CN104356022A - Synthetic method of N-methyl-4-(methyl amino)-3-nitrobenzamide - Google Patents
Synthetic method of N-methyl-4-(methyl amino)-3-nitrobenzamide Download PDFInfo
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- CN104356022A CN104356022A CN201410533410.2A CN201410533410A CN104356022A CN 104356022 A CN104356022 A CN 104356022A CN 201410533410 A CN201410533410 A CN 201410533410A CN 104356022 A CN104356022 A CN 104356022A
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- methylamino
- methyl
- nitrobenzamide
- nitrobenzoic acid
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Abstract
The invention discloses a synthetic method of N-methyl-4-(methyl amino)-3-nitrobenzamide. The method comprises the following steps: firstly, 4-chloro-3-nitrobenzoic acid and methylamine react to generate 4-methyl amino-3-nitrobenzoic acid; then 4-methyl amino-3-nitrobenzoic acid and thionyl chloride have an acylating chlorination reaction to generate 4-(methyl amino)-3-nitrobenzoyl chloride; and finally, 4-(methyl amino)-3-nitrobenzoyl chloride and methylamine react to obtain the N-methyl-4-(methyl amino)-3-nitrobenzamide. The synthetic method of the N-methyl-4-(methyl amino)-3-nitrobenzamide has the advantages that raw material source is wide, the price and the production cost are low, the synthetic process is simple, the operation is simple and convenient, short time is consumed, the product yield is very high, and the total yield of the final product can reach 97.5%.
Description
Technical field
The present invention relates to a kind of synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide, belong to the field of chemical synthesis.
Background technology
The application of N-methyl-4-(methylamino)-3-nitrobenzamide widely, as the intermediate of multi-medicament.It can as having treatment diabetes, hypertension, insulin resistance, dull-witted, the intermediate of the triazole derivative of schizophrenia pharmacodynamic feature, also can treat genetic immunodeficiency as one, the benzimidazole analogues of autoimmune disorder and hematopoietic disorder.Also may be used for synthesis and can treat baldness, promote the intermediate of the benzimidizole derivatives of natural on-off cycles of hair growth.
A kind of synthetic method of compound N-ethyl-4-(methylamino)-3-nitrobenzamide has been mentioned in 2010 world patent WO 2010001946 (A1), in this synthetic method, use organic bases as catalyzer, reaction yield is lower, be only 65%, the reaction equation of its building-up process is as follows:
American Chemical Society's magazine (J. Med. Chem. 2011 in 2011,54,1126 – 1139) kinases inhibitor AKT analogue is reported for work in be referred to the synthetic method of a kind of compound N-phenyl-4-phenyl amino-3-nitrobenzamide, the equation of its building-up process reaction is as follows:
Within 2012, be mentioned to the synthetic method of a kind of compound N-phenyl-4-ethylamino-3-nitrobenzamide in world patent WO 2012102937 (A2), the equation of its building-up process reaction is as follows:
Above-mentioned American Chemical Society's magazine and also use basic cpd for 2012 in patent and make catalyzer, but employ HOBT simultaneously, these condensation reagents of CDI, its productive rate improves relatively, but reaction cost adds.
In sum, the synthetic method of existing N-methyl-4-(methylamino)-3-nitrobenzamide mainly exists productive rate, and low (first section of document only has 65%, other two sections of documents are not carried), route cost is high (uses fluorochemical, organic alkali catalyst, and HOBT/CDI condensation reagent), the simple not (HOBT of operation, the use of CDI, makes severe reaction conditions) etc. shortcoming.
Summary of the invention
The object of the invention be in order to solve the expensive raw material price, the processing unit that exist in the synthetic method of above-mentioned N-methyl-4-(methylamino)-3-nitrobenzamide require high, produce the technical problems such as length consuming time, productive rate be low and provide that a kind of raw materials cost is lower, equipment requirements is not high, building-up process is simple, easy and simple to handle, ultimate yield up to more than 95% the synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide.
Technical scheme of the present invention
A kind of synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide, namely first, reacts chloro-for 4-3-nitrobenzoic acid and methylamine and generates 4-methylamino-3-nitrobenzoic acid; Then, 4-methylamino-3-nitrobenzoic acid and sulfur oxychloride carry out acyl chloride reaction and generate 4-(methylamino)-3-nitrobenzoyl chloride; Finally, 4-(methylamino)-3-nitrobenzoyl chloride and methylamine carry out reacting and namely obtain N-methyl-4-(methylamino)-3-nitrobenzamide.
The synthetic method of above-mentioned a kind of N-methyl-4-(methylamino)-3-nitrobenzamide, the concrete steps of its building-up process are as follows:
(1), the chloro-3-nitrobenzoic acid of 4-and methylamine react and generate 4-methylamino-3-nitrobenzoic acid
The chloro-3-nitrobenzoic acid of 4-is added in round-bottomed flask, after add the aqueous methylamine solution that mass percent concentration is 25%, under magnetic agitation condition, oil bath is warming up to backflow, reaction 3-5h, the reaction solution of gained cools 15 DEG C, by acetic acid adjust ph to 3, obtain yellow 4-methylamino-3-R substituted benzoic acid;
The amount of methylamine and the chloro-3-nitrobenzoic acid of 4-in above-mentioned aqueous methylamine solution, calculates, i.e. methylamine in molar ratio: the chloro-3-nitrobenzoic acid of 4-is 3.5 ~ 5:1;
(2), 4-methylamino-3-nitrobenzoic acid and sulfur oxychloride react and generate 4-(methylamino)-3-nitrobenzoyl chloride
At ambient temperature, in round-bottomed flask, add 4-(methylamino)-3-nitrobenzoic acid, dissolve with methylene dichloride, drip N, dinethylformamide, as catalyzer, drips sulfur oxychloride with constant pressure funnel, and dripping process control drop rate is 0.1mL/s, after dropwising, proceed to oil bath, be warming up to backflow, reaction 4h, removal of solvent under reduced pressure, obtaining yellow powdery solid is 4-(methylamino)-3-nitrobenzoyl chloride;
The add-on of above-mentioned 4-used (methylamino)-3-nitrobenzoic acid, methylene dichloride and sulfur oxychloride is in 4-(methylamino)-3-nitrobenzoic acid: methylene dichloride: sulfur oxychloride is that the ratio of 1mol:1.8L:0.2L calculates;
(3), 4-(methylamino)-3-nitrobenzoyl chloride and methylamine are obtained by reacting N-methyl-4-(methylamino)-3-nitrobenzamide
4-(methylamino)-3-nitrobenzoyl chloride is added in round-bottomed flask, dissolve with methylene dichloride, under normal temperature, with constant pressure funnel by mass percent concentration be the methylamine of 25% the aqueous solution control drop rate be that 0.1mL/s is added drop-wise to inside flask, reaction 0.5h, washes with water, is separated organic phase, removal of solvent under reduced pressure, obtains yellow solid and is N-methyl-4-(methylamino)-3-nitrobenzamide;
Above-mentioned 4-used (methylamino)-3-nitrobenzoyl chloride and mass percent concentration are the aqueous methylamine solution amount of 25%, by 4-(methylamino)-3-nitrobenzoyl chloride: mass percent concentration is that 25% aqueous methylamine solution calculates than for 1mol:1.9L.
The structural formula of N-methyl-4-(the methylamino)-3-nitrobenzamide of above-mentioned gained is as follows:
Wherein R
1for CH
3-, R
2for CH
3-, R
3for NO
2-;
Those skilled in the art, according to the existing technique means in this area, can select to adjust above-mentioned synthetic method step (1) aqueous methylamine solution used and step (3) aqueous methylamine solution used is other organic amine aqueous solution, thus synthesize the R in structural formula
3for NO
2-, R
1for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-; R
2for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-N-methyl-4-(the methylamino)-3-nitrobenzamide compounds that waits.
Beneficial effect of the present invention
A kind of N-methyl-4-(methylamino of the present invention) synthetic method of-3-nitrobenzamide, owing to have employed the chloro-3-nitrobenzoic acid of 4-, aqueous methylamine solution and thionyl chloride as raw material, these raw material sources are wide, low price, therefore synthetic method of the present invention has the low feature of production cost.Again because building-up process of the present invention is popular response, therefore there is building-up process simple, feature easy and simple to handle.
Further, the synthetic method of a kind of N-methyl-4-(methylamino)-3-nitrobenzamide of the present invention, because temperature of reaction is less demanding, without severe corrosive solvent, therefore this synthetic method is lower to equipment requirements.
Further, the synthetic method of a kind of N-methyl-4-(methylamino)-3-nitrobenzamide of the present invention, produce owing to not having virulent material in building-up process, and building-up process is consuming time short, substitute onto final step amidation from the first step and only need 24h, and building-up process is simple to operate, easy large-scale promotion.
In addition, the total recovery of the synthetic method the finished product of N-methyl-4-(methylamino)-3-nitrobenzamide of the present invention can reach 97.5%, and therefore this synthetic method has the very high feature of synthetic product total recovery.
Embodiment
Below by embodiment, the present invention is set forth further, but do not limit the present invention.
The present invention's raw material used, reagent are commercially available AR, CP level.
The present invention's melting point apparatus used is WRS-2A numeral melting point instrument.
The nuclear magnetic resonance spectrometer that the present invention is used, Avance III 500M, Bruker company of Switzerland produces.
embodiment 1
A kind of synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide, the structural formula of described N-methyl-4-(methylamino)-3-nitrobenzamide is as follows:
Wherein R
1for CH
3-, R
2for CH
3-, R
3for NO
2-.
The synthetic method of above-mentioned a kind of N-methyl-4-(methylamino)-3-nitrobenzamide, specifically comprises the steps:
(1) in the round-bottomed flask of 100mL, add the chloro-3-nitrobenzoic acid of 4-(10g, 0.05mol), add the aqueous methylamine solution that 30mL mass percent concentration is 25%, under magnetic agitation condition, oil bath is warming up to reflux state, reaction 3-5h, cooling drips acetic acid adjust ph to 3, separate out yellow 4-methylamino-3-nitrobenzoyl acid crude, rinse with a small amount of water, filter, dry and obtain 4-methylamino-3-nitrobenzoic acid, productive rate 99.4%;
The chloro-3-nitrobenzoic acid of 4-that above-mentioned reaction is used and mass percent concentration be the aqueous methylamine solution of 25% amount with, calculate in molar ratio, i.e. methylamine: the chloro-3-nitrobenzoic acid of 4-is 1:4;
(2) in 250mL round-bottomed flask, add 4-(methylamino)-3-nitrobenzoic acid (9.8g, 0.05mol), add 60mL methylene dichloride to dissolve, then, at ambient temperature 10mL thionyl chloride constant pressure funnel is added drop-wise to wherein, reacts 3-5h under being warming up to reflux conditions after dropwising, removal of solvent under reduced pressure, the yellow powdery solid obtained is 4-(methylamino)-3-nitrobenzoyl chloride, productive rate 98.6%;
4-(methylamino)-3-nitrobenzoic acid, methylene dichloride, sulfur oxychloride and N that above-mentioned reaction is used, the amount of dinethylformamide, in 4-(methylamino)-3-nitrobenzoic acid: methylene dichloride: sulfur oxychloride: the ratio that DMF is 1mol:1.8L:0.2L:0.002L as catalyzer calculates;
(3) in the round-bottomed flask of 250mL, add 4-(the methylamino)-3-nitrobenzoyl chloride (10.7g of step (2) gained, 0.05mol), add 60mL methylene dichloride to dissolve, then controlling drop rate under stirring at normal temperature is 0.1mL/s, add the aqueous methylamine solution that 30mL mass percent concentration is 25%, reaction 0.5h, wash with water, be separated organic phase, removal of solvent under reduced pressure, obtains yellow solid, productive rate 99.5%, it is 204.3-205.8 DEG C that WRS-2A numeral melting point instrument melting point tube test sample method carries out detecting its fusing point, total recovery 97.5%;
Above-mentioned reaction 4-(methylamino)-3-nitrobenzoyl chloride used, mass percent concentration are the aqueous methylamine solution of 25% and the amount of methylene dichloride, i.e. 4-(methylamino)-3-nitrobenzoyl chloride: methylamine: methylene dichloride is 1mol:1.1mol:1.2L.
The yellow solid product of above-mentioned gained is identified through nucleus magnetic resonance, and result is as follows:
1H NMR (500 MHz, DMSO-
d6) δ 8.60 (d,
J = 2.0 Hz, 1H), 7.98(d,
J = 2.1 Hz, 1H), 7.97 (d,
J = 2.1 Hz, 1H), 7.05 (s, 1H), 7.03(s, 1H), 3.00 (s, 3H), 2.53 – 2.49 (m, 3H)；
Above-mentioned data results shows that the yellow solid of above-mentioned gained is 4-(methylamino)-3-nitro-N-methyl-benzamide, and its structural formula is
, wherein R
1for CH
3-, R
2for CH
3-, R
3for NO
2 -.
Those skilled in the art are according to the existing technique means in this area, can be other organic amine aqueous solution by step (1) aqueous methylamine solution used in the above-mentioned synthetic method of adjustment and step (3) aqueous methylamine solution used, thus synthesize the R in above-mentioned structural formula
3for NO
2 -; R
1for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-; R
2for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-N-methyl-4-(the methylamino)-3-nitrobenzamide compounds that waits.
In sum, the synthetic method of class N-methyl-4-(methylamino)-3-nitrobenzamide of the present invention, because reaction raw materials is cheap, synthesis step is short, simple to operate, the operating time is shorter, therefore cost is lower, meets industrialization basic demand.The productive rate of final product can reach 99.5%.
Above said content be only the present invention conceive under basic explanation, and according to any equivalent transformation that technical scheme of the present invention is done, all should protection scope of the present invention be belonged to.
Claims (5)
1. a synthetic method for N-methyl-4-(methylamino)-3-nitrobenzamide, the structural formula of described N-methyl-4-(methylamino)-3-nitrobenzamide is as follows:
Wherein R
1for CH
3-, R
2for CH
3-, R
3for NO
2-;
It is characterized in that its building-up process specifically comprises the steps:
First, chloro-for 4-3-nitrobenzoic acid and methylamine are reacted generate 4-methylamino-3-nitrobenzoic acid;
Then, 4-methylamino-3-nitrobenzoic acid and sulfur oxychloride carry out acyl chloride reaction and generate 4-(methylamino)-3-nitrobenzoyl chloride;
Finally, 4-(methylamino)-3-nitrobenzoyl chloride and methylamine carry out reacting and namely obtain N-methyl-4-(methylamino)-3-nitrobenzamide.
2. the synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide as claimed in claim 1, it is characterized in that the chloro-3-nitrobenzoic acid of described 4-and methylamine react and generate 4-methylamino-3-nitrobenzoic acid, 3-5h is reacted under being heated to reflux state by the chloro-3-nitrobenzoic acid of 4-and the mass percent concentration aqueous methylamine solution that is 25%, after the reaction solution of gained is cooled to 15 DEG C by acetic acid adjust ph to 3, namely obtain yellow 4-methylamino-3-nitrobenzoic acid;
The chloro-3-nitrobenzoic acid of 4-that above-mentioned reaction is used and mass percent concentration be the aqueous methylamine solution of 25% amount with, calculate in molar ratio, i.e. methylamine: the chloro-3-nitrobenzoic acid of 4-is 3.5 ~ 5:1.
3. the synthetic method of a kind of N-methyl-4-(methylamino)-3-nitrobenzamide as claimed in claim 1, it is characterized in that described 4-methylamino-3-nitrobenzoic acid and sulfur oxychloride generate 4-(methylamino)-3-nitrobenzoyl chloride, namely at room temperature, take methylene dichloride as solvent, with N, dinethylformamide is as catalyzer, 4h is reacted under 4-(methylamino)-3-nitrobenzoic acid and sulfur oxychloride are heated to reflux state, removal of solvent under reduced pressure, obtains 4-(methylamino)-3-nitrobenzoyl chloride;
4-(methylamino)-3-nitrobenzoic acid, methylene dichloride, sulfur oxychloride and N that above-mentioned reaction is used, the amount of dinethylformamide, in 4-(methylamino)-3-nitrobenzoic acid: methylene dichloride: sulfur oxychloride: the ratio that DMF is 1mol:1.8L:0.2L:0.002L as catalyzer calculates.
4. the synthetic method of a kind of N-methyl-4-(methylamino)-3-nitrobenzamide as claimed in claim 1, it is characterized in that described 4-(methylamino)-3-nitrobenzoyl chloride and methylamine are obtained by reacting N-methyl-4-(methylamino)-3-nitrobenzamide, namely be solvent with methylene dichloride, under normal temperature, 4-(methylamino)-3-nitrobenzoyl chloride and mass percent concentration are react 0.5h under the aqueous methylamine solution magnetic agitation of 25%, the reaction solution removal of solvent under reduced pressure of gained, obtain N-methyl-4-(methylamino)-3-nitrobenzamide,
Above-mentioned reaction 4-(methylamino)-3-nitrobenzoyl chloride used, mass percent concentration are the aqueous methylamine solution of 25% and the amount of methylene dichloride, i.e. 4-(methylamino)-3-nitrobenzoyl chloride: methylamine: methylene dichloride is 1mol:1.1mol:1.2L.
5. the synthetic method of N-methyl-4-(methylamino)-3-nitrobenzamide as claimed in claim 1 is applicable to the synthesis of following N-methyl-4-(the methylamino)-3-nitrobenzamide compounds of structural formula:
Wherein R
3for NO
2 -; R
1for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-; R
2for CH
3cH
2-, CH
3cH
2cH
2-, (CH
3)
2cH-, CH
3(CH
2)
3-or C
6h
5-.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1160563A (en) * | 1997-08-12 | 1999-03-02 | Otsuka Pharmaceut Co Ltd | Dihydrophenazine derivative |
| CN102875529A (en) * | 2011-07-15 | 2013-01-16 | 天津药物研究院 | Dabigatran derivatives and preparation method thereof |
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2014
- 2014-10-11 CN CN201410533410.2A patent/CN104356022B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1160563A (en) * | 1997-08-12 | 1999-03-02 | Otsuka Pharmaceut Co Ltd | Dihydrophenazine derivative |
| CN102875529A (en) * | 2011-07-15 | 2013-01-16 | 天津药物研究院 | Dabigatran derivatives and preparation method thereof |
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