CN105085278A - Method for preparing 2-methyl-1-substituted phenyl-2-propyl amine compound - Google Patents
Method for preparing 2-methyl-1-substituted phenyl-2-propyl amine compound Download PDFInfo
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Abstract
The invention discloses a novel method for synthesizing a 2-methyl-1-substituted phenyl-2-propyl amine compound. The 2-methyl-1-substituted phenyl-2-propyl amine compound can be used for preparing beta2-adrenergic receptor stimulant drugs. Substituted benzyl halide is adopted as a raw material, and reacts with isobutyronitrile under the action of alkali, obtained 2-methyl-1-substituted phenyl-2-butyronitrile is subjected to hydrolysis, a Curtius rearrangement reaction and catalytic hydrogenation, and 2-methyl-1-substituted phenyl-2-propyl amine is generated. The method is easy and convenient to operate, and total yield is obviously improved.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly relate to the new synthetic method of a kind of 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds.
Background technology
Bronchial asthma (asthma) and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases common now, morbidity in the whole world and mortality ratio in rising trend, therefore the treatment of this kind of disease is received to the concern of whole world medical personal.β
2-adrenoceptor agonists causes bronchiectasic effect owing to having, and can reduce bronchial smooth muscle tension force quickly and effectively, has been used as treating the pulmonary disorder as asthma in the past few decades.Wherein, BI-167107 is a kind of long-acting β2agonists (long-actingbeta2agonists, LABA), has and causes bronchiectasic effect, therefore be used for the treatment of asthma and chronic obstructive pulmonary disease, carry out clinical trial at present.In the structure of BI-167107 and other similar compound, the side chain containing a 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propylamine is one of difficult point of this kind of complicated pharmaceutical synthesis.
2013, the people such as Wang Jiangbo were with 2-tolyl aldehyde for raw material, and through Wittig reaction, Ritter reaction and pyrohydrolysis, the overall yield with 16% has synthesized 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propylamine, is shown below.Wherein, the productive rate of Ritter reaction only has 30% (organic chemistry, 2013,33,634-639).
The people such as Hoenke utilize 2-methylbenzene propylene with sodium cyanide carry out Ritter reaction synthesize 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds (Bioorganic & MedicinalChemistryLetters, 2009,19,6640-6644), but, sodium cyanide is highly toxic product, and especially in acid condition, the prussic acid generated is fatal.They have also attempted aryl acetate and have been reduced by methyl Grignard, generate 2-methyl isophthalic acid-substituted-phenyl-2-propyl alcohol and carry out Ritter reaction in acid condition with acetonitrile again, be shown below.Problem is, the productive rate of Ritter reaction is not high, and some aryl acetate, such as 2-aminomethyl phenyl acetic ester, price is very expensive, even market is not easily bought.
Summary of the invention
Main purpose of the present invention is to provide a kind of novel method of synthesizing 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds, and a kind of novel method preparing 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid compound.
Instant invention overcomes the deficiency that productive rate of the prior art is low, by the overall yield of four-step reaction close to 50%.
The technical solution adopted for the present invention to solve the technical problems is:
A preparation method for 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds, comprises the following steps:
Step one: under organic bases effect, replacement benzyl chlorine and isopropyl cyanide, under the temperature of reaction condition of-78 DEG C ~ 0 DEG C, react in a solvent, generate 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile,
Described reaction raw materials is benzyl chlorine, benzyl bromine or benzylalcohol;
Step 2: by 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali under the temperature of reaction condition of 80 DEG C-220 DEG C, react in a solvent, obtain 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid;
Step 3: under weak base exists, 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide are under the temperature of reaction condition of 40 DEG C-120 DEG C, react in a solvent after 2 hours, in reaction system, add benzylalcohol again, generate 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester;
Step 4: under catalyst effect, 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester, under room temperature, reacts in a solvent, generates 2-methyl isophthalic acid-substituted-phenyl-2-propylamine.
Wherein, the general structure of 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds is as shown in structure I.Wherein, R is hydrogen atom, methyl, ethyl, methoxyl group, hydroxyl, nitro, dimethylamino, halogen atom (fluorine, chlorine, bromine, iodine).
As preferably, the preparation method of a kind of 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds, comprises the following steps:
Step one: under organic bases effect, replacement benzyl chlorine and isopropyl cyanide, under the temperature of reaction condition of-78 DEG C ~ 0 DEG C, react in a solvent, generate 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile,
Described solvent is tetrahydrofuran (THF), dioxane, toluene or hexane;
Step 2: by 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali under the temperature of reaction condition of 80 DEG C-220 DEG C, react in a solvent, obtain 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid,
Described solvent is ethylene glycol, propylene glycol, poly ethylene glycol;
Step 3: under weak base exists, 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide are under the temperature of reaction condition of 40 DEG C-120 DEG C, react in a solvent after 2 hours, benzylalcohol is added again in reaction system, generate 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester
Described solvent is toluene, benzene or tetrahydrofuran (THF);
Step 4: under catalyst effect, 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester, under room temperature, reacts in a solvent, generates 2-methyl isophthalic acid-substituted-phenyl-2-propylamine,
Described solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) or toluene.
As preferably, the mol ratio replacing benzyl chlorine and isopropyl cyanide in described step one is 1:1 ~ 3.
As preferably, in described step one, organic bases is Diisopropylamine lithium salts, n-Butyl Lithium, hexamethyldisilazane lithium salts or sodium hydride.
As preferably, in described step 2, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali is 1:2 ~ 8.
As preferably, in described step 2, alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide, and the alkali in described step 3 is triethylamine, pyridine, piperidines or diisopropyl ethyl amine.
As preferably, in described step 3, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide is 1:1 ~ 5.
As preferably, in described step 3, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and benzylalcohol is 1:3 ~ 20.
As preferably, in described step 4, the weight ratio of 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester and catalyzer is 10 ~ 100:1.
As preferably, in described step 4, catalyzer is palladium carbon, Raney nickel or platinum oxide.
The invention has the beneficial effects as follows: instant invention overcomes deficiency of the prior art, provide the new synthetic method of 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds, the overall yield of four-step reaction is close to 50%, apparently higher than the overall yield (about 15%) of literature method, significantly improve productive rate, and avoid highly toxic product such as using sodium cyanide, raw material is cheaply easy to get, whole preparation process is simple to operate, is suitable for a large amount of preparation and produces.
Embodiment
The present invention is further detailed explanation in conjunction with the embodiments now.
Embodiment one
2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propylamine (5a; R=2-Me) preparation
Step 1:2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyronitrile (2a; R=2-Me) preparation
Embodiment 1: get Diisopropylamine (1.88mL, 13.4mmol, 1.1eq) and be dissolved in 10mL tetrahydrofuran (THF), ice bath extremely-78 DEG C, at N
2drip n-Butyl Lithium (2.8mL, 7.0mmol, 1.1eq) under protection, after stirring 30min, prepared by flaxen LDA.Isopropyl cyanide (2.39mL, 26.6mmol, 1.1eq) is dropwise added drop-wise in reaction, stirs 1 hour, then add 2-methyl benzyl chlorine (1.5g, 10.6mmol), stopped reaction after stirring 25min.The shrend of the hydrochloric acid from 10mL10% concentration to mixed solution and 30ml that add is gone out reaction, with the extraction into ethyl acetate 3 times of 20mL, use the saturated common salt water washing 3 times of the water washing 3 times of 15mL, 15mL again, organic phase is poured in clean Erlenmeyer flask, adds appropriate anhydrous sodium sulfate drying half an hour.After column chromatography purification, obtain weak yellow liquid, productive rate is 98%.
1HNMR(300MHz,CDCl
3):δ7.30-7.16(m,4H),2.88(s,2H),2.38(s,3H),1.40(s,6H)。
Embodiment 2: the mol ratio of 2-methyl benzyl chlorine and isopropyl cyanide, with embodiment 1, is changed into 1:3 by other conditions, and the productive rate of products therefrom is 95%.
Embodiment 3: the mol ratio of 2-methyl benzyl chlorine and isopropyl cyanide, with embodiment 1, is changed into 1:1 by other conditions, and the productive rate of products therefrom is 82%.
Embodiment 4: 2-methyl benzyl chlorine, with embodiment 1, is changed into 2-methyl benzyl bromine by other conditions, and the productive rate of products therefrom is 96%.
Embodiment 5: other conditions are with embodiment 1, and used alkali Diisopropylamine lithium salts (LDA) is changed into hexamethyldisilazane lithium salts (being called for short LiHMDS), the productive rate of products therefrom is 90%.
Embodiment 6: LDA, with embodiment 1, is changed into sodium hydride by other conditions, the productive rate of products therefrom is 34%.
Embodiment 7: LDA, with embodiment 1, is changed into n-Butyl Lithium by other conditions, the productive rate of products therefrom is 31%.
Embodiment 8: temperature of reaction, with embodiment 1, is changed into-30 DEG C from-78 DEG C by other conditions, the productive rate of products therefrom is 81%.
Embodiment 9: temperature of reaction, with embodiment 1, is changed into 0 DEG C from-78 DEG C by other conditions, the productive rate of products therefrom is 62%.
Embodiment 10: solvent, with embodiment 1, is become toluene by other conditions, the productive rate of products therefrom is 44%.
Embodiment 11: solvent, with embodiment 1, is become dioxane by other conditions, the productive rate of products therefrom is 71%.
Embodiment 12: solvent, with embodiment 1, is become hexane by other conditions, the productive rate of products therefrom is 22%.
Step 2:2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyric acid (3a; R=2-Me) preparation
Embodiment 13: get 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyronitrile 2a (1.4g, 8.1mmol) be added in 50mL single port flask, add KOH (1.13g again, 20.2mmol, 2.5eq) with ethylene glycol (15mL), at 175 DEG C, reflux is after 6 hours after stopped reaction, and in reaction solution, add concentration is that 10% hydrochloric acid soln regulates pH=1; First use the extraction into ethyl acetate 3 times of 20mL; 3 times, the saturated common salt water washing of 15mL three times is extracted again with the water of 15mL; Organic phase poured in clean Erlenmeyer flask, anhydrous sodium sulfate drying, column chromatography purification, obtains brown liquid, and productive rate is 89%.
1HNMR(300MHz,CDCl
3):δ7.17-7.12(m,4H),2.97(s,2H),2.33(s,3H),1.24(d,J＝9.6Hz,6H)。
Embodiment 14: other conditions are with embodiment 13, and be 1:5 by the mol ratio of 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyronitrile and potassium hydroxide, the productive rate of products therefrom is 78%.
Embodiment 15: potassium hydroxide, with embodiment 13, is changed into lithium hydroxide by other conditions, the productive rate of products therefrom is 27%.
Embodiment 16: temperature of reaction, with embodiment 13, is changed into 110 DEG C by other conditions, the productive rate of products therefrom is 67%.
Embodiment 17: temperature of reaction, with embodiment 13, is changed into 80 DEG C by other conditions, the productive rate of products therefrom is 23%.
Embodiment 18: temperature of reaction, with embodiment 13, is changed into 220 DEG C by other conditions, the productive rate of products therefrom is 83%.
Embodiment 19: solvent, with embodiment 13, is changed into propylene glycol by other conditions, the productive rate of products therefrom is 45%.
Embodiment 20: solvent, with embodiment 13, is changed into poly ethylene glycol by other conditions, the productive rate of products therefrom is 38%.
Embodiment 21: other conditions are with embodiment 13, and the mol ratio of 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyronitrile and alkali is changed into 1:2, and the productive rate of products therefrom is 82%.
Embodiment 22: other conditions are with embodiment 13, and the mol ratio of 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyronitrile and alkali is changed into 1:8, and the productive rate of products therefrom is 77%.
Step 3:2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propyl group)-carbamic acid benzyl ester (4a; R=2-Me) preparation
Embodiment 23: get 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-butyric acid (495mg, 2.6mmol), triethylamine (284mg, 2.8mmol, 1.1eq) with dry toluene (20mL), be added in 50mL there-necked flask, then drip DPPA (752mg, 2.7mmol, 1.05eq), stir 1h at ambient temperature, temperature is risen to 84 DEG C, and reflux 2h.Stopped reaction after BnOH (2.05g, 19mmol, 7.4eq) stirring and refluxing 37h is added again in there-necked flask, reaction solution is concentrated, then adds 20mL ethyl acetate, use 5%HCl solution respectively, water and full, sodium hydrogen carbonate solution and saturated common salt water washing.Dry concentrated, column chromatography purification, obtains colourless transparent liquid, and productive rate is 71%.
1HNMR(400MHz,CDCl
3):δ7.38-6.99(m,9H),5.09(s,2H),3.03(d,J＝4.44Hz,2H),2.32(d,J＝10.92Hz,3H),1.31(d,J＝10.4Hz,6H)。
Embodiment 24: other conditions are with embodiment 23, and be 1:1 by 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid 3 and the mol ratio of diphenylphosphoryl azide, the productive rate of products therefrom is 66%.
Embodiment 25: other conditions are with embodiment 23, and 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid 3 and the mol ratio of diphenylphosphoryl azide are changed into 1:5, and the productive rate of products therefrom is 76%.
Embodiment 26: other conditions are with embodiment 23, and 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid 3 and the mol ratio of benzylalcohol are changed into 1:20, and the productive rate of products therefrom is 80%.
Embodiment 27: other conditions are with embodiment 23, and 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid 3 and the mol ratio of benzylalcohol are changed into 1:3, and the productive rate of products therefrom is 65%.
Embodiment 28: triethylamine, with embodiment 23, is changed into pyridine by other conditions, the productive rate of products therefrom is 15%.
Embodiment 29: temperature of reaction, with embodiment 23, is changed into 40 DEG C by other conditions, the productive rate of products therefrom is 55%.
Embodiment 30: temperature of reaction, with embodiment 23, is changed into 120 DEG C by other conditions, the productive rate of products therefrom is 65%.
Embodiment 31: reaction solvent, with embodiment 23, is changed into benzene by other conditions, the productive rate of products therefrom is 51%.
Embodiment 32: reaction solvent, with embodiment 23, is changed into tetrahydrofuran (THF) by other conditions, the productive rate of products therefrom is 48%.
Step 4:2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propylamine (5a; R=2-Me) preparation
Embodiment 33: take 2-methyl isophthalic acid-(2-aminomethyl phenyl)-2-propyl group)-carbamic acid benzyl ester 4a (1.0g, 3.3mmol) in 50mL single port flask, add MeOH (20mL) to dissolve, add 10% palladium/carbon (100mg) again, then, at hydrogen environment and room temperature for overnight.After filtration catalizer, concentrated, crude product column chromatography purification, obtains colourless liquid, productive rate 74%.
1HNMR(300MHz,CDCl
3):δ7.23-7.13(m,4H),3.17(s,2H),2.39(s,3H),2.05(s,2H)；
13CNMR(75MHz,CDCl
3):δ130.36,129.58,125.35,124.38,76.50,76.08,75.66,50.47,45.50,29.46,19.54.
Embodiment 34: catalyzer, with embodiment 33, is changed into Raney nickel by other conditions, the productive rate of products therefrom is 45%.
Embodiment 35: catalyzer, with embodiment 33, is changed into platinum oxide by other conditions, the productive rate of products therefrom is 62%.
Embodiment 36: other conditions are with embodiment 33, and be 100:1 by the weight ratio of 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester and catalyzer, the productive rate of products therefrom is 68%.
Embodiment 37: solvent, with embodiment 33, is changed into toluene by other conditions, the productive rate of products therefrom is 42%.
Embodiment 38: solvent, with embodiment 33, is changed into tetrahydrofuran (THF) by other conditions, the productive rate of products therefrom is 54%.
Embodiment two
2-methyl isophthalic acid-(4-fluorophenyl)-2-propylamine (5b; R=4-F) preparation
Step 1:2-methyl isophthalic acid-(4-fluorophenyl)-2-butyronitrile (2b; R=4-F) preparation
Embodiment 39: reaction raw materials, with embodiment 1, is changed into 4-fluorine benzyl chlorine, obtained weak yellow liquid, productive rate 97% by other conditions.
1HNMR(300MHz,CDCl
3):δ7.26-7.22(m,2H),7.06-7.00(m,2H),2.79(s,2H),1.35(s,6H).
Step 2:2-methyl isophthalic acid-(4-fluorophenyl)-2-butyric acid (3b; R=4-F) preparation
Embodiment 40: reaction substrate, with embodiment 13, is changed into 2-methyl isophthalic acid-(4-fluorophenyl)-2-butyronitrile 2b, obtained brown liquid, productive rate 83% by other conditions.
1HNMR(300MHz,CDCl
3):δ7.15-7.10(m,2H),6.99-6.93(m,2H),2.82(d,2H),1.20(s,6H).
Step 3:2-methyl isophthalic acid-(4-fluorophenyl)-2-propyl group)-carbamic acid benzyl ester (4b; R=4-F) preparation
Embodiment 41: reaction substrate, with embodiment 23, is changed into 2-methyl isophthalic acid-(4-fluorophenyl)-2-butyric acid 3b, obtained colourless transparent liquid, productive rate 82% by other conditions.
1HNMR(300MHz,CDCl
3):δ7.39-7.36(m,5H),7.01-6.95(m,2H),6.90-6.84(m,2H),5.09(s,2H),2.95(s,2H),1.27(s,6H).
Step 4:2-methyl isophthalic acid-(4-fluorophenyl)-2-propylamine (5b; R=4-F) preparation
Embodiment 42: reaction substrate, with embodiment 33, is changed into 2-methyl isophthalic acid-(4-fluorophenyl)-2-propyl group by other conditions)-carbamic acid benzyl ester 4b, obtain weak yellow liquid, productive rate 64%.
1HNMR(400MHz,CDCl
3):δ7.16-7.12(m,2H),7.01-6.96(m,2H),2.63(s,2H),1.11(s,6H)；
13CNMR(100MHz,CDCl
3):δ162.93,160.50,134.11,134.08,131.78,131.71,114.89,114.68,77.38,77.06,76.74,50.12,50.02,30.24,1.02.
Embodiment three
2-methyl isophthalic acid-(4-methoxyphenyl)-2-propylamine (5c; R=4-MeO) preparation
Step 1:2-methyl isophthalic acid-(4-methoxyphenyl)-2-butyronitrile (2c; R=4-MeO) preparation
Embodiment 43: reaction raw materials, with embodiment 1, is changed into 4-methoxy benzyl chlorine, obtained weak yellow liquid, productive rate 86% by other conditions.
1HNMR(400MHz,CDCl
3):δ7.20-7.17(m,2H),6.87(d,J＝4.4Hz,2H),3.80(s,3H),2.75(s,2H),1.33(s,6H)。
Step 2:2-methyl isophthalic acid-(4-methoxyphenyl)-2-butyric acid (3c; R=4-MeO) preparation
Embodiment 44: reaction substrate, with embodiment 13, is changed into 2-methyl isophthalic acid-(4-methoxyphenyl)-2-butyronitrile 2c, obtained brown liquid, productive rate 69% by other conditions.
1HNMR(300MHz,CDCl
3):δ7.08(d,J＝8.5Hz,2H),6.81(d,J＝8.5Hz,2H),3.79(s,3H),2.83(s,2H),1.19(s,6H).
Step 3:2-methyl isophthalic acid-(4-methoxyphenyl)-2-propyl group)-carbamic acid benzyl ester (4c; R=4-MeO) preparation
Embodiment 45: reaction substrate, with embodiment 23, is changed into 2-methyl isophthalic acid-(4-methoxyphenyl)-2-butyric acid 3c, obtained colourless transparent liquid, productive rate 58% by other conditions.
1HNMR(300MHz,CDCl
3):δ7.38-7.32(m,5H),6.97(d,J＝8.7Hz,2H),6.75(d,J＝8.7Hz,2H),5.09(s,2H),3.77(s,3H),1.28(s,6H).
Step 4:2-methyl isophthalic acid-(4-methoxyphenyl)-2-propylamine (5c; R=4-MeO) preparation
Embodiment 46: reaction substrate, with embodiment 33, is changed into 2-methyl isophthalic acid-(4-methoxyphenyl)-2-propyl group by other conditions)-carbamic acid benzyl ester 4c, obtain weak yellow liquid, productive rate 91%.
1HNMR(400MHz,CDCl
3):δ7.10(d,J＝8.6Hz,2H),6.84(d,J＝8.6Hz,2H),3.80(s,3H),2.60(s,2H),1.50(s,3H),1.10(s,6H)；
13CNMR(75MHz,CDCl
3):δ158.20,131.35,130.50,113.43,77.42,77.10,76.79,55.21,50.11,50.07,30.20,1.03.
With above-mentioned according to desirable embodiment of the present invention for enlightenment, by above-mentioned description, relevant staff in the scope not departing from this invention technological thought, can carry out various change and amendment completely.The technical scope of this invention is not limited to the content on specification sheets, must determine its technical scope according to right.
Claims (10)
1. a preparation method for 2-methyl isophthalic acid-substituted-phenyl-2-propylamine compounds, comprises the following steps:
Step one: under organic bases effect, reaction raw materials and isopropyl cyanide, under the temperature of reaction condition of-78 DEG C ~ 0 DEG C, react in a solvent, generate 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile,
Described reaction raw materials is benzyl chlorine or benzyl bromine;
Step 2: by 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali under the temperature of reaction condition of 80 DEG C-220 DEG C, react in a solvent, obtain 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid;
Step 3: in the presence of a base, 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide are under the temperature of reaction condition of 40 DEG C-120 DEG C, react in a solvent after 2 hours, in reaction system, add benzylalcohol again, generate 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester;
Step 4: under catalyst effect, 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester, under room temperature, reacts in a solvent, generates 2-methyl isophthalic acid-substituted-phenyl-2-propylamine.
2. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1-substituted-phenyl-2-propylamine compounds, is characterized in that comprising the following steps:
Step one: under organic bases effect, replacement benzyl chlorine and isopropyl cyanide, under the temperature of reaction condition of-100 DEG C ~ 25 DEG C, react in a solvent, generate 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile,
Described solvent is tetrahydrofuran (THF), dioxane, toluene or hexane;
Step 2: by 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali under the temperature of reaction condition of 80 DEG C-220 DEG C, react in a solvent, obtain 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid,
Described solvent is ethylene glycol, propylene glycol, poly ethylene glycol;
Step 3: in the presence of a base, 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide are under the temperature of reaction condition of 40 DEG C-120 DEG C, react in a solvent after 2 hours, benzylalcohol is added again in reaction system, generate 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester
Described solvent is toluene, benzene or tetrahydrofuran (THF);
Step 4: under catalyst effect, 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester, under the temperature of reaction condition of 10 DEG C-50 DEG C, reacts in a solvent, generates 2-methyl isophthalic acid-substituted-phenyl-2-propylamine,
Described solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) or toluene.
3. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: the mol ratio replacing benzyl chlorine and isopropyl cyanide in described step one is 1:1 ~ 3.
4. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step one, organic bases is Diisopropylamine lithium salts, n-Butyl Lithium, hexamethyldisilazane lithium salts or sodium hydride.
5. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step 2, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyronitrile and alkali is 1:2 ~ 8.
6. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, it is characterized in that: in described step 2, alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide, the alkali in described step 3 is triethylamine, pyridine, piperidines or diisopropyl ethyl amine.
7. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step 3, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and diphenylphosphoryl azide is 1:1 ~ 5.
8. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step 3, the mol ratio of 2-methyl isophthalic acid-substituted-phenyl-2-butyric acid and benzylalcohol is 1:3 ~ 20.
9. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step 4, the weight ratio of 2-methyl isophthalic acid-substituted-phenyl-2-propyll-carbamic acid benzyl ester and catalyzer is 10 ~ 100:1.
10. the preparation method of a kind of 2-methyl isophthalic acid as claimed in claim 1 or 2-substituted-phenyl-2-propylamine compounds, is characterized in that: in described step 4, catalyzer is palladium carbon, Raney nickel or platinum oxide.
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