Synthesis process of 6-bromo-1, 2, 3, 4-tetrahydroisoquinoline
By pretreating N-(3-bromophenethyl)-2,2,2-trifluoroacetamide and reacting with L-camphorsulfonic acid, the problem of difficulty in removing isomers in the prior art was solved, and the efficient and environmentally friendly synthesis of 6-bromo-1,2,3,4-tetrahydroisoquinoline was achieved, and the yield and purity of the product were improved.
Patent Information
- Application Number
- CN202411757893.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-03
- Publication Date
- 2025-03-18
AI Technical Summary
In the existing 6-bromo-1,2,3,4-tetrahydroisoquinoline synthesis method, it is difficult to efficiently remove isomers in the product, resulting in high cost and low efficiency, which is not suitable for industrial production.
Using a new synthesis process, N-(3-bromophenethyl)-2,2,2-trifluoroacetamide was pretreated and the crude product was mixed with the isomer with L-camphorsulfonic acid, and then the isomer of the 8-position was effectively removed by extraction.
The yield and purity of 6-bromo-1,2,3,4-tetrahydroisoquinoline is improved, and the use of chemical solvents and the emission of organic waste liquids are reduced, which is conducive to environmental protection.
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of organic synthesis, and in particular to a synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline. Background Art
[0002] Tetrahydroisoquinoline compounds have multiple biological activities, and their synthesis methods and biological activities have been widely studied. Among them, tetrahydroisoquinoline compounds have a great effect on adrenergic receptors and calcium channels; tetrahydroisoquinoline is the core skeleton of many physiologically active natural products. Some artificially synthesized isoquinoline compounds also show good biological activity, and the modification and transformation of the tetrahydroisoquinoline skeleton has become a hot area in the development of new drugs. Among them, 6-bromo-1,2,3,4-tetrahydroisoquinoline, as an important tetrahydroisoquinoline derivative, is not only in great demand in cardiovascular medicine, but can also be used to prepare Rho-associated protein kinase inhibitors. Therefore, the synthesis research of this compound has important practical significance.
[0003] However, in the related synthesis method, 3-bromophenylacetonitrile is used as the raw material, and the product is obtained through reduction, condensation, ring closure, and detrifluoroacetylation. However, this method finally obtains a mixture of 6- and 8-isomers, which are usually separated by column separation. This method is costly and inefficient, and is not suitable for industrial scale-up production. Summary of the invention
[0004] In order to efficiently remove isomers in the product, the present application provides a synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline.
[0005] This application provides a technical solution that adopts the following: A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline comprises the following steps: S1. Add 50-57 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 90-150 mL of acetic acid, control the temperature at 10-17° C., drop 55-65 mL of concentrated sulfuric acid, and then heat to 45-52° C. to react. Control the reaction to be complete, pour the reaction solution into 150-250 mL of ice water, add 80-120 mL of dichloromethane to extract the liquid; then extract the aqueous phase with 40-60 mL of dichloromethane, combine the organic phases, wash with water, wash with brine, dry, filter, and spin dry to obtain a mixture intermediate product; S2, add the intermediate product of S1 to a mixed solution of 50-70mL ethanol and 80-100mL water, then add 10-15g potassium carbonate, and then heat reflux and stir to react until the raw materials react; pour the reaction solution into 70-100mL water, add 70-150mL dichloromethane, and extract by separation; then add 40-80mL dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with water, wash with brine, dry, filter, and spin-dry the solution to obtain a crude product A; S3, crude product A is added to 90-110g tert-amyl alcohol, heated to 40 ℃, under stirring, 40-45g of L-camphorsulfonic acid is added to the reaction solution, and the temperature is continued to rise to 55-65 ℃, stirred for reaction, then cooled to 5-10 ℃, filtered with suction, rinsed, and crude product B is obtained; crude product B is added to a mixture of 30-50mL tert-amyl alcohol and 3-7mL water, heated to 55-65 ℃ and stirred for 0.6-1.5h, then cooled to 5-10 ℃, filtered with suction, rinsed, and 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate is obtained; S4. Add 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate to 90-130 ml of water, adjust the pH to 9-11, then add 100-150 ml of dichloromethane to the reaction solution for separation and extraction; add 40-60 ml of dichloromethane to the aqueous phase for extraction; combine the organic phases, wash with water, wash with brine, dry, and spin-dry to obtain the product 6-bromo-1,2,3,4-tetrahydroisoquinoline.
[0006] By adopting the above technical scheme, the present application improves the yield of 6-bromo-1,2,3,4-tetrahydroisoquinoline by optimizing the selection and dosage of raw materials. On this basis, the 8-isomer can be effectively removed by reacting L-camphorsulfonic acid with the crude mixed isomers and then extracting them. Compared with the traditional column purification method, the use of chemical solvents is greatly saved, the discharge of a large amount of organic waste liquid is reduced, and it is beneficial to environmental protection. In addition, the 6-bromo-1,2,3,4-tetrahydroisoquinoline obtained by the purification method of the present application is high in yield and purity.
[0007] Preferably, the brine in S1, S2 and S3 is a saturated sodium chloride aqueous solution or a saturated potassium chloride aqueous solution.
[0008] By adopting the above technical solution and using saturated salt water for washing, the dissolution of the reaction product in water can be effectively reduced, which is beneficial to improving the final yield.
[0009] Preferably, the desiccant used in the drying operations in S1, S2 and S3 is one or both of anhydrous magnesium sulfate and anhydrous sodium sulfate.
[0010] By adopting the above technical solution, both types of desiccants can be used to achieve effective drying, and basically no new impurities that are difficult to remove are introduced.
[0011] Preferably, the pH in S3 is adjusted by sodium hydroxide solution or potassium hydroxide solution.
[0012] By adopting the above technical solution, the metal ions in the sodium hydroxide solution or the potassium hydroxide solution are easily soluble in water. The use of these two substances for adjustment can effectively reduce the introduced impurities and almost no side reactions will occur with the substances in the system.
[0013] Preferably, the pH in S3 is adjusted to 10.
[0014] Preferably, S1 further comprises pretreatment of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide, and the specific steps are as follows: Add 50-55 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 120-180 mL of dichloromethane at 0-10° C., then add 32-40 g of phthalic anhydride, and continue to add 12-18 g of pyridine and 31-42 g of triethylamine. After stirring to dissolve, add 0.5-2 g of 4-dimethylaminopyridine as a catalyst, stir and react at 0-10° C. for 10-20 hours, spin dry to obtain a pretreated product, and then add the pretreated product to acetic acid and continue the reaction.
[0015] By adopting the above technical scheme, N-(3-bromophenethyl)-2,2,2-trifluoroacetamide is pretreated to make the nitrogen atom of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide react with anhydride, so that during the ring-forming reaction, the generation of the 8-isomer is greatly reduced due to the reaction steric hindrance; when phthalic anhydride is used, it is easier to remove during the ring-forming reaction, and the ring-forming reaction rate is higher. When trifluoroacetic anhydride is used, due to the strong electron-withdrawing ability of the fluorine atom, the electron cloud density of the nitrogen atom is greatly reduced, so that its ability to react with the nucleophilic substitution on the benzene ring becomes weak, and its ring-forming reaction is difficult to occur, and during the ring-forming reaction, its fluorine-containing group has a strong electron-withdrawing ability and is not easy to remove. As a preferred embodiment: the product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane, petroleum ether and methanol is 10:3.
[0016] By adopting the above technical solution, the purity can be further improved by recrystallization.
[0017] Preferably, the product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixture of dichloromethane, petroleum ether and methanol, wherein the volume ratio of dichloromethane, petroleum ether and methanol is 10:2:3.
[0018] By adopting the above technical solution, when a mixed solution of dichloromethane, petroleum ether and methanol is used, the recrystallization effect is better.
[0019] In summary, the present application includes at least one of the following beneficial technical effects: 1. The present application improves the yield of 6-bromo-1,2,3,4-tetrahydroisoquinoline by optimizing the selection and dosage of raw materials. On this basis, the 8-isomer can be effectively removed by reacting L-camphorsulfonic acid with a crude mixed product of isomers and then extracting it. Compared with the traditional column purification method, the use of chemical solvents is greatly saved, the discharge of a large amount of organic waste liquid is reduced, and it is beneficial to environmental protection. In addition, the 6-bromo-1,2,3,4-tetrahydroisoquinoline obtained by the purification method of the present application has a high yield and purity.
[0020] 2. Pre-treating N-(3-bromophenethyl)-2,2,2-trifluoroacetamide allows the nitrogen atom of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to react with anhydride, thereby greatly reducing the production of the 8-isomer during the cyclization reaction due to reaction steric hindrance.
[0021] 3. The yield of 6-bromo-1,2,3,4-tetrahydroisoquinoline prepared by the synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline designed in this application is 68.2%, and the highest can reach 82.4%. At the same time, its purity is 98.4% and above, and the highest can reach 99.5%. It can be seen that the synthesis process of this application greatly improves the yield and purity of the target product, and effectively improves the existing process. DETAILED DESCRIPTION
[0022] The present application is further described in detail below in conjunction with the specific contents.
[0023] raw material The raw materials used in the examples of this application are all commercially available products, and the drugs used are all analytically pure. Example
[0024] Example 1 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, comprising the following preparation steps: S1. Add 53.6 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 100 mL of acetic acid, control the temperature at 15°C, dropwise add 60 mL of concentrated sulfuric acid, then heat to 50°C for reaction, control the temperature until the reaction is complete, pour the reaction solution into 200 mL of ice water, add 100 mL of dichloromethane for extraction and separation; then extract the aqueous phase with 50 mL of dichloromethane, combine the organic phases, wash with water, wash with saturated sodium bicarbonate, dry with magnesium sulfate, filter, and spin dry to obtain a mixture intermediate product; the mass fraction of concentrated sulfuric acid is 98%; S2, the intermediate product of S1 is added to a mixed solution of 60mL ethanol and 90mL water, 13g potassium carbonate is added under stirring, and then the reaction is heated under reflux and stirred until the raw materials react; the reaction solution is poured into 90mL water, 100mL dichloromethane is added, and the liquid is separated and extracted; then 60mL dichloromethane is added to the aqueous phase for extraction, the organic phases are combined, washed with water, washed with brine, dried with sodium sulfate, filtered, and the solution is spin-dried to obtain a crude product A; the brine is a saturated aqueous solution of sodium chloride; S3, crude product A was added to 100g of tert-amyl alcohol, heated to 40°C, and 42g of L-camphorsulfonic acid was added to the reaction solution under stirring, and the temperature was continued to rise to 60°C, and the reaction was stirred for 1 hour, then cooled to 5-10°C, filtered, and washed to obtain crude product B; The crude product B was added to a mixture of 40 mL of tert-amyl alcohol and 5 mL of water, heated to 60° C. and stirred for 1 h, then cooled to 5-10° C., filtered and rinsed to obtain 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate; the mother liquors were combined and dried to recover the 8-bromo-1,2,3,4-tetrahydroisoquinoline product; S3. Add 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate to 100 ml of water, add 10% sodium hydroxide solution by mass to the solution under stirring, adjust pH=10, and then add 120 ml of dichloromethane to the reaction solution for liquid separation and extraction; add 50 ml of dichloromethane to the aqueous phase for extraction; combine the organic phases, wash with water, wash with brine, dry with magnesium sulfate, and spin-dry to obtain the product 6-bromo-1,2,3,4-tetrahydroisoquinoline, and determine its molecular structure by NMR; the brine is a saturated aqueous solution of sodium chloride.
[0025] Example 2 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, which is different from Example 1 in that S1 further includes pretreatment of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide, and the specific steps are as follows: Add 53.6 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 150 mL of dichloromethane at 5°C, then add 36.4 g of phthalic anhydride, and continue to add 15.5 g of pyridine and 36.5 g of triethylamine. After stirring to dissolve, add 1 g of 4-dimethylaminopyridine as a catalyst, stir and react at 5°C for 13 hours, spin dry to obtain a pretreated product, and then add the pretreated product to acetic acid and continue the reaction.
[0026] Example 3 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, which is different from that of Example 2 in that the obtained product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixed solution of dichloromethane, petroleum ether and methanol, the volume ratio of dichloromethane, petroleum ether and methanol is 10:2:3, and the remaining steps are the same as those of Example 2.
[0027] Example 4 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, which is different from Example 2 in that the obtained product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixed solution of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is 10:3, and the remaining steps are the same as those in Example 2.
[0028] Comparative Example Comparative Example 1 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, which is different from Example 1 in that the crude product A obtained by S2 is purified by a column, the column is a silica gel column, the eluent is a mixture of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is 6:1, and the remaining steps are the same as Example 1.
[0029] Comparative Example 2 A synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline, which is different from that of Example 2 in that trifluoroacetic anhydride in the pretreatment of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide is replaced by an equimolar amount of trifluoroacetic anhydride, and the remaining steps are the same as those of Example 2.
[0030] Performance testing Detection method / test method 6-Bromo-1,2,3,4-tetrahydroisoquinoline was prepared according to the preparation methods of Examples 1-4 and Comparative Example 1, and the yield was calculated. The purity of the obtained products was tested by HPLC, and the test results are shown in Table 1.
[0031] Table 1 Test results of Examples 1-4 and Comparative Example 1 Yield (%) purity(%) Example 1 68.2 98.4 Example 2 82.4 98.6 Example 3 81.9 99.5 Example 4 80.1 99.0 Comparative Example 1 66.7 98.5 Comparative Example 2 36.3 98.2 It can be seen from Examples 1-4 and Comparative Examples 1-2, as well as the test results of Table 1, that the yield of 6-bromo-1,2,3,4-tetrahydroisoquinoline prepared by the synthesis process of 6-bromo-1,2,3,4-tetrahydroisoquinoline designed by the present application is 68.2%, and the highest can reach 82.4%. At the same time, the purity is 98.4% and above, and the highest can reach 99.5%. It can be seen that the synthesis process of the present application greatly improves the yield and purity of the target product, and effectively improves the existing process.
[0032] It can be seen from the test data of Example 1 and Comparative Example 1 that the 8-isomer can be effectively removed by reacting L-camphorsulfonic acid with the crude mixed isomer product and then extracting it; compared with the traditional column purification method, the use of chemical solvents is greatly saved, the discharge of a large amount of organic waste liquid is reduced, and it is beneficial to environmental protection. In addition, the 6-bromo-1,2,3,4-tetrahydroisoquinoline obtained by the purification method of the present application has a high yield and purity.
[0033] It can be seen from the test data of Example 1 and Example 2 that by pre-treating N-(3-bromophenethyl)-2,2,2-trifluoroacetamide, the nitrogen atom of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide reacts with anhydride, so that during the ring-forming reaction, the generation of the 8-position isomer is greatly reduced due to the reaction steric hindrance. On this basis, in conjunction with Comparative Example 2, when the anhydride adopts phthalic anhydride, it is easier to remove during the ring-forming reaction, and the ring-forming reaction rate is higher. When trifluoroacetic anhydride is used, the electron-withdrawing ability of the fluorine atom is too strong, so that the electron cloud density of the nitrogen atom is greatly reduced, so that its ability to react with the nucleophilic substitution on the benzene ring is weakened, and its ring-forming reaction is difficult to occur, and during the ring-forming reaction, its electron-withdrawing ability is strong and not easy to remove; under the overall situation, its yield is greatly reduced.
[0034] It can be seen from the test data of Examples 3-4 that the purity can be further improved by recrystallization, and the effect of recrystallization is better when a mixture of dichloromethane, petroleum ether and methanol is used.
[0035] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.
Claims
1. A synthesis process for 6-bromo-1,2,3,4-tetrahydroisoquinoline, characterized in that: It includes the following steps: S1. Add 50-57 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 90-150 mL of acetic acid, control the temperature at 10-17° C., drop 55-65 mL of concentrated sulfuric acid, and then heat to 45-52° C. to react. Control the reaction to be complete, pour the reaction solution into 150-250 mL of ice water, add 80-120 mL of dichloromethane to extract the liquid; then extract the aqueous phase with 40-60 mL of dichloromethane, combine the organic phases, wash with water, wash with brine, dry, filter, and spin dry to obtain a mixture intermediate product; S2, add the intermediate product of S1 to a mixed solution of 50-70mL ethanol and 80-100mL water, then add 10-15g potassium carbonate, and then heat reflux and stir to react until the raw materials react; pour the reaction solution into 70-100mL water, add 70-150mL dichloromethane, and extract by separation; then add 40-80mL dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with water, wash with brine, dry, filter, and spin-dry the solution to obtain a crude product A; S3, the crude product A is added to 90-110g of tert-amyl alcohol, heated to 40°C, and 40-45g of L-camphorsulfonic acid is added to the reaction solution under stirring, and the temperature is continued to rise to 55-65°C, stirred for reaction, and then cooled to 5-10°C, filtered, and rinsed to obtain a crude product B; The crude product B is added to a mixture of 30-50 mL of tert-amyl alcohol and 3-7 mL of water, heated to 55-65° C. and stirred for 0.6-1.5 h, then cooled to 5-10° C., filtered and washed to obtain 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate; S4. Add 6-bromo-1,2,3,4-tetrahydroisoquinoline camphorsulfonate to 90-130 ml of water, adjust the pH to 9-11, then add 100-150 ml of dichloromethane to the reaction solution for separation and extraction; add 40-60 ml of dichloromethane to the aqueous phase for extraction; combine the organic phases, wash with water, wash with brine, dry, and spin-dry to obtain the product 6-bromo-1,2,3,4-tetrahydroisoquinoline.
2. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The brine in S1, S2 and S3 is a saturated sodium chloride aqueous solution or a saturated potassium chloride aqueous solution.
3. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The desiccant used in the drying operations in S1, S2 and S3 is one or both of anhydrous magnesium sulfate and anhydrous sodium sulfate.
4. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The pH in S3 is adjusted by sodium hydroxide solution or potassium hydroxide solution.
5. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The pH in S3 was adjusted to 10.
6. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The S1 further comprises pretreatment of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide, and the specific steps are as follows: Add 50-55 g of N-(3-bromophenethyl)-2,2,2-trifluoroacetamide to 120-180 mL of dichloromethane at 0-10° C., then add 32-40 g of phthalic anhydride, and continue to add 12-18 g of pyridine and 31-42 g of triethylamine. After stirring to dissolve, add 0.5-2 g of 4-dimethylaminopyridine as a catalyst, stir and react at 0-10° C. for 10-20 hours, spin dry to obtain a pretreated product, and then add the pretreated product to acetic acid and continue the reaction.
7. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 6, characterized in that: The product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixture of dichloromethane and methanol, wherein the volume ratio of dichloromethane, petroleum ether and methanol is 10:
3.
8. A process for synthesizing 6-bromo-1,2,3,4-tetrahydroisoquinoline according to claim 7, characterized in that: The product 6-bromo-1,2,3,4-tetrahydroisoquinoline is recrystallized from a mixture of dichloromethane, petroleum ether and methanol, wherein the volume ratio of dichloromethane, petroleum ether and methanol is 10:2:3.