Bis (2, 4-dichlorophenethyl) amine hydrochloride and preparation method thereof
阅读说明：本技术 双（2,4-二氯苯乙基）胺盐酸盐及其制备方法 (Bis (2, 4-dichlorophenethyl) amine hydrochloride and preparation method thereof ) 是由 郑广兵 李剑 侯卫 勾国峰 田超 于 2021-10-12 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一种双(2,4-二氯苯乙基)胺盐酸盐及其制备方法。所述的双(2,4-二氯苯乙基)胺盐酸盐,该化合物的结构式如下：该化合物的～(1)H NMR图谱参数为：～(1)H NMR(600MHz,(CD-(3))-(2)SO)δ9.22(s,1H),7.65(s,1H),7.45(d,2H),3.14-3.18(t,2H),3.09-3.13(t,2H)。制备方法：将2,4-二氯苯乙腈加入有机溶剂中,加入催化剂,通入氢气进行反应,经后处理得到双(2,4-二氯苯乙基)胺盐酸盐。本发明对2,4-二氯苯乙胺的质量控制有着重要意义,步骤短、原料易得,且产物的收率高、纯度高。(The invention belongs to the technical field of organic synthesis, and particularly relates to bis (2, 4-dichlorophenethyl) amine hydrochloride and a preparation method thereof. The bis (2, 4-dichlorophenethyl) amine hydrochloride has the following structural formula: of the compound 1 H NMR spectrum parameters were: 1 H NMR(600MHz，(CD 3 ) 2 SO) delta 9.22(s, 1H), 7.65(s, 1H), 7.45(d, 2H), 3.14-3.18(t, 2H), 3.09-3.13(t, 2H). Preparation methodThe method comprises the following steps: adding 2, 4-dichlorobenzyl cyanide into an organic solvent, adding a catalyst, introducing hydrogen for reaction, and carrying out aftertreatment to obtain bis (2, 4-dichlorophenethyl) amine hydrochloride. The method has important significance for controlling the quality of the 2, 4-dichlorophenethylamine, and has the advantages of short steps, easily obtained raw materials, high yield and high purity of the product.)
1. A bis (2, 4-dichlorophenethyl) amine hydrochloride characterized by: the structural formula of the compound is as follows:
2. a method for preparing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 1, characterized in that: adding 2, 4-dichlorobenzyl cyanide into an organic solvent, adding a catalyst, introducing hydrogen for reaction, and carrying out aftertreatment to obtain bis (2, 4-dichlorophenethyl) amine hydrochloride.
3. Preparation of bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2The method is characterized in that: the catalyst is alumina supported nickel Ni/Al2O3Or platinum Pt/Al loaded on alumina2O3One or two of them.
4. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2, characterized in that: the mass ratio of the 2, 4-dichlorobenzyl cyanide to the catalyst is 1: 0.005-0.02.
5. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2, characterized in that: the organic solvent is one or more of methanol, ethanol, propanol, methyl acetate or ethyl acetate.
6. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2, characterized in that: the dosage ratio of the 2, 4-dichlorobenzyl cyanide to the organic solvent is 1: 4-8, wherein the organic solvent is calculated by ml, and the 2, 4-dichlorobenzyl cyanide is calculated by g.
7. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2, characterized in that: the reaction temperature is 5-30 ℃, the reaction time is 0.5-3.5 h, and the reaction pressure is 0.1-0.5 MPa.
8. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 2, characterized in that: and the post-treatment is to distill the reaction liquid until no liquid flows out after the reaction is finished and filtering, add ethyl acetate and hydrochloric acid, cool and crystallize, and filter.
9. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 8, characterized in that: the dosage ratio of the ethyl acetate to the hydrochloric acid to the 2, 4-dichlorophenylacetonitrile is 2-2.5: 2.5-4: 1, wherein the ethyl acetate and the hydrochloric acid are counted by ml, and the 2, 4-dichlorophenylacetonitrile is counted by g; the concentration of the hydrochloric acid is 3-3.5 mol/L.
10. The method for producing bis (2, 4-dichlorophenethyl) amine hydrochloride according to claim 8, characterized in that: the temperature is controlled to be 15-20 ℃ when the hydrochloric acid is added, and the temperature is kept for 30-40 min after the hydrochloric acid is added.
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to bis (2, 4-dichlorophenethyl) amine hydrochloride and a preparation method thereof.
Background
2, 4-dichlorophenethylamine is also known as 2, 4-dichlorophenol furan and is an important intermediate in the synthesis of medicines and pesticides. Many steps for producing these amines are described in the literature, including: an amination reaction of reducing benzaldehyde with hydrogen and ammonia in the presence of a catalyst; catalytic reduction of benzonitrile or benzylhydroxylamine; or the condensation of benzaldehyde and benzylamine, followed by catalytic hydrogenation of the intermediate product. In these reactions, the intermediate imine reacts further with the primary amine to form a schiff base, releasing ammonia, which is further reduced to a secondary amine in the presence of a catalyst and hydrogen, which compete for reactants in a batch process to form various reaction products. Generally, the yields of benzylamine and dibenzylamine are low and care must be taken to separate each amine from a mixture containing primary, secondary or tertiary amines, imines, aldehydes, alcohols or amides to obtain a product of high purity.
US3117162 discloses a process for the preparation of 2, 4-dichlorophenethylamine, disclosing a batch process for the reduction of benzonitrile by hydrogenation over rhodium, palladium, platinum in a solution of a rare organic solvent such as hexane, octane, ethanol and benzene.
Bis (2, 4-dichlorophenethylamine) is an impurity in the synthesis process of 2, 4-dichlorophenethylamine, and the impurity has poor refining effect in the refining process of 2, 4-dichlorophenethylamine, so that the impurity exceeds the standard easily. Therefore, the research on the generation route of the impurity and the directional synthesis of the impurity are extremely important for the quality research of 2, 4-dichlorophenethylamine, but relevant documents disclosing the impurity are not found in the prior art.
Disclosure of Invention
The invention aims to provide the bis (2, 4-dichlorophenethylamine) hydrochloride, which has important significance on the quality control of 2, 4-dichlorophenethylamine.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the structural formula of the bis (2, 4-dichlorophenethyl) amine hydrochloride is as follows:
of the compound1HNMR map parameters were:1HNMR(600MHz，(CD3)2SO)δ9.22(s，1H)，7.65 (s，1H)，7.45(d，2H)，3.14-3.18(t，2H)，3.09-3.13(t，2H)。
the preparation method of the bis (2, 4-dichlorophenethyl) amine hydrochloride comprises the following steps: adding 2, 4-dichlorobenzyl cyanide into an organic solvent, adding a catalyst, introducing hydrogen for reaction, and carrying out aftertreatment to obtain bis (2, 4-dichlorophenethyl) amine hydrochloride; the reaction formula is as follows:
wherein:
the catalyst is alumina supported nickel Ni/Al2O3(NiCAT-5000P) or alumina-supported platinum Pt/Al2O3One or two of them. The catalyst has small particle size and light specific gravity, can be uniformly dispersed in a reaction system by stirring, improves the catalytic efficiency, and has loose structure, uniform particle size distribution and very good filtering effect.
The mass ratio of the 2, 4-dichlorobenzyl cyanide to the catalyst is 1: 0.005-0.02, and preferably 1: 0.01-0.015.
The organic solvent is one or more of methanol, ethanol, propanol, methyl acetate or ethyl acetate.
The dosage ratio of the 2, 4-dichlorophenylacetonitrile to the organic solvent is 1: 4-8, preferably 1: 5-6, wherein the organic solvent is calculated by ml, and the 2, 4-dichlorophenylacetonitrile is calculated by g.
The reaction temperature is 5-30 ℃, and preferably 5-15 ℃; the reaction time is 0.5-3.5 h, preferably 1.0-2.0 h; the reaction pressure is 0.1 to 0.5MPa, preferably 0.2 to 0.4 MPa.
And the post-treatment is to distill the reaction liquid until no liquid flows out after the reaction is finished and filtering, add ethyl acetate and hydrochloric acid, cool and crystallize, and filter.
The dosage ratio of the ethyl acetate to the hydrochloric acid to the 2, 4-dichlorophenylacetonitrile is 2-2.5: 2.5-4: 1, wherein the ethyl acetate and the hydrochloric acid are counted by ml, and the 2, 4-dichlorophenylacetonitrile is counted by g; the concentration of the hydrochloric acid is 3-3.5 mol/L.
The temperature is controlled to be 15-20 ℃ when the hydrochloric acid is added, and the temperature is kept for 30-40 min after the hydrochloric acid is added.
The invention has the following beneficial effects:
the invention selects alumina loaded nickel Ni/Al2O3Or platinum Pt/Al loaded on alumina2O3As the catalyst, the catalyst has small particle size and light specific gravity, can be uniformly dispersed in a reaction system by stirring, improves the catalytic efficiency, is favorable for improving the yield and the purity of the bis (2, 4-dichlorophenethyl) amine hydrochloride, and has loose structure, uniform particle size distribution and very good filtering effect.
In the production process of 2, 4-dichlorophenethylamine, the content of bis (2, 4-dichlorophenethylamine hydrochloride impurities in the synthesis of 2, 4-dichlorophenethylamine is high, the impurities have obvious influence on the quality of finished products, and the refining effect of the impurities is poor in the refining procedure of the 2, 4-dichlorophenethylamine, so that the impurities are easy to exceed the standard. Therefore, the invention researches the generation way of the hydrochloride of the bis (2, 4-dichlorophenethyl) amine, takes 2, 4-dichlorobenzyl cyanide as a raw material, and carries nickel Ni/Al on catalyst alumina2O3Or platinum Pt/Al loaded on alumina2O3The compound reacts with hydrogen under the action of (1), the temperature is controlled to be 5-30 ℃, and the compound is directionally synthesized, so that the compound has important significance for controlling the quality of 2, 4-dichlorophenethylamine.
In the prior art, in Synthesis 2The synthesis process of the 4-dichlorophenethylamine is generally carried out in an alkaline environment, but the alkaline environment is not required in the invention. The invention loads nickel Ni/Al on alumina at low temperature2O3Or platinum Pt/Al loaded on alumina2O3Under the action of (3), the bis (2, 4-dichlorophenethyl) amine hydrochloride is directionally synthesized. The bis (2, 4-dichlorophenethyl) amine hydrochloride is used as a standard sample, and the content of impurities in the bis (2, 4-dichlorophenethylamine hydrochloride in the synthesis process of the 2, 4-dichlorophenethylamine can be monitored.
The synthesis method of the bis (2, 4-dichlorophenethyl) amine hydrochloride provided by the invention has the advantages of short reaction steps, easily obtained raw materials, high yield of the product and high purity.
Drawings
FIG. 1 is a NMR spectrum of bis (2, 4-dichlorophenethyl) amine hydrochloride according to the present invention;
FIG. 2 is a mass spectrum of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in example 1 of the present invention;
FIG. 3 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in example 1 of the present invention;
FIG. 4 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in example 2 of the present invention;
FIG. 5 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in example 3 of the present invention;
FIG. 6 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in example 4 of the present invention;
FIG. 7 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in comparative example 1 of the present invention;
FIG. 8 is an HPLC chromatogram of bis (2, 4-dichlorophenethyl) amine hydrochloride prepared in comparative example 2 of the present invention.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
100ml of methanol was charged into a 250ml autoclave at room temperature, 20g of 2, 4-dichlorobenzyl cyanide was added, and nickel Ni/Al supported on alumina was added under nitrogen purge2O3(NiCAT-5000P)0.2g, performing nitrogen replacement for three times, introducing hydrogen to ensure that the pressure of the autoclave is 0.3MPa, controlling the temperature to be 15 ℃, reacting for 1h, performing nitrogen replacement for three times, filtering the reaction solution, performing reduced pressure distillation until no liquid flows out, adding 50ml of ethyl acetate, controlling the temperature to be 15-20 ℃, slowly dropwise adding 50ml of 3N hydrochloric acid, separating out a solid in the dropwise adding process, preserving the temperature for 30min after the dropwise adding is finished, and performing suction filtration to obtain 38.7g of bis (2, 4-dichlorophenethyl) amine hydrochloride solid, wherein the yield is 90.08% and the purity is 99.026%. The NMR spectrum of the product bis (2, 4-dichlorophenethyl) amine hydrochloride is shown in FIG. 1, which shows1HNMR map parameters were:1HNMR(600MHz，(CD3)2SO)δ9.22(s，1H)，7.65(s，1H)，7.45(d，2H)，3.14-3.18 (t，2H)，3.09-3.13(t，2H)。
performing mass spectrometry on the generated product, wherein the spectrogram is shown in figure 2; the purity of the HPLC analysis is shown in Table 1, and the spectrum is shown in FIG. 3.
Table 1 HPLC data table for the products of example 1
Example 2
120ml of ethanol was put into a 250ml autoclave at room temperature, 20g of 2, 4-dichlorobenzyl cyanide was added, and nickel Ni/Al supported on alumina was added under nitrogen purge2O30.2g of (NiCAT-5000P), replacing with nitrogen for three times, introducing hydrogen to ensure that the pressure of an autoclave is 0.4MPa, controlling the temperature to be 10 ℃, reacting for 2 hours, replacing with nitrogen for three times, filtering the reaction solution, distilling under reduced pressure until no liquid flows out, adding 50ml of ethyl acetate, controlling the temperature to be 15-20 ℃, slowly dropwise adding 60ml of 3N hydrochloric acid, separating out a solid in the dropwise adding process, preserving heat for 30min after dropwise adding is finished, and performing suction filtration to obtain 40g of bis (2, 4-dichlorophenethyl) amine hydrochloride solid, wherein the yield is 93.10%, and the purity is 99.361%. The purity of the resulting product was analyzed by HPLC, the HPLC data are shown in Table 2, and the spectrum is shown in FIG. 4.
Table 2 HPLC data table for the products of example 2
Peak number
Retention time (min)
Relative peak area (%)
Peak area
Peak height
1
1.957
0.132
0.035
0.757
2
2.043
0.188
0.050
0.913
3
3.573
99.347
26.557
155.525
4
4.120
0.333
0.089
0.837
Example 3
100ml of ethyl acetate was charged into a 250ml autoclave at room temperature, 20g of 2, 4-dichlorophenylacetonitrile was added, and platinum-supported alumina Pt/Al was added under nitrogen purge2O30.3g, performing nitrogen replacement for three times, introducing hydrogen, controlling the pressure of an autoclave to be 0.25MPa, controlling the temperature to be 5 ℃, reacting for 1.5h, performing nitrogen replacement for three times, filtering the reaction solution, performing reduced pressure distillation until no liquid flows out, adding 40ml of ethyl acetate, slowly dropwise adding 80ml of 3N hydrochloric acid at the temperature of 15-20 ℃, separating out a solid in the dropwise adding process, preserving heat for 30min after dropwise adding, and performing suction filtration to obtain 36.5g of bis (2, 4-dichlorophenethyl) amine hydrochloride solid, wherein the yield is 84.96%, and the purity is 99.066%. The purity of the resulting product was analyzed by HPLC, the HPLC data are shown in Table 3, and the spectrum is shown in FIG. 5.
Table 3 HPLC data for the products of example 3
Peak number
Retention time (min)
Relative peak area (%)
Peak area
Peak height
1
1.970
0.260
0.070
1.540
2
2.050
0.264
0.071
1.648
3
3.413
0.134
0.036
0.548
4
3.577
99.066
26.792
158.964
5
4.127
0.276
0.075
0.753
Example 4
110ml of methyl acetate was charged into a 250ml autoclave at room temperature, 20g of 2, 4-dichlorophenylacetonitrile was added, and platinum-supported alumina Pt/Al was added under nitrogen purge2O30.3g, replacing with nitrogen for three times, introducing hydrogen to ensure that the pressure of an autoclave is 0.4MPa, controlling the temperature to be 10 ℃, reacting for 2.0h, replacing with nitrogen for three times, filtering the reaction solution, distilling under reduced pressure until no liquid flows out, adding 45ml of ethyl acetate, slowly dropwise adding 70ml of 3N hydrochloric acid at the temperature of 15-20 ℃, separating out solids in the dropwise adding process, preserving heat for 30min after the dropwise adding is finished, pumping out, and performing vacuum distillation to obtain the productFiltration gave 38.0g of bis (2, 4-dichlorophenethyl) amine hydrochloride solid in 88.45% yield and 99.246% purity. The purity of the resulting product was analyzed by HPLC, the HPLC data are shown in Table 4, and the spectrum is shown in FIG. 6.
Table 4 HPLC data table for the products of example 4
Peak number
Retention time (min)
Relative peak area (%)
Peak area
Peak height
1
1.970
0.261
0.070
1.540
2
2.050
0.264
0.071
1.648
3
3.577
99.248
26.644
158.651
4
4.127
0.227
0.061
0.665
Comparative example 1
The procedure of example 1 was repeated except for changing the "temperature control of 15 ℃ C" to "temperature control of 40 ℃ C" in example 1 to give bis (2, 4-dichlorophenethyl) amine hydrochloride as a solid in an amount of 29.21g, in a yield of 67.99% and in a purity of 81.898%.
The purity of the resulting product was analyzed by HPLC, the HPLC data are shown in Table 5, and the spectrum is shown in FIG. 7.
TABLE 5 HPLC DATA TABLE FOR THE PRODUCTS OF COMPARATIVE EXAMPLE 1
Peak number
Retention time (min)
Relative peak area (%)
Peak area
Peak height
1
1.967
6.404
2.072
32.662
2
2.050
8.459
2.737
39.265
3
3.383
0.468
0.151
1.583
4
3.590
81.898
26.499
155.387
5
3.967
1.981
0.641
3.273
6
5.417
0.790
0.256
2.580
Comparative example 2
The temperature control of 15 ℃ in example 1 was changed to 0 ℃ and the procedure was the same as in example 1 to give bis (2, 4-dichlorophenethyl) amine hydrochloride as a solid in an amount of 31.35g, a yield of 72.97% and a purity of 87.477%.
The purity of the resulting product was analyzed by HPLC, the HPLC data are shown in Table 6, and the spectrum is shown in FIG. 8.
Table 6 HPLC data for the products of comparative example 2
Peak number
Retention time (min)
Relative peak area (%)
Peak area
Peak height
1
1.803
1.286
0.379
3.747
2
1.940
4.072
1.201
20.840
3
2.030
4.978
1.468
20.092
4
3.387
0.273
0.080
0.729
5
3.570
87.477
25.789
148.452
6
4.080
1.5
0.442
2.797
7
5.390
0.414
0.172
1.246
The chromatographic conditions for HPLC in examples and comparative examples are as follows:
chromatograph: thermo UItimate 3000
A chromatographic column: ECliseplus C18, 4.6 × 50mm, 3.5 μm
Mobile phase A: 0.05% phosphoric acid aqueous solution
Mobile phase B: acetonitrile
Flow rate: 1.5ml/min
Column temperature: 25 deg.C
Wavelength: 215nm
Diluent agent: pure acetonitrile
Sample introduction amount: 2 μ l
Gradient elution procedure.
T(min)
B vol% (acetonitrile)
0
20
5
90
10
90
20
90
25
20
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