CN110156608B - Method for synthesizing chlorophenylethylamine as intermediate of lorcaserin - Google Patents
Method for synthesizing chlorophenylethylamine as intermediate of lorcaserin Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title abstract description 8
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 title description 10
- 229960005060 lorcaserin Drugs 0.000 title description 10
- PIWRNJHNOGWIMX-UHFFFAOYSA-N n-chloro-2-phenylethanamine Chemical compound ClNCCC1=CC=CC=C1 PIWRNJHNOGWIMX-UHFFFAOYSA-N 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- 239000000203 mixture Substances 0.000 claims abstract description 55
- 239000007787 solid Substances 0.000 claims abstract description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003513 alkali Substances 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910001868 water Inorganic materials 0.000 claims abstract description 20
- SRXFXCKTIGELTI-UHFFFAOYSA-N 2-(4-chlorophenyl)ethanamine Chemical compound NCCC1=CC=C(Cl)C=C1 SRXFXCKTIGELTI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 14
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 239000002585 base Substances 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 239000012074 organic phase Substances 0.000 claims abstract description 6
- 239000002274 desiccant Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 239000003223 protective agent Substances 0.000 claims abstract description 5
- 230000001681 protective effect Effects 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- 239000005543 nano-size silicon particle Substances 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical group CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical group NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical group ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 6
- GWQSENYKCGJTRI-UHFFFAOYSA-N 1-chloro-4-iodobenzene Chemical compound ClC1=CC=C(I)C=C1 GWQSENYKCGJTRI-UHFFFAOYSA-N 0.000 claims description 6
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical compound NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000010304 firing Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000002791 soaking Methods 0.000 claims description 5
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 3
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 238000013517 stratification Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 5
- 231100000614 poison Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 239000012141 concentrate Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 15
- 235000012239 silicon dioxide Nutrition 0.000 description 12
- 150000003947 ethylamines Chemical class 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 238000006887 Ullmann reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- AXZNIFHZRQTQDM-UHFFFAOYSA-N chlorobenzene ethanamine Chemical compound C(C)N.ClC1=CC=CC=C1 AXZNIFHZRQTQDM-UHFFFAOYSA-N 0.000 description 2
- -1 cyclic amine Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 1
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 102000006969 5-HT2B Serotonin Receptor Human genes 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 101150104779 HTR2A gene Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 101150013372 Htr2c gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 229940099898 chlorophyllin Drugs 0.000 description 1
- 235000019805 chlorophyllin Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 101150075901 htr2 gene Proteins 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000462 teratogen Toxicity 0.000 description 1
- 239000003439 teratogenic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种绿卡色林中间体对氯苯乙胺的合成方法，其特征在于，将对卤氯苯与卤代乙胺在催化剂的作用下生成对氯苯乙胺，所述反应过程为：1)将卤代乙胺、保护剂、碱1和溶剂S1混匀，在50～70℃下搅拌反应6～8h结束，过滤除去固体得到混合物M1；2)在保护气保护下，将对卤氯苯、碘化亚铜、固体碱和溶剂S2混匀，控制反应温度为130～145℃，反应压力为3～5个大气压，搅拌50～70min后，滴加混合物M1，滴加结束后，控制反应温度为150～170℃，反应压力为5～7个大气压，反应1～2h结束，得到混合物M2；3)将盐酸水溶液加入至混合物M2中，然后控制反应温度80～90℃，反应压力2～3个大气压，反应40～60min结束，得到混合物M3；4)将碱2加入混合物M3进行调节pH至4，控制温度不超过70℃，冷却后静置分层，有机相经水洗、干燥剂干燥后，浓缩蒸除溶剂得产物。该方法操作相对简单，不使用剧毒物质。The invention discloses a method for synthesizing p-chlorophenethylamine, an intermediate of green caserin. The steps are: 1) mixing haloethylamine, protective agent, base 1 and solvent S1, stirring the reaction at 50-70°C for 6-8 h, and removing the solid by filtration to obtain mixture M1; 2) under the protection of protective gas, the p-halochlorobenzene, cuprous iodide, solid base and solvent S2 are mixed uniformly, the reaction temperature is controlled to be 130-145°C, and the reaction pressure is 3-5 atmospheres. After stirring for 50-70min, the mixture M1 is added dropwise, and the dropwise addition is completed. Then, the reaction temperature is controlled to be 150～170°C, the reaction pressure is 5～7 atmospheres, and the reaction is completed for 1～2h to obtain a mixture M2; 3) an aqueous hydrochloric acid solution is added to the mixture M2, and then the reaction temperature is controlled to 80～90°C, The reaction pressure is 2 to 3 atmospheres, and the reaction is finished for 40 to 60 min to obtain a mixture M3; 4) the alkali 2 is added to the mixture M3 to adjust the pH to 4, the temperature is controlled not to exceed 70 ° C, the layers are left to stand after cooling, and the organic phase is washed with water , After drying with desiccant, concentrate and evaporate the solvent to obtain the product. The method is relatively simple to operate and does not use highly toxic substances.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for synthesizing chlorophyllin intermediate p-chlorophenylethylamine.
Background
With the improvement of economic development and the living standard of people, the incidence rate of obesity is rapidly increased, and a series of complications caused by obesity greatly threaten the health of human beings and are generally concerned by people. The method for preventing and treating obesity through medicines is a currently effective method, Lorcaserin (Lorcaserin) is a novel weight-reducing medicine developed by Arena pharmaceutical companies, and has been approved by the US FDA to be on the market in 6 months of 2012, and after long-term clinical research, the Lorcaserin has obvious curative effect on overweight adult groups for treating obesity and complications, which is the first prescription weight-reducing medicine in 13 years in the United states. The compound has the characteristic target of 5-HT2C, produces appetite suppression and satiety induction effects by specifically stimulating central 5-HT2c receptors, has no effect on 5-HT2A and 5-HT2B receptors, does not cause other complications, can improve heart rate, blood pressure and low-density lipoprotein cholesterol level, and has better health safety than the existing weight-losing drugs.
The lorcaserin is a cyclic amine with R configuration, and the structure is as follows:
in the prior art, parachlorophenethylamine is generally adopted as a raw material to synthesize lorcaserin, and two process routes are provided, as shown in the following formula:
method A
Method B
Thus, p-chlorophenylethylamine is an important intermediate for synthesizing lorcaserin.
In the prior art, CN18010766 describes a method for synthesizing p-chlorophenylethylamine by using p-chlorobenzonitrile as a raw material, in the method, potassium borohydride and raney nickel are used as a reduction system, and finally p-chlorobenzenethylamine is obtained by column chromatography, the yield is about 80%, however, raney nickel is used as a highly toxic catalyst, the storage and recovery conditions are harsh, and nickel for preparing raney nickel is an internationally recognized carcinogen and teratogen; the p-chlorobenzene ethylamine can be obtained only by column chromatography after the reaction, and the operation is complicated. CN18010765 describes a method for synthesizing p-chlorophenylethylamine by using p-chlorophenylacetonitrile as a raw material, in which potassium borohydride and raney nickel are used as a reduction system, and finally p-chlorophenylethylamine is obtained by column chromatography with a yield of about 80%.
Disclosure of Invention
The invention aims to provide a method for synthesizing p-chlorophenylethylamine as a lorcaserin intermediate, which is simple to operate and does not use highly toxic substances.
In order to achieve the purpose, the invention adopts the following technical scheme:
the synthesis method of the chlorophenethylamine as the intermediate of lorcaserin is characterized in that the chlorophenethylamine is generated by the reaction of p-halochlorobenzene and halogenated ethylamine under the action of a catalyst, and the reaction process comprises the following steps:
1) uniformly mixing halogenated ethylamine, a protective agent, alkali 1 and a solvent S1, stirring and reacting at 50-70 ℃ for 6-8 h, and filtering to remove solids to obtain a mixture M1;
2) under the protection of protective gas, uniformly mixing p-halochlorobenzene, cuprous iodide, solid alkali and a solvent S2, controlling the reaction temperature to be 130-145 ℃, the reaction pressure to be 3-5 atmospheres, stirring for 50-70 min (aiming at fully contacting the cuprous iodide, the solid alkali and the p-halochlorobenzene and enabling each reactant in a reaction system to be in an activated state under the conditions of high temperature and high pressure), dropwise adding a mixture M1, controlling the reaction temperature to be 150-170 ℃ after dropwise adding, controlling the reaction pressure to be 5-7 atmospheres, and finishing the reaction for 1-2 h to obtain a mixture M2;
3) adding a hydrochloric acid aqueous solution into the mixture M2, controlling the reaction temperature to be 80-90 ℃, the reaction pressure to be 2-3 atmospheric pressures, and finishing the reaction for 40-60 min to obtain a mixture M3;
4) adding alkali 2 into the mixture M3 to adjust the pH value to 4, controlling the temperature not to exceed 70 ℃, cooling, standing for layering, washing an organic phase with water, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain a product.
The preparation method of the solid alkali comprises the following steps: preparing sodium carbonate, potassium carbonate and water into a solution, then soaking nano silicon dioxide in the solution for 1-3 days to obtain a mixture, concentrating the mixture by using a rotary evaporation method to remove water to obtain a solid, and firing the solid at 700-900 ℃ for 5-10 hours to obtain the nano silicon dioxide-based ceramic material; the weight ratio of the sodium carbonate, the potassium carbonate, the water and the nano silicon dioxide is 1 (1.2-1.4) to 10-15 to 3-4.5.
The p-halochlorobenzene is p-dichlorobenzene, p-chlorobromobenzene or p-chloroiodobenzene; the halogenated ethylamine is 2-chloroethylamine or 2-bromoethylamine; the protective agent is di-tert-butyl dicarbonate; the alkali 1 is sodium carbonate or potassium carbonate; the alkali 2 is an aqueous solution of potassium hydroxide or sodium hydroxide, and the concentration of the aqueous solution is 20% by mass; the solvent S1 is tetrahydrofuran; the solvent S2 is benzene or toluene; the concentration of the hydrochloric acid aqueous solution is 15-20% by mass; the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate; the protective gas is nitrogen or argon.
The molar ratio of the p-halochlorobenzene to the halogenated ethylamine to the cuprous iodide is 1 (1-1.1) to 0.1-0.15; the mass ratio of the p-halochlorobenzene to the solid alkali is 1: (0.12-0.16); the dosage ratio of the halogenated ethylamine to the alkali 1 to the solvent S1 is 1mol, (2.5-3.1) mol, (260-350) mL; the dosage ratio of the p-halochlorobenzene to the solvent S2 is 1g (5-8) mL; the molar ratio of the halogenated ethylamine to HCl in the hydrochloric acid aqueous solution is 1 (1-1.1).
The reaction principle of the present invention is presumed to be as shown in the following formula:
the amino group in the halogenated ethylamine is an active group, and di-tert-butyl dicarbonate is firstly used for reacting with the halogenated ethylamine to generate an amino-protected product 1, so that a byproduct of the reaction of the amino group is avoided. The product 1 and the p-halochlorobenzene both contain halogen atoms, and the two react under the combined action of solid alkali and cuprous iodide and assisted by high temperature and high pressure to generate a similar Ullmann reaction (the reaction conditions of the invention are more severe than the general Ullmann reaction): namely, the copper atom enters between the halogen atom and the benzene ring in the para-halochlorobenzene to form PhCuX1Structure, then coupled with product 1, each free of halogen atoms X1And X2To generate a product 2; the reaction being selective due to the different tendency to leave, i.e. the halogen atom X of the product 12And halogen atom X of p-halochlorobenzene1Stripping and generating a coupled product 2; product 2 is deprotected under acidic conditions to protect the Boc group and thenAdjusting the pH value to finally obtain the final product p-chlorobenzene ethylamine.
Compared with the prior art, the invention has the advantages that:
1. simple operation
2. The reaction yield is high;
3. no use of toxic and harmful substances.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The synthesis method of p-chlorophenylethylamine comprises the following steps:
1) 2-chloroethylamine, di-tert-butyl dicarbonate, sodium carbonate and tetrahydrofuran are mixed uniformly, the mixture is stirred and reacted for 7 hours at the temperature of 65 ℃, and the mixture is filtered to remove solids to obtain a mixture M1.
2) Under the protection of argon, p-chlorobromobenzene, cuprous iodide, solid alkali and benzene are uniformly mixed, the reaction temperature is controlled to be 142 ℃, the reaction pressure is 4 atm, after stirring is carried out for 62min, the mixture M1 is dropwise added, after the dropwise addition is finished, the reaction temperature is controlled to be 163 ℃, the reaction pressure is 6 atm, and the reaction is finished for 1.5h, so that the mixture M2 is obtained.
The preparation method of the solid alkali comprises the following steps: preparing sodium carbonate, potassium carbonate and water into a solution, then soaking nano silicon dioxide in the solution for 2 days to obtain a mixture, concentrating the mixture by using a rotary evaporator to remove water to obtain a solid, and firing the solid at 850 ℃ for 8 hours to obtain the nano silicon dioxide-based catalyst; the weight ratio of the sodium carbonate to the potassium carbonate to the water to the nano silicon dioxide is 1:1.3:13: 4.
The molar ratio of the p-chlorobromobenzene to the 2-chloroethylamine to the cuprous iodide is 1:1.05: 0.12; the mass ratio of the p-halochlorobenzene to the solid alkali is 1: 0.14; the dosage ratio of the 2-chloroethylamine to the sodium carbonate to the tetrahydrofuran is 1mol:2.8mol:330 mL; the dosage ratio of the p-halochlorobenzene to the benzene is 1g:7 mL.
3) Adding 18% by mass of hydrochloric acid aqueous solution into the mixture M2, controlling the reaction temperature at 88 ℃ and the reaction pressure at 2.5 atmospheric pressures, and finishing the reaction for 50min to obtain a mixture M3, wherein the molar ratio of the haloethylamine to HCl in the hydrochloric acid aqueous solution is 1: 1.06.
4) Adding 20 mass percent of sodium hydroxide aqueous solution into the mixture M3 to adjust the pH value to 4, controlling the temperature not to exceed 70 ℃, cooling, standing for layering, washing an organic phase with water, drying with anhydrous sodium sulfate, concentrating, and evaporating to remove the solvent to obtain the product.
The molar yield was 98.5% and the GC purity 98.7%.
Example 2
The synthesis method of p-chlorophenylethylamine comprises the following steps:
1) mixing 2-bromoethylamine, di-tert-butyl dicarbonate, potassium carbonate and tetrahydrofuran uniformly, stirring at 50 ℃ to react for 6 hours, and filtering to remove solids to obtain a mixture M1.
2) Under the protection of nitrogen, p-dichlorobenzene, cuprous iodide, solid base and toluene are uniformly mixed, the reaction temperature is controlled to be 130 ℃, the reaction pressure is 3 atmospheres, after stirring for 50min, the mixture M1 is dropwise added, after dropwise addition, the reaction temperature is controlled to be 150 ℃, the reaction pressure is 5 atmospheres, and after reaction for 1h, the mixture M2 is obtained.
The preparation method of the solid alkali comprises the following steps: preparing sodium carbonate, potassium carbonate and water into a solution, then soaking nano silicon dioxide in the solution for 1 day to obtain a mixture, concentrating the mixture by using a rotary evaporator to remove water to obtain a solid, and firing the solid at 700 ℃ for 5 hours to obtain the nano silicon dioxide-based catalyst; the weight ratio of the sodium carbonate to the potassium carbonate to the water to the nano silicon dioxide is 1:1.2:10: 3.
The molar ratio of the p-dichlorobenzene to the 2-bromoethylamine to the cuprous iodide is 1:1: 0.1; the mass ratio of the p-dichlorobenzene to the solid alkali is 1: 0.12; the dosage ratio of the 2-bromoethylamine to the potassium carbonate to the tetrahydrofuran is 1mol:2.5mol:260 mL; the dosage ratio of the p-dichlorobenzene to the toluene is 1g:5 mL.
3) Adding 15% by mass of hydrochloric acid aqueous solution into the mixture M2, controlling the reaction temperature at 80 ℃ and the reaction pressure at 2 atmospheric pressures, and finishing the reaction for 40min to obtain a mixture M3, 2-bromoethylamine and HCl in the hydrochloric acid aqueous solution in a molar ratio of 1:1.
4) Adding a potassium hydroxide aqueous solution with the mass fraction of 20% into the mixture M3 to adjust the pH value to 4, controlling the temperature not to exceed 70 ℃, cooling, standing for layering, washing an organic phase with water, drying with anhydrous magnesium sulfate, concentrating, and evaporating to remove the solvent to obtain the product.
The molar yield was 97.8%, GC purity 98.0%
Example 3
The synthesis method of p-chlorophenylethylamine comprises the following steps:
1) 2-chloroethylamine, di-tert-butyl dicarbonate, sodium carbonate and tetrahydrofuran are mixed uniformly, the mixture is stirred and reacted for 8 hours at the temperature of 70 ℃, and the mixture is filtered to remove solids to obtain a mixture M1.
2) Under the protection of argon, p-chloroiodobenzene, cuprous iodide, solid alkali and benzene are uniformly mixed, the reaction temperature is controlled to be 130 ℃, the reaction pressure is 5 atm, after stirring is carried out for 70min, the mixture M1 is dropwise added, after the dropwise addition is finished, the reaction temperature is controlled to be 170 ℃, the reaction pressure is 7 atm, and the mixture M2 is obtained after the reaction is finished for 2 h.
The preparation method of the solid alkali comprises the following steps: preparing sodium carbonate, potassium carbonate and water into a solution, then soaking nano silicon dioxide in the solution for 3 days to obtain a mixture, concentrating the mixture by using a rotary evaporator to remove water to obtain a solid, and firing the solid at 900 ℃ for 10 hours to obtain the nano silicon dioxide-based catalyst; the weight ratio of the sodium carbonate to the potassium carbonate to the water to the nano silicon dioxide is 1:1.4:15: 4.5.
The molar ratio of the p-chloroiodobenzene to the 2-chloroethylamine to the cuprous iodide is 1:1.1: 0.15; the mass ratio of the p-chloroiodobenzene to the solid alkali is 1: 0.16; the dosage ratio of the 2-chloroethylamine to the sodium carbonate to the tetrahydrofuran is 1mol:3.1mol:350 mL; the dosage ratio of the p-chloroiodobenzene to the benzene is 1g:8 mL.
3) Adding 20% by mass of hydrochloric acid aqueous solution into the mixture M2, controlling the reaction temperature at 90 ℃ and the reaction pressure at 3 atmospheric pressures, and finishing the reaction for 60min to obtain a mixture M3, 2-chloroethylamine and HCl in the hydrochloric acid aqueous solution with the molar ratio of 1: 1.1.
4) Adding 20 mass percent of aqueous solution of potassium hydroxide or sodium hydroxide into the mixture M3 to adjust the pH value to 4, controlling the temperature not to exceed 70 ℃, cooling, standing for layering, washing an organic phase with water, drying with anhydrous sodium sulfate, concentrating, and evaporating to remove the solvent to obtain the product.
The molar yield was 98.1% and the GC purity 98.2%.
Example 4
No cuprous iodide was added, and no target product was detected under the same reaction conditions and material ratios as in example 1.
Example 5
The solid base was not added, and other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 23.1% and a GC purity of 50.3%.
Example 6
The reaction pressure before the dropwise addition of the mixture M1 was set to 2 atmospheres, the reaction temperature was set to 100 ℃, and the other reaction conditions and the material ratio were the same as in example 1, with a molar yield of 42.6% and a GC purity of 55.2%.
Example 7
The reaction pressure before the dropwise addition of the mixture M1 was set to 8 atmospheres, the reaction temperature was set to 175 ℃, and the other reaction conditions and the material use ratio were the same as in example 1, the molar yield was 69.2%, and the GC purity was 75.2%.
Example 8
The reaction pressure after the dropwise addition of the mixture M1 was set to 3 atmospheres, the reaction temperature was set to 124 ℃, and the other reaction conditions and the material ratio were the same as in example 1, with a molar yield of 53.5% and a GC purity of 66.7%.
Example 9
The reaction pressure after the dropwise addition of the mixture M1 was set to 10 atmospheres, the reaction temperature was set to 180 ℃, and the other reaction conditions and the material ratio were the same as in example 1, the molar yield was 77.8%, and the GC purity was 82.1%.
Example 10
Taking the product of example 1 as an example, the structural analysis data are as follows.
1) Mass spectrometry
Molecular ion peak 155.
2) Nuclear magnetic hydrogen spectrum analysis
1H-NMR (DMSO): δ 7.46(2H), δ 7.30(2H), δ 5.11(2H), δ 3.01(2H), δ 2.89 (2H). The various hydrogens are assigned to the product structure as follows:
and (4) performing nuclear magnetic analysis, wherein the structure of the product conforms to the target object, namely the p-chlorophenylethylamine.
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