. according to claim 2 or 3 described preparation methods, it is characterized in that: described alkali is the one or two or more in sodium hydroxide, potassium hydroxide, sodium ethylate or the triethylamine.
5. according to claim 2 method is wherein in step 1) described in the ratio (in molar ratio) of consumption and the consumption of 0412 of alkali be 0.8～3:1, preferred 1.2～2.5:1, more preferably 1.5～2.0:1.
6. according to claim 3 preparation method is wherein in step 2) described in the consumption of alkali be 0.8～3:1 with the ratio (in molar ratio) that 3-hydroxyl-4-encircles the consumption of the third methoxybenzaldehyde, preferred 1.2～2.5:1, more preferably 1.5～2.0:1.
The compound of claim 1 for detection of or improve N-(3,5-dichloropyridine-4-yl)-3-encircles the purposes of the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast) quality product, wherein adopt ultraviolet visible spectrophotometry, use the detection wavelength of 233nm to carry out UV scanning, detect roflumilast product and other related impurities except compound I B, and when detection compound IB (being impurity IB), use 0.7 correction factor.
8. according to claim 7 purposes, wherein adjust N-(3 according to the content of compound I A and IB, 5-dichloropyridine-4-yl)-3-encircles the synthesis technique of the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast), encircling the third methoxyl group-4-difluoro-methoxy-benzoic acid (being intermediate compound IV) for 3-adopts recrystallization method to purify, so that in the intermediate compound IV 3, the total content that 4-two (difluoro-methoxy) phenylformic acid (being impurity E) and 3-difluoro-methoxy-4-encircle the third methoxybenzoic acid (being impurity F) is reduced to 0.30wt%, based on the quality of roflumilast product.
9. utilize the compound test N-(3 of claim 1,5-dichloropyridine-4-yl)-3-encircles the method for the third methoxyl group-4-difluoro-methoxy-benzamide (being roflumilast) quality product, wherein adopt ultraviolet visible spectrophotometry, use the detection wavelength of 233nm to carry out UV scanning, detect roflumilast product and other related impurities except compound I B, and when detection compound IB (being impurity IB), use 0.7 correction factor.
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Citations (3)
| 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 |
| CN102633714A (en) * | 2012-04-11 | 2012-08-15 | 四川蜀中制药有限公司 | Preparation method of 3-(difluoromethoxy)-N-(3, 5-dichloropyridin-4-yl)-4-(cyclopropylmethoxy) benzamide |
| WO2013072938A2 (en) * | 2011-11-09 | 2013-05-23 | Mylan Laboratories Ltd | An improved process for the preparation of roflumilast |
-
2013
- 2013-06-13 CN CN2013102332134A patent/CN103304475A/en active Pending
Patent Citations (3)
| 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 |
| WO2013072938A2 (en) * | 2011-11-09 | 2013-05-23 | Mylan Laboratories Ltd | An improved process for the preparation of roflumilast |
| CN102633714A (en) * | 2012-04-11 | 2012-08-15 | 四川蜀中制药有限公司 | Preparation method of 3-(difluoromethoxy)-N-(3, 5-dichloropyridin-4-yl)-4-(cyclopropylmethoxy) benzamide |
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|---|
| CHANG-HAI SUN 等: "Synthesis and structure confirmation of the impurity in crude roflumilast product", 《RES CHEM INTERMED》 * |
| EUROPEAN MEDICINES AGENCY: "Daxas", 《CHMP ASSESSMENT REPORT》 * |
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