CN1024192C - Process for preparing 1,4-dihydro-pyridine derivatives - Google Patents
Process for preparing 1,4-dihydro-pyridine derivatives Download PDFInfo
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- CN1024192C CN1024192C CN 89102015 CN89102015A CN1024192C CN 1024192 C CN1024192 C CN 1024192C CN 89102015 CN89102015 CN 89102015 CN 89102015 A CN89102015 A CN 89102015A CN 1024192 C CN1024192 C CN 1024192C
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Abstract
The present invention relates to a method to prepare a substance with structural formula I of dimethyl-1, 4-dihydrogen-2, 6- dimethyl-4-(2'-nitryl-phenyl)-naphthyridine-3, 5-dicarboxylic ester, which is applicable to industrial production and can get high-purity product with excellent recovery ratio. Application time of the method is shorter than prior methods. Partial or all expensive raw materials are replaced with low-cost raw materials.
Description
The invention relates to a kind of new, improved preparation 1, the method for 4-dihydrogen pyridine derivative, and method about can be used for preparing the new intermediate product of this derivative and preparing this new intermediate product.
Particularly, the present invention relates to new, the improved dimethyl-1 that is prepared as follows the structural formula I, 4-dihydro-2,6-dimethyl-4-(2 '-nitrophenyl)-pyridine-3, the method for 5-dicarboxylic ester
(hereinafter also being referred to as " NIFEDIPINE ").
The known NIFEDIPINE of people is a kind of valuable calcium antagonist, is widely used in various hypertension of treatment and cardiomyopathy (United States Patent (USP) NO.3,485,847).
The known several methods that prepare NIFEDIPINE of people, AHantzsch (Justus Liebigs Annalen der Chemie 215,1(1882)) preparation 1 has been described, the general method of 4-dihydro-pyridine derivate, be that aldehyde and 3-ketone-carboxylicesters react when having excess ammonia, this reaction is with reaction circuit A explanation.
R-CHO+2R
1-CO-CH
2-COOR
2+ NH
3(excessive) →
Reaction circuit A
A.Hantzsch-Beyer (1662(1891)) another general method is shown in reaction circuit B for C.Beyer, Ber.Dtsch.Chem.Ges.24,
Reaction circuit B
According to this method, aldehyde and two normal enamine carboxylicesters reactions.E.Knoevenagel (Ber.Dtsch.Chem.Ges.31,743(1898)) describes the reaction of inferior ester of carboxylic acid and enamine carboxylicesters in detail, and this reaction is shown in reaction circuit C.
Reaction circuit C
H.H.Fox et al. (J.Org.Chem.16,1259(1951)) has studied the reaction of aldehyde, 3-ketone-carboxylicesters and enamine carboxylicesters, and reaction is shown in reaction circuit D.
Reaction circuit D
According to Deutsches Reichs-Patent No.2,117,571, nitro-phenyl-benzylidene-acetylacetic ester and beta-amino-crotonate or ammonia and acetylacetic ester prepared in reaction dihydropyridine, this reaction is shown in reaction circuit E.
Reaction circuit E
Aforesaid method is used to prepare NIFEDIPINE, therefore, according to Deutsches Reichs-Patent No.1,620,827, there is prepared in reaction NIFEDIPINE under the condition of excess ammonia by the methyl acetoacetate in 2-nitro-phenyl aldehyde and the methyl alcohol, yet, the product of this method is polluted by a large amount of byproducts, is the sorrel NIFEDIPINE.Hungarian patent NO.192546 has comprised the pertinent evaluation to this method, and the application has repeated the NIFEDIPINE that is subjected to 7 kinds of by-product contamination that Deutsches Reichs-Patent No.1620827 embodiment 1 obtains.
Hungarian patent No.192,546 relate to the improved form of above-mentioned Knoevenagel synthesis method, be used to prepare symmetric 1,4-dihydro-pyridine-dicarboxylic ester, it comprises NIFEDIPINE.
The synthetic the first step is with 2-nitro-phenyl aldehyde and methyl acetoacetate, at significant quantity (0.01～0.7mole, with respect to the 1mole methyl acetoacetate) the Piperidineacetic acid ester catalyst have reaction down, obtain productive rate up to methyl-2-nitro-benzylidene-acetylacetic ester of about 97%.This product reacts with methyl-3-amino-crotonate after separating or not separating, and the productive rate in second step is that the overall yield in 87%, two step reaches 84.4%.According to the Hungarian patent of quoting, the thin-layer chromatographic analysis of the NIFEDIPINE that so obtains shows that no coupling product generates (use and scribble the Merck template of Kieselgel, and scribble 3: 2: 5 chloroform, acetone and gasoline ether mixture again).
In early days in the procedure, Hantzsch type synthesis method particularly, if finish between the reaction period, have free ammonia, then unwanted reaction may take place, possible form is polluted the by product of the finished product, because pharmacopeia is very high to the requirement of NIFEDIPINE, the quality standard of medicine also improves day by day, and therefore, an urgent demand prepares high-quality free of contamination NIFEDIPINE.
The industrial application of disclosed method has some shortcomings in Hungarian patent NO.192546.Consider that from economic point of view the ester composition that uses its half is expensive methyl-3-amino-crotonate, so be out of favour in reaction.Another shortcoming is a long reaction time.The reaction times that the first step generates methyl-2-nitro-benzylidene-acetylacetic ester is 16 hours, and above-mentioned ylidene compounds of second step changes into the reaction process of NIFEDIPINE and needs 36 hours, need 52 hours thereby amount to, the methyl of use-3-amino-crotons ester is preparation separately, and is more expensive.
The commercial run that the purpose of this invention is to provide a kind of preparation NIFEDIPINE of less expensive shortens the reaction times, obtains free of contamination pure product.
Method of the present invention is applicable to economically, the high-quality NIFEDIPINE of high productivity suitability for industrialized production.
According to the present invention, provide a kind of dimethyl-1 for preparing the structural formula I, 4-dihydro-2,6-dimethyl-4-(2 '-nitro-phenyl)-pyridine-3, the 5-dicarboxylic ester, it comprises:
A) with the compound of following general formula II
(wherein n is 1 or 3; If n is 1, then R is expressed as follows general formula (a)
Or (b)
Group; If n is 3, then R represents hydrogen atom) with the methyl acetoacetate of following structural formula III
The aminocompound of following arbitrarily general formula IV
(wherein Z is the group of following general formula (C)
K is that 1, two symbol P is 0; Or Z represents C
1～5Straight or branched alcohol oxygen base or carbonate, bicarbonate radical or hydrogen cation, K is that 1, two symbol P is 1; Or K is that one of 0, two P is 0, and another is 1) reaction in the presence of inert solvent; Or
B) methyl acetoacetate and the aqueous ammonium hydroxide of 2-nitro-phenyl aldehyde and formula III carry out single step reaction in the presence of inert solvent, temperature of reaction is 101-120 ℃, and pressure is 2.0～6.0bar.
According to implementation method form a), 1-methoxyl group-1-(2 '-nitro-phenyl of following structural formula II A)-N-(2 '-nitro-phenyl)-methylene radical-methylamine
As raw material, this is the compound of general formula II, and wherein R is formula (a) group, and n is 1, and this reaction is represented with reaction circuit F
Reaction circuit F
In reaction process, the compound of 1mole structural formula II A and the methyl of 3mole methyl acetoacetate and 1mole-3-amino-crotons ester reaction, back one component also can prepare on the spot by methyl acetoacetate and ammonia react, can use aqueous ammonium hydroxide or methanol ammonium hydroxide for this reason, reaction can be carried out in inert solvent or solvent mixture, any suitable inert solvent can be used as reaction medium, as long as it is not had an effect with initial substance under the reaction conditions that uses.Therefore, can use polar aprotic solvent (water for example; Alcohols: for example, methyl alcohol, ethanol etc.; Acid amides: as methane amide, ethanamide etc.) or bipolarity aprotonic solvent (for example acetonitrile, ethyl ketone, dimethyl sulfoxide (DMSO), oil of mirbane etc.).It is most preferred that and use methyl alcohol as medium, this reaction can be carried out in a wide temperature range, preferably-10 ℃～+ 120 ℃, be preferably in 5～100 ℃, particularly 25～80 ℃.Reaction times is depended on temperature, can be 12～60 hours, is preferably 25～55 hours, and reaction was generally finished with high yield in 36 hours.
A kind of preferred method is to add suspension, 3mole methyl acetoacetate and the 1mole methyl-3-amino-crotonate of 1mole formula II A compound in methyl alcohol, and the reacting by heating mixture reacted 36 hours to boiling point.
Also having a kind of method is that formula II A compound is changed into NIFEDIPINE without separation in same equipment.
After reaction is finished, by simple method NIFEDIPINE is separated from reaction mixture, reaction mixture filters out sedimentary NIFEDIPINE, is dissolved in the hot acetate, uses water precipitation, and washing is also dry.This product satisfies the pharmacopeia needs, does not need recrystallize.
According to method other embodiment a), 1-(2 '-nitro-phenyl of utilization structure formula II B)-N, N '-two-(2 '-nitro-phenyl)-methylene radical-methanediamine.This is the compound of structural formula II, and wherein n is 1, and R is structural formula (b) group, and this reaction is with reacting circuit G explanation
Reaction circuit G
In reaction process, the following structural formula II of 1mole B compound
With 5mole methyl acetoacetate and 1mole methyl-3-amino-crotons ester reaction.This is a general formula IV compound, and wherein Z is the group of structural formula (C), and K is 1, and symbol P is 0.Back one component also can prepare on the spot by methyl acetoacetate and ammonia react, can use aqueous ammonium hydroxide or methanol ammonium hydroxide for this reason, be reflected in inert solvent or the solvent mixture and carry out, anyly under reaction conditions all not can be used as reaction medium, can use the cited inert solvent of the starting raw material that is used for structural formula II A with the inert solvent of starting raw material effect.Especially preferably in METHANOL MEDIUM, react, this reaction can be carried out in a very wide temperature range, temperature of reaction can change between-10 ℃～+ 120 ℃, preferably 5～100 ℃, particularly 25～80 ℃, the reaction times is depended on temperature of reaction, wants 12～60 hours usually, be preferably 25～55 hours, reaction was finished with high yield in 36～40 hours usually.
Can also in same equipment, structural formula II B compound be changed into NIFEDIPINE without separating.
After reaction is finished, with simple method NIFEDIPINE is separated from reaction mixture, preferably filter out sedimentary NIFEDIPINE earlier, dry then through washing, can also under heating condition, NIFEDIPINE be dissolved in the acetate, aqueous precipitation goes out product, and the NIFEDIPINE that obtains thus satisfies the pharmacopeia requirement, does not need recrystallize.
According to method other embodiment a), with the trimerization 2-nitro benzylidene imines of following structural formula II C
As starting material, this compound also can a combinate form formula exist, and is general formula II compound, and wherein n is 3, and R represents hydrogen, and reaction is with reacting circuit H explanation
Reaction circuit H
In reaction process, 1mole structural formula II C compound and the reaction of 6mole methyl acetoacetate, be reflected in the inert solvent and carry out, as long as inert solvent under used reaction conditions not with the starting material effect, can use those solvents relevant with the starting material that is used for structural formula II A or solvent mixture as reaction medium, methyl alcohol is especially favourable as medium in reaction.
Temperature of reaction can change in wide range, generally at-10 ℃ to+120 ℃, and preferably 5～100 ℃, particularly 25-80 ℃, the reaction times is depended on temperature, generally wants 12～60 hours, be preferably 25～55 hours, the particularly preferred reaction times is 36～50 hours.
Also can in same equipment, structural formula II C compound be changed into NIFEDIPINE without separation.
The NIFEDIPINE that obtains thus can be separated from reaction mixture by simple method, can reaction mixture, isolate NIFEDIPINE by filtration or centrifugation, or NIFEDIPINE is dissolved in the acetate, add water and precipitate, washing and dry then, the NIFEDIPINE that obtains thus satisfies the pharmacopeia requirement.
The starting raw material of general formula II is a new compound, does not introduce in the prior art.
According to another aspect of the present invention, provide a kind of method for preparing general formula II compound, it comprises:
A) preparation general formula II compound, wherein n is 1, the group of R representative structure formula (a) is with 2-nitro-phenyl aldehyde and general formula R
1-COONH
4(R wherein
1Be hydrogen or C
1-4Alkyl) ammonium salt and methyl alcohol reaction; Or
B) compound of preparation general formula II, wherein n is 1, R represents the group of structural formula (b), with 2-nitro-phenyl aldehyde and general formula R
1-COONH
4(R wherein
1As above definition) ammonium salt or ammonium hydroxide reaction; Or
C) preparation general formula II compound, wherein n is 3, R represents hydrogen, and 2-nitro-phenyl aldehyde and ammonia are reacted in inert solvent; And, from reaction mixture, separate the general formula II compound that obtains if need.
According to aforesaid method A), 2-nitro-phenyl aldehyde and general formula R
1-COONH
4Ammonium salt and methyl alcohol reaction, R
1It can be the straight or branched alkyl (for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the like) of 1-4 carbon atom.As general formula R
1-COONH
4Ammonium salt preferentially use ammonium acetate, the best excessive use of methyl alcohol as reaction reagent, thereby also as reaction medium, this reaction can be carried out in very wide temperature range, can be-10 ℃～+ 80 ℃, is preferably 15～40 ℃, be reflected in the quite short time and finish, offer 1.5～7 hours in about 7 hours reaction time, obtains the high desired structure formula II A compound of productive rate.
Reaction also can be carried out in other inert solvent, as long as inert solvent does not react with starting material under used reaction conditions.
With currently known methods the structural formula II A compound that this obtains is separated from reaction mixture, by reaction mixture, filtration or centrifugation, then the washing and drying can isolate product at an easy rate.Also can in same equipment, directly structural formula II A compound be changed into NIFEDIPINE without separating.
According to method B), 2-nitro-phenyl aldehyde and formula R
1-COONH
4Ammonium salt or ammonium hydroxide reaction, as general formula R
1-COONH
4Ammonium salt, preferentially use ammonium acetate.The reaction of 2-nitro-phenyl aldehyde and ammonium acetate can be carried out in inert solvent medium., can use under used reaction conditions not and the interactional inert solvent of starting material for this reason, therefore, preferably use polar aprotic solvent (for example: water; Fatty Alcohol(C12-C14 and C12-C18) with at least two carbon atoms is as ethanol, Virahol etc.; Acid amides is as methane amide, ethanamide etc.) or bipolarity aprotonic solvent (for example: acetonitrile, ethyl ketone, dimethyl alum, oil of mirbane etc.), reaction is preferably carried out in isopropanol medium.
Also can be with 2-nitro-phenyl aldehyde and ammonium hydroxide reaction, reaction medium preferably uses methyl alcohol.
Method B) reaction can be carried out in a very wide temperature range, is preferably between-10 ℃ to+80 ℃ particularly 15～40 ℃.Reaction times is quite short, generally wants 6～7 hours, and the structural formula II B compound productive rate that obtains during about 7 hours of reaction times is very high.
The structural formula II B compound that obtains separates with known simple method, as, resemble and introduced in the isolating construction formula II A compound.
Also can in same equipment,, structural formula II B compound be changed into NIFEDIPINE without separation.
According to method C), 2-nitro-phenyl aldehyde in inert solvent with ammonia react, preferably with the solution and the methanol ammonium hydroxide solution reaction of 2-nitrobenzaldehyde and methyl alcohol, yet where reaction can be in office with in the interactional solvent of starting material not be carried out under the used reaction conditions yet, therefore can use to be used for structural formula II B(method B) the cited solvent of starting material.
Reaction can be carried out in a very wide temperature range, between-10 ℃～+ 80 ℃, is preferably 15～40 ℃, and reaction is generally wanted 5～25 hours.
Structural formula II C compound can be with as method A) the simple method separation introduced, also can in same equipment,, structural formula II C compound be changed into NIFEDIPINE without separation.
We have found that, productive rate that general formula II compound can be high and purity preparation, this purity makes and can directly change into the highly purified NIFEDIPINE that satisfies pharmacopeia requirement and quality standard without recrystallization.
We are surprisingly found out that, if the 2-nitrobenzaldehyde reacts in same organic solvent (as methyl alcohol), the structural formula of the general formula II compound that forms depends on the Material Characteristics of employed ammonia, and the relation of gained ammonia source and general formula II compound structure is shown in table 1.
Table 1
Ammonia product-derived structure productive rate
Ammonium acetate II A 98%
Ammonium hydroxide II B 92%
Anhydrous ammonia II C 75%
The starting raw material (2-nitro-phenyl aldehyde, the general formula R that use
1-COONH
4Ammonium salt, ammonium hydroxide, methyl alcohol) be commercial available product.
According to method b), NIFEDIPINE is prepared as follows: the methyl acetoacetate of 2-nitro-phenyl aldehyde and structural formula III and aqueous ammonium hydroxide react in a step in inert solvent, 101～120 ℃ of temperature of reaction, pressure is 2.0～6.0bar.
Have been found that, if at pressure 2.0～6.0bar, 101～120 ℃ of temperature, 2-nitro-phenyl aldehyde, methyl acetoacetate and ammonium hydroxide inert organic solvents under react, being reflected in the very short time step takes place, obtain straight product, need not purify and promptly satisfy the pharmacopeia needs.
According to prior art, under pressure, use the reaction of ammonia to obtain highly purified product like this at 101～120 ℃, and be astonishing less than prediction.Be surprisingly found out that elevated temperature to above-mentioned interval, the main reaction that generates NIFEDIPINE is carried out with suitable speed, and generates the not quickening of side reaction of byproduct, even can not take place in the time at the short reaction that uses.What be taken aback especially is, when ammonia exists, carries out if be reflected under the ammonia excessive in a large number (2.0mole), does not even form a so-called diamines and an amine structure byproduct.
The method according to this invention b), for the most handy 2～4mole methyl acetoacetate of 1mole2-nitrobenzaldehyde and 1～3mole ammonia (with the ammonium hydroxide aqueous solution form), especially advantageously, use 2.2～3.5mole methyl acetoacetate and 1.04～2.00mole aqueous ammonium hydroxide for 1mole2-nitro-phenyl aldehyde, the concentration of solution of ammonium hydroxide is preferably 20～30%(weight ratio), 25%(weight ratio particularly).
Method b) is single step reaction, do not need methyl-3-amino-crotons ester, be reflected in the inert organic solvents and carry out, preferentially use lower aliphatic alcohols, particularly methyl alcohol.
According to method b) particularly preferred embodiment, depress adding, with mixture heating up to 101～120 of 2-nitro-phenyl aldehyde, methyl acetoacetate, ammonium hydroxide aqueous solution and inert organic solvents (preferably methyl alcohol) ℃, used working pressure is 2.0～6.0bar, 2.0～3.0bar particularly, be reflected in very short time and finish, about 2～5 hours.
Reaction mixture is handled in very simple mode, be reflected at 101～120 ℃ carry out finishing in several hours after, with the reaction mixture cooling, be cooled to 0～5 ℃ usually, by filtering or centrifugation, isolate sedimentary nitropyridine, use methanol wash.
The product that obtains thus satisfies the officinal requirement, does not need further purification.
This method is particularly suitable for industrial production.
The advantage of this method is summarized as follows:
Method a)
In the currently known methods of non-Hantzsch type reaction (for example, except that β-ketone-carboxylicesters, also use more expensive alkene ammonia carboxylicesters), the alkene ammonia carboxylicesters composition of above-mentioned costliness accounts for half of used starting material ester amount, therefore, according to Hungarian patent NO.192, disclosed method in 546, for the 1mole methyl acetoacetate, use 1mole methyl-3-amino-crotons ester.
On the other hand, the method according to this invention a), alkene ammonia carboxylicesters (methyl-3-amino-crotons ester) or do not use (being under the situation of structural formula II C at starting material), perhaps its consumption is under the situation of structural formula II B at starting material for the 1/6(of used total ester composition only), perhaps consumption is that the 1/4(of used total ester composition is under the situation of structural formula II A at starting material).
Reaction times is than Hungarian patent NO.192, the used time of disclosed method is short in 546, in this known synthetic the first step, forming ylidene derivatives needs 16 hours, and the inventive method starting material a) in about 7 hours almost quantitatively, form (especially referring to reaction circuit G and F) more quickly.General formula II compound changes into NIFEDIPINE and Hungarian patent NO.192, and second step (the subunit intermediate product changes into NIFEDIPINE) of 546 listed methods needs the roughly the same time.
Amazing not prediction be, although the reaction mechanism complexity, according to method a), new synthetic line provides fabulous productive rate, highly purified NIFEDIPINE, it is suitable for pharmacy procedure, and does not need further crystallization and purification step.
Method b)
-single step reaction;
-several hours utmost point short reaction time;
-do not use methyl-3-amino-crotons ester;
-high yield;
-high purity.
What not do not expect is not, under used reaction conditions, ammonia does not cause unwanted side reaction, does not generate the by product of amine or two amine structures, and ammonia is a large amount of to carry out when excessive if be reflected at, even has suppressed side reaction.
Detail of the present invention is seen embodiment, but protection domain is not limited to these embodiment.
Embodiment 1
To 315.3g(1mole) 1-methoxyl group-1-(2 '-nitro-phenyl)-N-(2 '-nitro-phenyl)-add 348.3g(3mole in the suspension of methylene radical-methylamine and 1 liter of methyl alcohol) methyl acetoacetate, add 115.1g(1mole then) methyl-3-amino-crotons ester, reaction mixture is heated to boiling point, reacted 36 hours, cooling then, leach throw out, blot, be dissolved in the acetate under heating, the water precipitated product filters, with methanol wash and dry, obtain the 572g NIFEDIPINE, productive rate 82.6%, fusing point: 172～174 ℃.
The product that obtains is dissolved in chloroform, carried out thin-layer chromatographic analysis 2 hours on the 60 blocks of plates of HPTLC Kieselgel in diisopropyl ether is bathed, stratographic analysis shows does not have additional (strange) point.
Starting material can prepare as follows:
With 151.1g(1mole) 2-nitro-phenyl aldehyde is dissolved in the 250ml methyl alcohol, stir and add 80g(1.04mole) ammonium acetate, at 40 ℃ reaction mixture was stirred 15 minutes, at room temperature stirred then 7 hours, reaction mixture leaches throw out, wash with water and drying, obtain 154.5g1-methoxyl group-1-(2 '-nitro-phenyl)-N-(2 '-nitro-phenyl)-methylene radical-methylamine, productive rate 98%, fusing point: 117～118 ℃.
Embodiment 2
With 31.5g(0.1mole) 1-methoxyl group-1-(2 '-nitro-phenyl)-N-(2 '-nitro-phenyl)-methylene radical-methylamine is suspended in the 100ml methyl alcohol, add 46.45g(0.4mole) methyl acetoacetate, dropwise add the ammonium hydroxide that contains 1 equivalent ammonia then.Reaction mixture is heated to boiling point, reacted 14 hours, cooling leaches precipitated product then, with cold methanol and water washing and dry, thereby obtains the 49.2g NIFEDIPINE, productive rate 71%, fusing point: 170～172 ℃.
Embodiment 3
To 31.5g(0.1mole) 1-methoxyl group-1-(2 '-nitro-phenyl)-N-(2 '-nitro-phenyl)-add 46.45g(0.4mole earlier in methylene radical-methylamine and the 68ml methanol mixture) methyl acetoacetate, add then and contain 1.7g(0.1mole) the methanol ammonium hydroxide solution of ammonia, reaction mixture is heated to boiling point, reacted 36 hours, cooling then, leach throw out, blot, under heating condition, be dissolved in the acetate, with water precipitation, filtration, washing is also dry, thereby obtains the 51.2g NIFEDIPINE, productive rate 74%, fusing point: 171～175 ℃.
Embodiment 4
To 433.4g(1mole) 1-(2 '-nitro-phenyl)-N, stir in the suspension of N '-two-(2 '-nitro-phenyl)-methylene radical-methanediamine and 1.5 liters of methyl alcohol and add 580.6g(5mole) methyl acetoacetate and 115.1g(1mole) methyl-3-amino-crotonate, reaction mixture is heated to boiling point, reacted 46 hours, cooling then, leach throw out, blot, under heating condition, be dissolved in acetate, with water precipitation, filtration and dry, thereby obtain the 810.2g NIFEDIPINE, productive rate 78.5%, fusing point: 173～174 ℃.
Starting material is prepared as follows:
A) in the 500ml Virahol, add 151.1g(1mole earlier) 2-nitro-phenyl aldehyde, add 80g(1.04mole then) ammonium acetate, 40 ℃ of stirred reaction mixtures 15 minutes, at room temperature stirred reaction mixture then 7 hours, leach throw out, washing is also dry, thereby obtains 141.6g1-(2 '-nitro-phenyl)-N, N '-two-(2 '-nitro-phenyl)-methylene radical-methanediamine, productive rate 98%, fusing point: 124～127 ℃.
B) to the 15.1g(0.1mole that is in stirring) add in the solution of 2-nitro-phenyl aldehyde and 40ml methyl alcohol and contain 1.7g(0.1mole) solution of ammonium hydroxide of ammonia, at room temperature stirred this solution 25 hours, cooling then, leach throw out, with methanol wash and dry, thereby obtain 13.3g1-(2 '-nitro-phenyl)-N, N '-two-(2 '-nitro-phenyl)-methylene radical-methanediamine, productive rate 92%, fusing point: 123～126 ℃.
Embodiment 5
To 43.3g(0.1mole) 1-(2 '-nitro-phenyl)-N, in the suspension of N '-two-(2 '-nitro-phenyl)-methylene radical-methanediamine and 140ml methyl alcohol, stir and add 69.7g(0.6mole) methyl acetoacetate and 8.7ml 25% ammonium hydroxide aqueous solution, 45 ℃ of stirred reaction mixtures 42 hours, cooling leached throw out then, under heating condition, be dissolved in acetate, thereby obtain the 79.0g NIFEDIPINE, productive rate 76%, 172～173 ℃ of fusing points with water precipitation and drying.
Embodiment 6
With 9g(0.02mole) trimerization 2-nitro-phenyl aldehyde imines and 14g(0.12mole) methyl acetoacetate is dissolved in the 25ml methyl alcohol, reaction mixture stirred 25 hours at boiling state, cooling will precipitate crystal and be dissolved in acetate under heating condition then, use water precipitation, cooling, filtration, water and methanol wash, and dry, thus obtain the 12.4g NIFEDIPINE, productive rate 60%, fusing point: 170～173 ℃.
Starting material is prepared as follows:
To 15.1g(0.1mole) in the solution of 2-nitro-phenyl aldehyde and 40ml methyl alcohol, the following 1.7g(0.1mole that dropwise adds of stirring) methanol solution of ammonia, at room temperature stirred reaction mixture is 20 hours, cooling then, leach throw out,, obtain 11.3g trimerization 2-nitro-phenyl aldehyde imines with methanol wash and dry, productive rate 75.3%, fusing point: 117～119 ℃.
Embodiment 7
In 1 liter glass reactor, 60.4g(0.4mole packs into) 2-nitro-phenyl aldehyde, 102.1g(0.88mole) methyl acetoacetate, 28.25g(0.415mole) 25% ammonium hydroxide aqueous solution and 150ml methyl alcohol, sealed reactor.101～103 ℃ of temperature, pressure 2.0～2.2bar is heated to boiling point with reaction mixture then, reacts 5 hours, reaction mixture is cooled to 0～5 ℃, leaches throw out, use methanol wash, thereby obtain the 110.5g NIFEDIPINE, productive rate 79.8%, fusing point: 171.5～175 ℃.
According to thin-layer chromatographic analysis, do not detect by product, on the Merck of the commercial available Kieselgel of scribbling thin plate, carry out TLC, use the mixture of 3: 2: 5 chloroform, ethyl ketone and sherwood oil to produce thin-layer chromatography.(page 2018 for USP XXI, Supplement3 according to up-to-date HPLC analysis; Validity period is from 1986.1.1), the NIFEDIPINE content of product reaches 98.39%, and quality product meets the pharmacopeia requirement, does not need further purification.
Embodiment 8
Carry out according to the method that embodiment 7 introduces, just be reflected at 120 ℃, pressure 6.0bar and carried out 3 hours, obtain the 110.7g NIFEDIPINE, productive rate 80.0%, fusing point: 172～175 ℃, product meets USP XXI requirement, does not need to purify.
Embodiment 9
According to the method for describing among the embodiment 7, only be to use 0.4mole2-nitro-phenyl aldehyde, 0.8mole25% ammonium hydroxide aqueous solution and 0.88mole methyl acetoacetate, obtain the 111.4g NIFEDIPINE, productive rate 80.5%, product meets USP XXI requirement, do not need further purification, fusing point: 172～175 ℃.
Embodiment 10
Method according to embodiment 7 descriptions, only be to use 0.4mole2-nitro-phenyl aldehyde, the ammonium hydroxide aqueous solution of 0.415mole25% and 1.40mole methyl acetoacetate, obtain the 112.1g NIFEDIPINE, productive rate 81%, fusing point: 172～175 ℃, product meets USP XXI requirement, does not need further purification.
Embodiment 11
25kg(0.165Kmole packs in 250 liters of enamel autoclaves) 2-nitro-phenyl aldehyde, 53kg(0.456Kmole) methyl acetoacetate, 16kg(0.235Kmole) 25% ammonium hydroxide aqueous solution and 80 liters of methyl alcohol, sealing equipment, 101～103 ℃ of temperature and pressure 2.0～2.2bar stirred reaction mixture 5 hours, cool off reactant to 0～5 ℃ then, leach sedimentary NIFEDIPINE, use methanol wash, obtain the 44.4kg NIFEDIPINE, productive rate 77.5%, according to TLC, product is even.According to HPLC NIFEDIPINE content is 98.24%, and product meets USP XXI requirement, does not need further purification, fusing point: 171.5～175 ℃.
Claims (8)
1, be prepared as follows the dimethyl-1 of structural formula I, 4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-pyridine-3, the method for 5-dicarboxylic ester,
It is characterized in that:
A) with the compound of following general formula II
(wherein n is 1 or 3; If n is 1, then R is expressed as follows structural formula (a)
Or (b)
And the aminocompound of at random following general formula IV reacts in inert solvent
(wherein Z is the group of following structural formula (C),
CH
3-
=CH-COOCH
3(c)
K is that 1, two P is 0; Or Z represents C
1～5Straight or branched alcohol oxygen base or carbonate, bicarbonate radical or hydroxide ion, K is that 1, two P is 1; Or K be among 0, two P one be 0; Another is 1);
B) 101～120 ℃ of temperature, under pressure 2.0～6.0bar, the methyl acetoacetate of 2-nitro-phenyl aldehyde and structural formula III and ammonium hydroxide aqueous solution carry out single step reaction in inert solvent.
2, according to the described method of claim 1a, it comprises with general formula II compound makes starting material, wherein R is the group of structural formula (a), and n is 1, is 1-methoxyl group-1-(2 '-nitro-phenyl of structural formula II A)-N-(2 '-nitro-phenyl)-methylene radical-methylamine:
3, method according to claim 2, it comprises compound and 3mole methyl acetoacetate and the reaction of 1mole general formula IV compound of 1mole structural formula II A, wherein Z is the group of structural formula (C), K=1, two P are 0, i.e. methyl-3-amino-crotons ester.
4, according to the described method of claim 1a, it comprises and uses general formula II compound to make starting material, and wherein R is the group of structural formula (b), and n is 1, be 1-(2 '-nitro-phenyl of following structural formula II B)-N, N '-two (2 '-nitro-phenyl)-the methylene radical methanediamine
5, method according to claim 4, it comprises 1mole general formula II B compound and 5mole methyl acetoacetate and 1mole methyl-3-amino-crotons ester (general formula IV compound, wherein Z is the group of structural formula (C), K is that 1, two P is 0) reaction.
6, according to the described method of claim 1a, it comprises and uses trimerization 2-nitro-benzylidene imines of following structural formula II C to make starting material
Be general formula II compound, wherein R is a hydrogen, and n is 3.
7, method according to claim 6, it comprises 1mole structural formula II c compound and the reaction of 6mole methyl acetoacetate.
8, method according to claim 1, it comprises nitro-phenyl aldehyde for 1mole2-, uses 2-4mole methyl acetoacetate and 1-3mole ammonium hydroxide aqueous solution.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1112/88 | 1988-03-08 | ||
| HU111188A HU201912B (en) | 1988-03-08 | 1988-03-08 | Process for producing dihydropyridine-carboxylic acid esters |
| HU1111/88 | 1988-03-08 | ||
| HU4055/88 | 1988-08-02 | ||
| HU405588A HUT54647A (en) | 1988-08-02 | 1988-08-02 | Process for producing nifedipine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1037505A CN1037505A (en) | 1989-11-29 |
| CN1024192C true CN1024192C (en) | 1994-04-13 |
Family
ID=26317328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 89102015 Expired - Fee Related CN1024192C (en) | 1988-03-08 | 1989-03-08 | Process for preparing 1,4-dihydro-pyridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1024192C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204814A (en) * | 2010-09-02 | 2013-07-17 | 常州市第四制药厂有限公司 | Preparation method of nifedipine as well as impurity separating method and application of nifedipine |
-
1989
- 1989-03-08 CN CN 89102015 patent/CN1024192C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204814A (en) * | 2010-09-02 | 2013-07-17 | 常州市第四制药厂有限公司 | Preparation method of nifedipine as well as impurity separating method and application of nifedipine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1037505A (en) | 1989-11-29 |
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