CN101575303A - Preparation method of 3- anilino-2-(3,4,5-trimethoxy benzyl) acrylonitrile - Google Patents
Preparation method of 3- anilino-2-(3,4,5-trimethoxy benzyl) acrylonitrile Download PDFInfo
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- CN101575303A CN101575303A CNA2008100369684A CN200810036968A CN101575303A CN 101575303 A CN101575303 A CN 101575303A CN A2008100369684 A CNA2008100369684 A CN A2008100369684A CN 200810036968 A CN200810036968 A CN 200810036968A CN 101575303 A CN101575303 A CN 101575303A
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Abstract
The invention discloses a preparation method of 3-anilino-2-(3,4,5-trimethoxy benzyl) acrylonitrile, which comprises the following steps: dissolving acrylonitrile derivative 3-dimethyl amino propionitrile and 3,4,5-trimethoxy benzaldehyde in an aprotic solvent, i.e. dimethyl sulfoxide, and adding a catalytic amount of alcoholic solution of potassium hydroxide; carrying out a first step of condensation reaction to generate 3-dimethylamino-2-(3,4,5-trimethoxy benzyl) acrylonitrile under the condition of heat; diluting the product after the condensation reaction with methyl alcohol, adding aniline with a catalytic amount, fully stirring, dropwise adding one of dilute sulphuric acid, diluted hydrochloric acid or acetic acid in the mixture until the pH value is 0.5-6.5 and heating the mixture for reaction to complete the second step of reaction of replacing dimethylamine functional groups by the aniline; after the reaction, steaming to eliminate the methyl alcohol in the system, freezing the system after adding an appropriate amount of water to 0-5 DEG C, separating out the 3-anilino-2-(3,4,5-trimethoxy benzyl) acrylonitrile which is a yellow solid product, and filtering and drying the product. The invention has the advantages of reasonable technology design, high yield, lower production cost, simple and convenient operation and convenient for mass production in industry.
Description
[technical field]
The invention belongs to technical field of medicine synthesis, relate to the preparation method that a kind of high yield prepares material medicine trimethoprim key intermediate 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide.
[background technology]
3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide is material medicine trimethoprim (Trimethoprim, TMP) synthetic key intermediate, TMP is widely used on medical treatment and herding industry as antiseptic-germicide and Trimethoprim, 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide and trimethoprim structural formula are as shown in Figure 1.
TMP is as the dihydrofolate reductase inhibitor of the classics applicating history of existing decades, owing to its good bacteriostatic action and antibiotic synergism are recorded by multinational pharmacopeia.Trimethoprim is the important drug manufacture kind of China, own the expanding to antimalarial agent, cephalosporins medicine, antidiarrheal etc. from the sulfonamide combined utilization of TMP united use in recent years, has good cooperative synergism effect, be widely used in clinical treatment and the livestock industry, become one of pillar product of China's pharmaceutical industries, the output of China occupies the whole world 70% above share, and annual production reaches more than two kilotons.Its turnout presents the trend that rises year by year.
Zunyi No.2 Pharmaceutical Factory discloses a kind of method of drawing the production trimethoprim with tower, and China Patent No. CN1077951 is to be that raw material extracts tannic acid (Weibull) after hydrolysis with the Turkey-galls, methylate, esterification makes intermediate 3,4, the 5-tri-methoxybenzoate; Prepare intermediate 3,4 owing to directly carry out esterification reaction of organic acid after Turkey-galls resource scarcity, the present invention go real beanpod (Tara, the transliteration tower draws) for raw material lixiviate talas of tannic acid so that South America is perverse, the 5-tri-methoxybenzoate further prepares TMP again.In this synthetic route, TMP is to intermediate 3,4, and the yield of 5-TMB (TMB) is lower.The major cause of restriction TMP cost factor is that the consumption of expensive intermediate TMB is higher, and the method for therefore adopting new technology reduces the consumption of TMB, the yield of raising TMP is the target that pharmaceutical industry circle is pursued always.
Early stage U.S. Pat 3697512, US 3878252 have disclosed with 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide is that high yield and the Guanidinium hydrochloride cyclization that raw material can 94% makes TMP (as shown in Figure 2), key intermediate 3-anilino-2-(3 is described, 4,5-trimethoxy benzyl) vinyl cyanide is with free guanidine cyclization the time, utilize well the leaving away performance of aniline and show high cyclization activity, but these patents lack efficiently, low-cost preparation 3-anilino-2-(3,4,5-trimethoxy benzyl) method of vinyl cyanide.Can the Technology of therefore developing efficient synthetic 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide just becomes utilize intermediate 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide to come the key of actual fabrication TMP.
U.S. Pat 3697512 adopts the directly synthetic 3-anilino-2-(3 of 3-anilino propionitrile and TMB, 4,5-trimethoxy benzyl) vinyl cyanide, use the potassium tert.-butoxide of reacting weight can reach 88% as its yield of reaction condensing agent, but since relatively the use of the 3-anilino propionitrile of high price and potassium tert.-butoxide bring economically unfavorable; Its sodium methylate that uses catalytic amount during as condensing agent yield have only 71%, cause and can not fully effectively utilize expensive intermediate TMB.
In view of this, this area press for a kind ofly simplify most, low-cost, high-level efficiency prepares 3-anilino-2-(3,4,5-trimethoxy benzyl) processing method of vinyl cyanide, fully reduce the consumption of expensive intermediate TMB, get rid of the reaction reagent of relative high price, to satisfy the needs that branch of industry produces TMP.
[summary of the invention]
The objective of the invention is to overcome prior art uses alkoxyl group potassium to cause production cost height and use sodium alkylate to cause the low defective of yield, 3-anilino-the 2-(3 that provide a kind of low cost, simplifies most, 4,5-trimethoxy benzyl) preparation method of vinyl cyanide, can realize large-scale industrial production, satisfy the needs of branch of industry.
For realizing above goal of the invention, the technological line that the present invention adopts is:
(1) at first, with acrylonitrile derivative 3-dimethylamine propionitrile and 3,4, the 5-TMB is dissolved in the aprotic solvent methyl-sulphoxide, adds the alcoholic solution of catalytic amount potassium hydroxide; Wherein, 3,4, the mol ratio of 5-TMB and acrylonitrile derivative 3-dimethylamine propionitrile is 1.0: 1.0～1.0: 2.0, is preferably 1.0: 1.1～1.0: 1.5; 3,4, the mol ratio of 5-TMB and condensation catalyst potassium hydroxide is 1.0: 0.05～1.0: 0.50, is preferably 1.0: 0.10～1.0: 0.30;
(2) secondly, under heating condition, carry out condensation reaction generation 3-dimethylin-2-(3,4,5-trimethoxy benzyl) vinyl cyanide of the first step; Wherein, 3-dimethylamino propionitrile and 3,4, the temperature of reaction of 5-TMB condensation reaction is 0～150 ℃, is preferably 20～100 ℃, the reaction times is 0.50～15 hour, preferred 3.0～8 hours;
(3) then, after finishing condensation reaction, dilute with low-carbon alcohol, the aniline that adds reacting weight, fully stir, drip in dilute sulphuric acid or dilute hydrochloric acid or the acetic acid a kind of to pH be 0.5～6.5, be preferably 3.0～3.5, heating is reacted, and finishes the second step replacement(metathesis)reaction of aniline to dimethylamine functional group; Wherein, described low-carbon alcohol is selected from methyl alcohol, ethanol, and propyl alcohol, butanols, Virahol, a kind of in the trimethyl carbinol, particular methanol, 3,4, the mol ratio of 5-TMB and aniline is 1.0: 1.0～1.0: 1.50, is preferably 1.0: 1.0～1.0: 1.10; Aniline is 20～150 ℃ to the second step replacement(metathesis)reaction temperature of dimethylamine functional group, is preferably 50～100 ℃, and the reaction times is 0.10～10 hour, is preferably 0.5～4 hour;
(4) last, reaction finishes, and steams the methyl alcohol of the system of removing, and adds an amount of water, is refrigerated to 5～0 ℃, separates out xanchromatic solid product 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide, filtration, drying.
The preparation method's of a kind of 3-anilino-2-of the present invention (3,4,5-trimethoxy benzyl) vinyl cyanide synthetic route is shown in Figure 3.
The preparation method's of a kind of 3-anilino-2-of the present invention (3,4,5-trimethoxy benzyl) vinyl cyanide positively effect is:
(1) preparation technology reasonable in design, to the yield height of main raw material TMB;
(2) do not use the auxiliary material of relative high price, production cost lower, easy and simple to handle, be easy to industrial scale production.
[description of drawings]
Figure 11 is the structural formula of 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide; 4 is trimethoprim (Trimethoprim, structural formula TMP);
The TMP synthetic route chart of Fig. 2 U.S. Pat 3697512;
The synthetic route chart of Figure 33-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide.
Label among the figure is respectively: 1,3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide; 2,3-dimethylamine propionitrile; 3,3-dimethylin-2-(3,4,5-trimethoxy benzyl) vinyl cyanide; 4, trimethoprim, 5,3,4, the 5-TMB.
[embodiment]
A kind of 3-anilino-2-of the present invention (3,4,5-trimethoxy benzyl) below is provided preparation method's embodiment of vinyl cyanide, but the embodiment that provided is provided.
The 3-dimethylamine propionitrile (2) of methyl-sulphoxide, 127.6g that adds 250mL in being furnished with churned mechanically there-necked flask successively fully stirred 0.5 hour down at 45 ℃ (1.30mol) with by the solution that 11.8g (0.21mol) potassium hydroxide and 50mL methyl alcohol are disposed.In the TMB (1.0mol) that in 1 hour, adds 196.2g under this temperature in batches, be warmed up to 85 ℃ then and continued stirring reaction 4 hours, some thin layer plate chromatography (TLC) is followed the tracks of and is disappeared until TMB raw material spot.Be cooled to 40 ℃, the methyl alcohol agitation and dilution that under agitation adds 250mL adds the aniline (1.06mol) of 98.7g again, drips the dilute sulphuric acid of 2mol/L up to the scope of pH at 3.0-3.5 in 1 hour, temperature rising reflux reaction 2 hours, the spot that TLC follows the tracks of until 3 disappears.Remove methyl alcohol under reduced pressure, add 250mL water, reaction mixture is refrigerated to 3 ℃, separates out a large amount of yellow mercury oxides, filters.Filter cake washs with the cold aqueous ethanolic solution 500mL of 15% (v/v), gets the faint yellow solid 1 of 294.5g after the vacuum-drying.130～132 ℃ of fusing points (mp), yield 90.8%.
1H NMR (500MHz, CDCl
3, 1 includes along anti-two kinds of isomer, and the part proton has two chemical shifts): 3.44,3.53 (s, 2H, CH
2), 3.82 (s, 3H, OCH
3), 3.86 (s, 6H, OCH
3), 6.26,6.71 (d, J=13.0Hz, 1H, NH), 6.46,6.52 (s, 2H, ArH), 6.78,6.87 (d, J=7.4Hz, 2H, ArH), 7.01 (t, J=7.4Hz, 1H, ArH), 7.14,7.36 (d, J=13.0Hz, 1H ,=CH), and 7.28-7.32 (m, 2H, ArH).
EI-MS?m/z：324(M
+，100)，293(20)，232(17)，168(20)。
In being furnished with churned mechanically there-necked flask, add the methyl-sulphoxide of 250mL, 2 (1.30mol) of 127.6g and the solution that is disposed by 11.8g (0.21mol) potassium hydroxide and the 50mL trimethyl carbinol successively, fully stirred 0.5 hour down at 45 ℃.In the TMB (1.0mol) that in 1 hour, adds 196.2g under this temperature in batches, be warmed up to 85 ℃ then and continued stirring reaction 4 hours, TLC follows the tracks of and disappears until TMB raw material spot.Be cooled to 40 ℃, the trimethyl carbinol agitation and dilution that under agitation adds 250mL adds the aniline (1.06mol) of 98.7g again, drips the dilute sulphuric acid of 2mol/L up to the scope of pH at 3.0-3.5 in 1 hour, temperature rising reflux reaction 2 hours, the spot that TLC follows the tracks of until 3 disappears.Remove the trimethyl carbinol under reduced pressure, add 250mL water, reaction mixture is refrigerated to 3 ℃, separates out a large amount of yellow mercury oxides, filters.Filter cake washs with the cold aqueous ethanolic solution 500mL of 15% (v/v), gets the faint yellow solid 1 of 296.6g after the vacuum-drying.130～132 ℃ of fusing points (mp), yield 91.4%.
Embodiment 3
The TMB (1.0mol) of 2 (1.30mol), 11.8g (0.21mol) potassium hydroxide and 196.2g that in being furnished with churned mechanically there-necked flask, adds methyl alcohol, the 127.6g of methyl-sulphoxide, the 50mL of 250mL successively, abundant stirring reaction is 5 hours under 80 ℃, and TLC follows the tracks of and disappears until TMB raw material spot.Be cooled to 40 ℃, the methyl alcohol agitation and dilution that under agitation adds 250mL adds the aniline (1.06mol) of 98.7g again, drips the dilute sulphuric acid of 2mol/L up to the scope of pH at 3.0-3.5 in 0.5 hour, temperature rising reflux reaction 2 hours, the spot that TLC follows the tracks of until 3 disappears.Remove methyl alcohol under reduced pressure, add 250mL water, reaction mixture is refrigerated to 3 ℃, separates out a large amount of yellow mercury oxides, filters.Filter cake washs with the cold aqueous ethanolic solution 500mL of 15% (v/v), gets the faint yellow solid 1 of 289.3g after the vacuum-drying.130～132 ℃ of fusing points (mp), yield 89.2%.
The TMB (1.0mol) of 2 (1.30mol), 11.8g (0.21mol) potassium hydroxide and 196.2g that adds methyl-sulphoxide, the 127.6g of 250mL in being furnished with churned mechanically there-necked flask successively is at 80 ℃ of abundant stirring reactions 5 hours down.Be cooled to 40 ℃, under agitation add the methyl alcohol agitation and dilution of 250mL, add the aniline (1.06mol) of 98.7g again, the dilute sulphuric acid that dripped 2mol/L in 0.5 hour is up to the scope of pH at 3.0-3.5, and temperature rising reflux reacted 2 hours.Remove methyl alcohol under reduced pressure, add 250mL water, reaction mixture is refrigerated to 3 ℃, separates out a large amount of yellow mercury oxides, filters.Filter cake washs with the cold aqueous ethanolic solution 500mL of 15% (v/v), gets the faint yellow solid 1 of 254.0g after the vacuum-drying.129～130 ℃ of fusing points (mp), yield 78.3%.This be because in the first step condensation reaction, do not add alcoholic solvent then yield reduce greatly.
Embodiment 5 synthetic 1 are used to prepare TMP
In being furnished with churned mechanically there-necked flask, add successively 120mL methyl alcohol and, the sodium Metal 99.5 (0.23mol) of 5.3g, reflux is all dissolved up to sodium Metal 99.5, makes fresh methanol solution of sodium methylate.Add the Guanidinium nitrate (0.15mol) of 18.5g in this solution, reflux 20 minutes is chilled to 45 ℃, adds 1 (0.10mol) of 32.4g again, heating reflux reaction 10h.Remove methyl alcohol under reduced pressure, add the water of 200mL, stir, be cooled to 5 ℃, separate out a large amount of light-yellow precipitate.Filter, filter cake gets light yellow crude product TMP with the 150mL water washing.Dissolving crude product in 20% dilute formic acid, is added activated carbon in 95 ℃ of decolourings, heat filter, filtrate in 70 ℃ with ammoniacal liquor pH=8.5～9.5 that neutralize, separate out a large amount of white solids, be cooled to room temperature, filter 150mL deionized water wash, dry 27.0g elaboration TMP.202～204 ℃ of fusing points (mp), yield 93.0%.
1H?NMR(500MHz，DMSO-d6)：3.51(s，2H，CH
2)，3.60(s，3H，OCH
3)，3.71(s，6H，OCH
3)，5.69(s，2H，NH
2)，6.08(s，2H，NH2)，6.54(s，2H，ArH)，7.50(s，1H，pyrimidine)。
EI-MS?m/z：290(M
+，100)，275(23)，259(28)，243(14)。
Claims (4)
1. the preparation method of a 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide is characterized in that, concrete steps are,
(1) at first, with acrylonitrile derivative 3-dimethylamine propionitrile and 3,4, the 5-TMB is dissolved in the aprotic solvent methyl-sulphoxide, adds the alcoholic solution of catalytic amount potassium hydroxide; Wherein, 3,4, the mol ratio of 5-TMB and acrylonitrile derivative 3-dimethylamine propionitrile is 1.0: 1.0～1.0: 2.0; 3,4, the mol ratio of 5-TMB and condensation catalyst potassium hydroxide is 1.0: 0.05～1.0: 0.50;
(2) secondly, under heating condition, carry out condensation reaction generation 3-dimethylin-2-(3,4,5-trimethoxy benzyl) vinyl cyanide of the first step; Wherein, 3-dimethylamino propionitrile and 3,4, the temperature of reaction of 5-TMB condensation reaction is 0～150 ℃, the reaction times is 0.50～15 hour;
(3) then, after finishing condensation reaction, dilute, add the aniline of reacting weight with low-carbon alcohol, fully stir, drip in dilute sulphuric acid or dilute hydrochloric acid or the acetic acid a kind of to pH be 0.5～6.5, heating is reacted, and finishes the second step replacement(metathesis)reaction of aniline to dimethylamine functional group; Wherein, described low-carbon alcohol is selected from methyl alcohol, ethanol, and propyl alcohol, butanols, Virahol, a kind of in the trimethyl carbinol, 3,4, the mol ratio of 5-TMB and aniline is 1.0: 1.0～1.0: 1.50; Aniline is 20～150 ℃ to the second step replacement(metathesis)reaction temperature of dimethylamine functional group, and the reaction times is 0.10～10 hour;
(4) last, reaction finishes, and steams the methyl alcohol of the system of removing, and adds an amount of water, is refrigerated to 5～0 ℃, separates out xanchromatic solid product 3-anilino-2-(3,4,5-trimethoxy benzyl) vinyl cyanide, filtration, drying.
2. a kind of 3-anilino-2-(3 according to claim 1,4,5-trimethoxy benzyl) preparation method of vinyl cyanide is characterized in that, in the described step (1), 3,4, the mol ratio of 5-TMB and acrylonitrile derivative 3-dimethylamine propionitrile is preferably 1.0: 1.1～and 1.0: 1.5,3,4, the mol ratio of 5-TMB and condensation catalyst potassium hydroxide is preferably 1.0: 0.10～and 1.0: 0.30.
3. a kind of 3-anilino-2-(3 according to claim 1,4,5-trimethoxy benzyl) preparation method of vinyl cyanide, it is characterized in that, in the described step (2), 3-dimethylamino propionitrile and 3,4, the range of reaction temperature of 5-TMB condensation reaction is preferably 20～100 ℃, and the reaction times is preferably 3.0～8 hours.
4. a kind of 3-anilino-2-(3 according to claim 1,4,5-trimethoxy benzyl) preparation method of vinyl cyanide, it is characterized in that in the described step (3), it drips, and a kind of back pH is preferably 3.0～3.5 in dilute sulphuric acid or dilute hydrochloric acid or the acetic acid, described low-carbon alcohol is preferably methyl alcohol, 3,4, the mol ratio of 5-TMB and aniline is preferably 1.0: 1.0～and 1.0: 1.10; Aniline is preferably 50～100 ℃ to the second step replacement(metathesis)reaction temperature range of dimethylamine functional group, and the reaction times is preferably 0.5～4 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601688A (en) * | 2013-11-25 | 2014-02-26 | 四川大学 | Synthetic method of trimethoprim impurity |
| CN107382876A (en) * | 2017-06-29 | 2017-11-24 | 南通天泽化工有限公司 | A kind of preparation method of TMP |
| CN112480012A (en) * | 2020-12-30 | 2021-03-12 | 寿光富康制药有限公司 | Preparation method of 5- [ (3,4, 5-trimethoxyphenyl) -methyl ] -2, 4-pyrimidinediamine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3878252A (en) * | 1970-09-24 | 1975-04-15 | Burroughs Wellcome Co | Ring substituted beta-hydroxy-phenyethylmethyl sulphone or sulphoxide |
| GB1261455A (en) * | 1969-03-06 | 1972-01-26 | Burroughs Wellcome Co | Improvements in or relating to substituted acrylonitriles |
| CN1077951A (en) * | 1992-04-21 | 1993-11-03 | 遵义第二制药厂 | Draw the method for producing trimethoprim with tower |
-
2008
- 2008-05-05 CN CN2008100369684A patent/CN101575303B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601688A (en) * | 2013-11-25 | 2014-02-26 | 四川大学 | Synthetic method of trimethoprim impurity |
| CN107382876A (en) * | 2017-06-29 | 2017-11-24 | 南通天泽化工有限公司 | A kind of preparation method of TMP |
| CN112480012A (en) * | 2020-12-30 | 2021-03-12 | 寿光富康制药有限公司 | Preparation method of 5- [ (3,4, 5-trimethoxyphenyl) -methyl ] -2, 4-pyrimidinediamine |
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