CN114539147B - Preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline - Google Patents

Preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline Download PDF

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CN114539147B
CN114539147B CN202210202444.8A CN202210202444A CN114539147B CN 114539147 B CN114539147 B CN 114539147B CN 202210202444 A CN202210202444 A CN 202210202444A CN 114539147 B CN114539147 B CN 114539147B
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tetrahydroisoquinoline
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CN114539147A (en
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王亚农
高阳
周洁
周竹青
周继宁
包卫国
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Suzhou Medinoah Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline, which comprises the following steps: (1) Hydrogenating the 3-amino-isoquinoline in the presence of a solvent and a catalyst to produce 3-amino-5, 6,7, 8-tetrahydroisoquinoline; (2) Diazotizing 3-amino-5, 6,7, 8-tetrahydroisoquinoline with a diazonium reagent and then halogenating with a halogenating reagent to produce 3-halo-5, 6,7, 8-tetrahydroisoquinoline, wherein the halogenating reagent is selected from the group consisting of a chlorinating reagent, a brominating reagent, an iodinating reagent, and a fluorinating reagent. According to the invention, 3-amino-isoquinoline is taken as a starting material, 3-amino-5, 6,7, 8-tetrahydroisoquinoline obtained through hydrogenation reduction is taken as an intermediate, and after diazotization, different 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline can be prepared through halogenated reaction with different halogenated reagents, so that the product requirements of different 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline are met.

Description

Preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline.
Background
The 3-halogeno-5, 6,7, 8-tetrahydroisoquinoline compounds are important molecular building blocks in the field of drug synthesis, are used as organic synthesis intermediates for synthesizing lead compounds such as mitogen activated protein kinase 2 (MK 2) inhibitors, mu Opioid Receptor (MOR) antagonists, alpha 7-nicotinic acetylcholine receptor agonists, beta-secretase inhibitors and the like, and have important application value in drug development in various disease fields.
In the prior art, the preparation method of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is reported, and mainly comprises the following steps:
(1) 3-chloro-5, 6 mentioned in CN105163738AThe preparation of 7, 8-tetrahydroisoquinoline is to take 3-hydroxy-isoquinoline as a starting material, react to generate 5,6,7, 8-tetrahydroisoquinoline-3-alcohol under the catalysis of a large amount of platinum dioxide, and then react with POCl 3 Sealing the tube and heating at 170 ℃ for 16h to obtain 3-chloro-5, 6,7, 8-tetrahydroisoquinoline. Although the method successfully prepares the 3-chloro-5, 6,7, 8-tetrahydroisoquinoline, the chlorination reaction in the method uses a great deal of dangerous chemical POCl 3 The reaction and post-treatment processes have potential safety hazards and are not beneficial to environmental protection; meanwhile, the chlorination reaction is also required to be carried out under the condition of high Wen Fengguan, so that the risk coefficient is high, and the safety production is not facilitated. In addition, in the hydrogenation reduction of 3-hydroxy-isoquinoline in the step, the patent mentions that the crude product yield is 44%, but the yield after purification is less than 20%, so the total yield of the two steps is less than 8%, the economic benefit is low, and the method is not suitable for industrial production.
(2) The preparation of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline as mentioned in US8980908B2 is useful as a side chain fragment for the preparation of a Mu Opioid Receptor (MOR) selective non-peptide antagonist. In the patent, 3-hydroxy-isoquinoline is taken as an initial raw material, trifluoro methane sulfonic acid and antimony trifluoride are taken as a catalyst, water is taken as a solvent, and the 5,6,7, 8-tetrahydroisoquinoline-3-ol is prepared by catalytic reduction under alkaline condition, and then the 5,6,7, 8-tetrahydroisoquinoline-3-ol and POCl are combined 3 The 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is obtained by chlorination reaction. The method also uses POCl as dangerous chemical 3 The reaction and post-treatment processes have potential safety hazards, are not beneficial to environmental protection, and are also not suitable for industrial production due to the use of the dangerous chemical trifluoro methane sulfonic acid.
(3) CN108658860a discloses a method for preparing 3-chloro-5, 6,7, 8-tetrahydroisoquinoline, which uses 3-chloroisoquinoline as raw material, a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid as solvent, and platinum dioxide as catalyst to prepare the 3-chloro-5, 6,7, 8-tetrahydroisoquinoline. Although the route does not adopt unsafe reaction conditions of high temperature and high pressure, the method adopts the trifluoro methane sulfonic acid which is a dangerous chemical and has strong corrosiveness, and is not suitable for industrial production.
In a word, the existing preparation method of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline uses trifluoro methanesulfonic acid and P in the reactionOCl 3 Dangerous chemicals such as ammonia, and the reaction conditions relate to conditions such as high temperature and high pressure, are unfavorable for environmental protection and safe production, and cannot meet the requirements of industrial production. Meanwhile, the initial raw materials adopted by the existing preparation method can only be used for producing single chlorinated products, and can not meet the preparation requirements of different halogenated products.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline which can be industrially produced.
In order to achieve the above purpose, the technical scheme adopted is as follows:
a method for preparing 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline, comprising the following steps:
(1) Hydrogenating the 3-amino-isoquinoline in the presence of a solvent and a catalyst to produce 3-amino-5, 6,7, 8-tetrahydroisoquinoline;
(2) Diazotizing 3-amino-5, 6,7, 8-tetrahydroisoquinoline with a diazonium reagent and then halogenating with a halogenating reagent to produce 3-halo-5, 6,7, 8-tetrahydroisoquinoline, wherein the halogenating reagent is selected from the group consisting of a chlorinating reagent, a brominating reagent, an iodinating reagent, and a fluorinating reagent.
According to some preferred aspects of the invention, in step (2), the halogenated reagent is a chlorinated reagent selected from cuprous chloride, cupric chloride, and the diazonium reagent is selected from sodium nitrite.
According to some specific aspects of the invention, the molar ratio of the chlorinating agent to 3-amino-5, 6,7, 8-tetrahydroisoquinoline is from 1 to 5:1, preferably in a molar ratio of 1 to 1.5:1, a step of; the molar ratio of the sodium nitrite to the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1.2-5: 1, preferably in a molar ratio of 1.2 to 5:1, a step of; the diazonium reaction temperature is-10 ℃ to-5 ℃, the chlorination reaction time is 1-10 h, and the chlorination reaction temperature is 0-50 ℃. Preferably, the chlorination reaction time is 1-5 h, and the chlorination reaction temperature is 15-40 ℃. The chlorination reaction condition is mild and the time is short.
According to some specific aspects of the invention, the specific implementation of step (2) is: 3-amino-5, 6,7, 8-tetrahydroisoquinoline, a chloro reagent and acid are mixed, dropwise added with an aqueous solution of sodium nitrite at the temperature of minus 10 ℃ to minus 5 ℃ for diazotization, heated to 15 ℃ to 40 ℃ for reaction for 1 to 5 hours, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried, filtered, decompressed and concentrated, and purified by column chromatography or recrystallization to obtain 3-chloro-5, 6,7, 8-tetrahydroisoquinoline. Preferably, the acid is one or a combination of more of hydrochloric acid and sulfuric acid.
According to further preferred aspects of the invention, in step (2), the halogenated reagent is a brominating reagent selected from the group consisting of bromine, cuprous bromide and the diazonium reagent is selected from the group consisting of sodium nitrite.
According to some specific aspects of the invention, the molar ratio of the brominating reagent to 3-amino-5, 6,7, 8-tetrahydroisoquinoline is from 1 to 10:1, preferably in a molar ratio of 4 to 10:1, a step of; the molar ratio of the sodium nitrite to the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1-10: 1, preferably in a molar ratio of 1.2 to 5:1, a step of; the diazonium reaction temperature is-5 ℃ to 5 ℃, the bromination reaction time is 1 h to 10h, and the bromination reaction temperature is 0 ℃ to 50 ℃. Preferably, the bromination reaction time is 1-5 h, and the bromination reaction temperature is 15-40 ℃.
According to some specific aspects of the invention, the specific implementation of step (2) is: 3-amino-5, 6,7, 8-tetrahydroisoquinoline, hydrobromic acid and brominating reagent are mixed, sodium nitrite aqueous solution is dripped at the temperature of minus 5 ℃ to 0 ℃ for diazotization reaction, the temperature is raised to 15 ℃ to 40 ℃ for reaction for 1 to 5 hours, the reaction solution is diluted by water, neutralized by saturated sodium bicarbonate aqueous solution, extracted by ethyl acetate, dried, filtered, decompressed and concentrated, and the 3-bromo-5, 6,7, 8-tetrahydroisoquinoline is obtained by column chromatography purification.
According to still further preferred aspects of the present invention, in step (2), the halogenated reagent is an iodinated reagent selected from the group consisting of cuprous iodide, cupric iodide, and the diazonium reagent is selected from the group consisting of isoamyl nitrite, tert-butyl nitrite.
According to some specific aspects of the invention, the molar ratio of the iodinating agent to 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1 to 5:1, preferably in a molar ratio of 1 to 1.5:1, a step of; the molar ratio of the diazonium reagent to the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1-5: 1, preferably in a molar ratio of 1.2 to 5:1, a step of; the diazo reaction temperature is-5 ℃ to 5 ℃, the iodination reaction time is 1 to 10 hours, and the iodination reaction temperature is 0 to 50 ℃. Preferably, the iodination time is 1-5 h, and the iodination temperature is 15-40 ℃.
According to some specific aspects of the invention, the specific implementation of step (2) is: adding 3-amino-5, 6,7, 8-tetrahydroisoquinoline into an organic solvent, adding a diazonium reagent and an iodination reagent at 15-40 ℃, reacting for 1-5 h, adding water for dilution, extracting with ethyl acetate, drying, filtering, concentrating, and purifying by column chromatography to obtain 3-iodo-5, 6,7, 8-tetrahydroisoquinoline.
Preferably, the organic solvent is selected from acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, dimethyl sulfoxide.
According to further preferred aspects of the invention, in step (2), the halogenated reagent is a fluorinated reagent selected from the group consisting of pyridinium hydrofluoride, sodium fluoride, potassium fluoride and the diazonium reagent is selected from the group consisting of sodium nitrite. When the fluoro reagent is selected from sodium fluoride and potassium fluoride, hydrofluoric acid is also required to be matched for use. The pyridine hydrofluoric acid salt is added in the form of a solution, and the pyridine hydrofluoric acid salt solution is used as a solvent and also used as a fluoro reagent.
According to some specific aspects of the invention, the molar ratio of the fluoro reagent to 3-amino-5, 6,7, 8-tetrahydroisoquinoline is from 1 to 5:1, preferably in a molar ratio of 1 to 1.5:1, a step of; the molar ratio of the diazonium reagent to the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1-5: 1, preferably in a molar ratio of 1.2 to 5:1, a step of; the diazonium reaction temperature is minus 100 ℃ to minus 70 ℃, the fluorination reaction time is 1 to 10 hours, and the fluorination reaction temperature is 0 to 50 ℃. Preferably, the fluorination reaction time is 1-5 h, and the fluorination reaction temperature is 15-35 ℃.
According to some specific aspects of the invention, the specific implementation of step (2) is: mixing 3-amino-5, 6,7, 8-tetrahydroisoquinoline with a fluoro reagent, adding sodium nitrite at-100 ℃ to-70 ℃, then heating to 15 ℃ to 35 ℃ for reaction for 1 to 5 hours, adding water for dilution, neutralizing with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline.
According to some preferred aspects of the invention, in step (1), the solvent is trifluoroacetic acid, the catalyst is selected from platinum dioxide and platinum, the mass of the catalyst accounts for 5-15% of the mass of the 3-amino-isoquinoline, the hydrogenation reduction uses hydrogen, and the hydrogenation reduction is carried out at 30-55 ℃. Preferably, the mass of the catalyst accounts for 10% of the mass of the 3-amino-isoquinoline.
According to some preferred aspects of the present invention, the production method further comprises a step of post-treating the reaction liquid obtained after the hydrogenation reduction in step (1), the post-treating step comprising: the reaction solution was filtered, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted with a mixture of methanol and dichloromethane, the organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to give 3-amino-5, 6,7, 8-tetrahydroisoquinoline.
Further, in the mixed solution of methanol and dichloromethane, the mass percentage of the methanol is 4-6%, preferably 5%.
According to still other preferred aspects of the present invention, the production method further comprises a step of subjecting the reaction liquid obtained after the hydrogenation reduction in step (1) to a post-treatment comprising: the reaction solution is filtered, decompressed and concentrated, neutralized by saturated sodium bicarbonate solution, extracted by ethyl acetate, dried by an organic phase, decompressed and concentrated to obtain a crude product, then the crude product is dissolved in a mixed solution of methanol and water, alkali is added, the mixture is stirred for reaction, then water is added for dilution, extraction is performed by ethyl acetate, the organic phase is dried, filtered, decompressed and concentrated, and the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is obtained by column chromatography purification.
Further, in the mixed solution of the methanol and the water, the volume ratio of the methanol to the water is 2-3: 1, preferably a volume ratio of 2.5:1.
further, the alkali is one or a combination of more of potassium carbonate and sodium carbonate; the mass ratio of the alkali to the 3-amino-isoquinoline is 1:5 to 10; the stirring reaction is carried out at 35-45 ℃, and the stirring reaction time is 1-5 h.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the invention, 3-amino-isoquinoline is taken as a starting material, 3-amino-5, 6,7, 8-tetrahydroisoquinoline obtained through hydrogenation reduction is taken as an intermediate, and after diazotization, different 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline can be prepared through halogenated reaction with different halogenated reagents, so that the product requirements of different 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline are met.
The method of the invention completely does not need to adopt any extremely toxic or highly corrosive substances, does not need to adopt dangerous conditions such as high temperature, high pressure and the like, has safe and convenient operation process and mild and controllable reaction conditions, accords with the green chemical process, and is obviously more suitable for industrial production compared with the existing method.
The method of the invention fills the blank of the prior art about the preparation method of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline, 3-iodo-5, 6,7, 8-tetrahydroisoquinoline and 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline compounds.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 3-amino-5, 6,7, 8-tetrahydroisoquinoline of example 1;
FIG. 2 is a liquid phase diagram of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline of example 1;
FIG. 3 is a mass spectrum of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline of example 1;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline of example 1;
FIG. 5 is a liquid phase diagram of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline of example 3;
FIG. 6 is a mass spectrum of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline of example 3;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline of example 3;
FIG. 8 is a liquid phase diagram of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline of example 5;
FIG. 9 is a mass spectrum of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline of example 5;
FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline of example 5
FIG. 11 is a liquid phase diagram of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline of example 8;
FIG. 12 is a mass spectrum of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline of example 8;
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline of example 8.
Detailed Description
Compared with the existing 3-hydroxy-isoquinoline, the 3-amino-isoquinoline is adopted as the starting material, the hydrogenation reduction selectivity is good, the 3-amino-5, 6,7, 8-tetrahydroisoquinoline with higher yield can be obtained by adopting a small amount of catalyst and mild reaction temperature, and then the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is taken as the intermediate to prepare a series of 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline compounds through diazonium-halogenation reaction, wherein the 3-halogenated-5, 6,7, 8-tetrahydroisoquinoline compounds comprise chlorination, iodination and fluoro. And the total yield of the 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is obviously improved compared with the existing reaction route which takes 3-hydroxy-isoquinoline as the starting material (the existing research shows that the total yield is improved to more than 17 percent). The method of the invention also fills the blank of the prior art about the preparation method of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline, 3-iodo-5, 6,7, 8-tetrahydroisoquinoline and 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline compounds. Furthermore, the whole route avoids using any extremely toxic or highly corrosive substances, does not need to adopt dangerous conditions such as high temperature, high pressure and the like, has mild reaction and is more suitable for industrial production.
The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
Example 1
This example provides a process for the preparation of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline comprising the steps of:
(1) Preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline
260g of 3-amino-isoquinoline was added to 2L of trifluoroacetic acid, 26g of platinum dioxide was added, and hydrogenation was carried out at 40℃overnight. After the reaction of the starting materials was completed, the reaction solution was cooled to room temperature. Filtering, concentrating under reduced pressure, neutralizing with saturated sodium bicarbonate solution, extracting with 5% methanol/dichloromethane, drying the organic phase, concentrating under reduced pressure, and purifying the crude product by column chromatography to obtain 3-amino-5, 6,7, 8-tetrahydroisoquinoline: 160g, yellow solid. The yield thereof was found to be 60%.
The nuclear magnetic resonance hydrogen spectrum of the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is shown in figure 1, and the specific data are as follows:
1 H NMR(400MHz,CDCl 3 ):δ1.74-1.78(m,4H),2.65(dt,4H),6.3(s,1H),7.68(s,1H).
(2) Preparation of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline
160g of 3-amino-5, 6,7, 8-tetrahydroisoquinoline and 128g of cuprous chloride are added to 1L of concentrated hydrochloric acid, 193g of sodium nitrite is dissolved in 1L of water, the temperature is controlled to minus 10 ℃ to minus 5 ℃, and an aqueous solution of sodium nitrite is added dropwise to the reaction solution. The reaction was carried out at room temperature for 2 hours. After the reaction of the starting materials was completed, the ph=10 of the reaction solution was adjusted with a saturated aqueous sodium bicarbonate solution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline: 52.5g, white solid. The yield thereof was found to be 29%.
The liquid phase diagram of the 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is shown in figure 2;
the mass spectrum of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 3, and the specific values are as follows: LC_MS (ES+): m/z 168.1[ M+H ].
The nuclear magnetic resonance hydrogen spectrum of the 3-chloro-5, 6,7, 8-tetrahydroisoquinoline is shown in fig. 4, and specific numerical values are as follows: 1 H NMR(400MHz,CDCl 3 ):δ1.75-1.82(m,4H),2.71(q,4H),7.01(s,1H),8.06(s,1H).
example 2
This example provides a process for the preparation of 3-chloro-5, 6,7, 8-tetrahydroisoquinoline, wherein the preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline is prepared in accordance with the following procedure, otherwise as in example 1 (i.e., the second step is in accordance with the second step of example 1).
40g of 3-amino-isoquinoline was added to 400mL of trifluoroacetic acid, 4g of platinum dioxide was added, and hydrogenation was carried out at 40℃overnight. After the reaction of the starting materials was completed, the reaction solution was cooled to room temperature. Filtering, concentrating under reduced pressure, neutralizing with saturated sodium bicarbonate solution, extracting with ethyl acetate, drying the organic phase, and concentrating under reduced pressure. The crude product was dissolved in a mixed solvent of 50mL of methanol and 20mL of water, 5g of potassium carbonate was added, and the reaction was stirred at 40℃for 3 hours. Diluting the reaction solution with water, extracting with ethyl acetate, drying an organic phase, filtering, concentrating under reduced pressure, and purifying the crude product by column chromatography to obtain the product 3-amino-5, 6,7, 8-tetrahydroisoquinoline: 37g, yellow solid. The yield thereof was found to be 91%.
Example 3
This example provides a process for the preparation of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline using bromine),
5g of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 1) is added to 400mL hydrobromic acid (40% wt.%) and 32.35g of bromine is added at a controlled temperature of 0 ℃. 11.6g of sodium nitrite was dissolved in 50mL of water, the temperature was controlled at 0℃and an aqueous sodium nitrite solution was added to the reaction solution. Then reacted at room temperature for 2 hours. After the completion of the reaction of the raw materials, 100mL of water was added to the reaction solution for dilution, and the ph=7 of the reaction solution was adjusted with a saturated aqueous sodium bicarbonate solution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline: 3g, light reddish brown oil.
The liquid phase diagram of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 5;
the mass spectrum of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 6, and the specific values are as follows: LC_MS (ES+): m/z 214.0[ M+2].
The nuclear magnetic resonance hydrogen spectrum of the 3-bromo-5, 6,7, 8-tetrahydroisoquinoline is shown in fig. 7, and specific values are as follows: 1 H NMR(400MHz,CDCl 3 ):δ1.79-1.80(m,4H),2.69-2.72(m,4H),7.17(s,1H),8.05(s,1H).
example 4
This example provides a process for the preparation of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline using cuprous bromide),
100mg of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 2) and 115mg of cuprous bromide are added to 10mL of hydrobromic acid (40% wt.%). 120mg of sodium nitrite was dissolved in 1mL of water, the temperature was controlled at 0℃and an aqueous sodium nitrite solution was added to the reaction solution. The reaction was carried out at room temperature for 2 hours. After the completion of the reaction of the raw materials, 2mL of water was added to the reaction solution for dilution, and the ph=7 of the reaction solution was adjusted with a saturated aqueous sodium bicarbonate solution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-bromo-5, 6,7, 8-tetrahydroisoquinoline: 54mg, light reddish brown oil.
Example 5
This example provides a process for the preparation of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline,
200mg of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 2) was added to 7mL of acetonitrile, and 385mg of cuprous iodide and 316mg of isoamyl nitrite were added at room temperature. Then reacted at room temperature for 2 hours. After the reaction of the raw materials was completed, 20mL of water was added to the reaction solution for dilution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline: 45mg, colorless oil.
The liquid phase diagram of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 8;
the mass spectrum of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 9, and the specific values are as follows: LC_MS (ES+): m/z 260.0[ M+H ].
The nuclear magnetic resonance hydrogen spectrum of the 3-iodo-5, 6,7, 8-tetrahydroisoquinoline is shown in fig. 10, and specific values are as follows: 1 H NMR(400MHz,CDCl 3 ):δ1.79-1.80(m,4H),2.68(s,4H),7.42(s,1H),8.05(s,1H).
example 6
This example provides a method for preparing 3-iodo-5, 6,7, 8-tetrahydroisoquinoline:
2g of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 2) was added to 50mL of acetonitrile, and 5.14g of copper iodide and 2.78g of tert-butyl nitrite were added at room temperature. The reaction was carried out at room temperature for 2 hours. After the completion of the reaction of the raw materials, 200mL of water was added to the reaction mixture for dilution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline: 1.43g, colorless oil.
Example 7
This example provides a method for preparing 3-iodo-5, 6,7, 8-tetrahydroisoquinoline:
200mg of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 2) was added to 7mL of tetrahydrofuran, and 514mg of copper iodide and 316mg of isoamyl nitrite were added at room temperature. The reaction was carried out at room temperature for 2 hours. After the reaction of the raw materials was completed, 20mL of water was added to the reaction solution for dilution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-iodo-5, 6,7, 8-tetrahydroisoquinoline: 126mg, colorless oil.
Example 8
This example provides a process for the preparation of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline,
100mg of 3-amino-5, 6,7, 8-tetrahydroisoquinoline (preparation of 3-amino-5, 6,7, 8-tetrahydroisoquinoline as in example 2) was added to 5mL of pyridine hydrofluoric acid salt. 55.89mg of sodium nitrite was added at-78℃under controlled temperature. Then, the reaction was carried out at room temperature for 1 hour. After the completion of the reaction of the raw materials, 20mL of water was added to the reaction solution for dilution, and the ph=9 of the reaction solution was adjusted with a saturated aqueous sodium carbonate solution. Extracting with ethyl acetate, drying, filtering and concentrating an organic phase, and purifying a crude product by column chromatography to obtain a product of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline: 69mg, colorless oil. The yield thereof was found to be 68%.
The liquid phase diagram of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 11;
the mass spectrum of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline is shown in FIG. 12, and the specific values are as follows: LC_MS (ES+): M/z152.1[ M+H ].
The nuclear magnetic resonance hydrogen spectrum of 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline is shown in fig. 13, and specific values are as follows: 1 H NMR(400MHz,CDCl 3 ):δ1.79-1.81(m,4H),2.75(d,J=20.9Hz,4H),6.61(s,1H),7.89(s,1H).
the above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.

Claims (5)

1. A method for preparing 3-halogeno-5, 6,7, 8-tetrahydroisoquinoline, which is characterized by comprising the following steps:
(1) Hydrogenating the 3-amino-isoquinoline in the presence of a solvent and a catalyst to produce 3-amino-5, 6,7, 8-tetrahydroisoquinoline;
(2) Diazotizing 3-amino-5, 6,7, 8-tetrahydroisoquinoline with a diazonium reagent, and then carrying out halogenation reaction with a halogenating reagent to generate 3-halogeno-5, 6,7, 8-tetrahydroisoquinoline, wherein the halogenating reagent is a fluoro reagent, the fluoro reagent is selected from pyridine hydrofluoric acid salt, sodium fluoride and potassium fluoride, and the diazonium reagent is selected from sodium nitrite;
the diazonium reaction temperature is minus 100 ℃ to minus 70 ℃, and the fluoridation reaction temperature is 0-50 ℃.
2. The method for preparing 3-halo-5, 6,7, 8-tetrahydroisoquinoline according to claim 1, wherein in the step (2), the molar ratio of the fluoro reagent to 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1 to 5:1, a step of; and/or the molar ratio of the diazonium reagent to the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is 1-5: 1, the fluoro reaction time is 1-10 h.
3. The method for preparing 3-halo-5, 6,7, 8-tetrahydroisoquinoline according to claim 2, wherein the specific implementation of step (2) is as follows: mixing 3-amino-5, 6,7, 8-tetrahydroisoquinoline with a fluoro reagent, adding sodium nitrite at-100 ℃ to-70 ℃, then heating to 15 ℃ to 35 ℃ for reaction for 1-5 hours, adding water for dilution, neutralizing with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain 3-fluoro-5, 6,7, 8-tetrahydroisoquinoline.
4. The method for preparing 3-halo-5, 6,7, 8-tetrahydroisoquinoline according to any one of claims 1 to 3, characterized by comprising the steps of: in the step (1), the solvent is trifluoroacetic acid, the catalyst is selected from platinum dioxide and platinum, the mass of the catalyst accounts for 5-15% of the mass of the 3-amino-isoquinoline, hydrogen is used for hydrogenation reduction, and the hydrogenation reduction is carried out at 30-55 ℃.
5. The method for preparing 3-halogeno-5, 6,7, 8-tetrahydroisoquinoline according to claim 1, characterized in that: the preparation method further comprises the step of carrying out post-treatment on the reaction liquid obtained after the hydrogenation reduction in the step (1), wherein the post-treatment step comprises the following steps: filtering the reaction liquid, concentrating under reduced pressure, neutralizing with saturated sodium bicarbonate solution, extracting with a mixed solution of methanol and dichloromethane, drying an organic phase, concentrating under reduced pressure, and purifying by column chromatography to obtain 3-amino-5, 6,7, 8-tetrahydroisoquinoline; or, the step of post-processing includes: the reaction solution is filtered, decompressed and concentrated, neutralized by saturated sodium bicarbonate solution, extracted by ethyl acetate, dried by an organic phase, decompressed and concentrated to obtain a crude product, then the crude product is dissolved in a mixed solution of methanol and water, alkali is added, the mixture is stirred for reaction, then water is added for dilution, extraction is performed by ethyl acetate, the organic phase is dried, filtered, decompressed and concentrated, and the 3-amino-5, 6,7, 8-tetrahydroisoquinoline is obtained by column chromatography purification.
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