Preparation method of 5, 6-dihydroxyindole

Abstract

The invention discloses a preparation method of 5, 6-dihydroxyindole, which comprises the following steps: mixing levodopa, hydrochloric acid and water to obtain a first solution; heating the first solution to 80-95 DEG C and reacting for 1-2 hours to obtain a second solution; the second solution is cooled to 20-40 DEG C, inert metal powder is added into the second solution, hydrogen peroxide is dropwise added, heat preservation is conducted till the reaction is completed, and a third solution is obtained; the third solution is cooled, crystallized and subjected to suction filtration, and a 5, 6-dihydroxyindole crude product is obtained; wherein the cooling crystallization time is 2-3 hours, and the cooling cutoff temperature is 0-5 DEG C; according to the method, levodopa is used as a raw material, the solubility and reaction activity of the material in water are greatly improved through acidification and racemization, the reaction time is shortened, the process efficiency is high, the product yield can be improved, and the technological process is simple.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 5,6-dihydroxyindole. Background Art

[0002] 5,6-Dihydroxyindole is a precursor of melanin in the human body. When it comes into contact with an oxidant, it is rapidly oxidized to melanin. Therefore, when used as a hair dye, it has the advantages of natural non-toxicity, high hair dyeing fastness, and not easy to fade, becoming a substitute for traditional phenylenediamine hair dyes and having a broad market prospect.

[0003] Currently reported synthesis methods of 5,6-dihydroxyindole include benzaldehyde method, phenylacetonitrile method and phenethylamine method. These synthesis methods have long reaction routes, usually requiring 6-8 steps of reaction to prepare 5,6-dihydroxyindole, and need to protect and deprotect the hydroxyl functional group. Therefore, the reaction yields (30-60%) are generally low. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing 5,6-dihydroxyindole to improve the reaction yield.

[0005] The present invention adopts the following technical scheme: A method for preparing 5,6-dihydroxyindole, comprising the following steps: Mix levodopa, hydrochloric acid and water to obtain a first solution; wherein, the molar ratio of levodopa to hydrochloric acid is 1:(1-2), and the mass ratio of levodopa to water is 197:(1000-2955); Heat the first solution to 80-95°C and react for 1-2 h to obtain a second solution; Cool the second solution to 20-40°C, add an inert metal powder to the second solution and dropwise add hydrogen peroxide, and keep warm until the reaction is complete to obtain a third solution; wherein, the mass ratio of the inert metal powder to levodopa is (4-10):197, the mass ratio of hydrogen peroxide to levodopa is (1.1-3):1, and the dropping time is 20-50 min; Cool the third solution to crystallize and filter by suction to obtain the crude product of 5,6-dihydroxyindole; wherein, the cooling crystallization time is 2-3 h, and the cut-off temperature for cooling is 0-5°C; Wherein, all the above steps are carried out under a protective gas atmosphere.

[0006] Further, after obtaining the crude product of 5,6-dihydroxyindole, it further includes: Dissolve the crude product of 5,6-dihydroxyindole in water for recrystallization to obtain the finished product of 5,6-dihydroxyindole.

[0007] Further, when water is used as the solvent for recrystallization, the mass ratio of the crude 5,6-dihydroxyindole to water is 1:(3 - 8), the heating temperature is 60 - 70°C, the cooling temperature is 0 - 10°C, and the cooling time is 2 - 3 h.

[0008] Further, the method for judging the completion of the reaction is that the solution changes from dark red to light yellow.

[0009] Further, the heat preservation time for heat preservation until the reaction is complete is 2 - 4 h.

[0010] Further, after the reaction of levodopa and hydrochloric acid, racemic dopa acid is obtained.

[0011] Further, the mass ratio of the inert metal powder to levodopa is (4 - 6):197.

[0012] Further, the mass fraction of hydrogen peroxide is 20 - 30%.

[0013] The beneficial effects of the present invention are as follows: The present invention uses levodopa as the raw material, and through acidification and racemization, the solubility and reaction activity of the material in water are greatly improved, the reaction time is shortened, the process efficiency is high, the product yield can be increased, and the process flow is simple. Specific Embodiments

[0014] The present invention will be described in detail below in conjunction with specific embodiments.

[0015] In the current preparation method of 5,6-dihydroxyindole, the reactant potassium ferricyanide is extremely likely to release hydrogen cyanide gas under acidic conditions, with extremely high danger. Moreover, a large number of metal ions are involved in the reaction system, making the waste liquid treatment difficult, and the product yield is also relatively low. In addition, there are reports on the preparation of 5,6-dihydroxyindole by biological fermentation methods, but such methods have great difficulties in industrialization and still face great challenges for large-scale production.

[0016] The present invention discloses a preparation method of 5,6-dihydroxyindole, which includes the following steps: mixing levodopa, hydrochloric acid and water to obtain a first solution; wherein, the molar ratio of levodopa to hydrochloric acid is 1:(1 - 2), and the mass ratio of levodopa to water is 197:(1000 - 2955). Specifically, after the reaction of levodopa and hydrochloric acid, racemic dopa acid hydrochloride is obtained, and this racemization is the key to the subsequent cyclization reaction of hydrogen peroxide.

[0017] Heat the first solution to 80 - 95 °C and react for 1 - 2 h to obtain the second solution; by raising the temperature, the dissolved oxygen in the solution can be further removed. Cool the second solution to 20 - 40 °C, add inert metal powder to the second solution and dropwise add hydrogen peroxide, and keep warm until the reaction is complete to obtain the third solution; wherein, the mass ratio of the inert metal powder to levodopa is (4 - 10):197, the mass ratio of hydrogen peroxide to levodopa is (1.1 - 3):1, and the dropping time is 20 - 50 min; cool the third solution for crystallization and perform suction filtration to obtain the crude product of 5,6 - dihydroxyindole; wherein, the crystallization time for cooling is 2 - 3 h, and the cut - off temperature for cooling is 0 - 5 °C; wherein, all the above steps are carried out under the atmosphere of a protective gas (such as nitrogen). Using hydrogen peroxide as the cyclization reagent, the reaction conditions are mild, there are no three - waste by - products, and the process conditions are simple.

[0018] In the present invention, using levodopa as the raw material, through acidification and racemization, the solubility and reaction activity of the material in water are greatly improved, the reaction time is shortened, the process efficiency is high, the product yield can be increased, and the process flow is simple.

[0019] In the present invention, after obtaining the crude product of 5,6 - dihydroxyindole, it further includes: dissolving the crude product of 5,6 - dihydroxyindole in water for recrystallization to obtain the finished product of 5,6 - dihydroxyindole. The purity of the product can be improved through recrystallization.

[0020] When water is used as the solvent for recrystallization, the mass ratio of the crude product of 5,6 - dihydroxyindole to water is 1:(3 - 8), the temperature for heating up is 60 - 70 °C, the temperature for cooling down is 0 - 10 °C, and the cooling time is 2 - 3 h. By controlling the mass ratio of the crude product of 5,6 - dihydroxyindole to water and the cooling time, the amount of crystal precipitation can be increased and the product yield can be improved.

[0021] In one embodiment, the method for judging the completion of the reaction is that the solution changes from dark red to light yellow.

[0022] In another embodiment, the holding time for keeping warm until the reaction is complete is 2 - 4 h. This holding time can ensure the completion of the reaction.

[0023] More preferably, the mass ratio of the inert metal powder to levodopa is (4 - 6):197.

[0024] In the present invention, as the cyclization reagent, the mass fraction of hydrogen peroxide is 20 - 30%. As the antioxidant, the inert metal powder can be selected as zinc powder, copper powder, aluminum powder, etc.

[0025] Example 1: 197 g (1 mol) of L - dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 1000 g of water were added into a reactor. Nitrogen was continuously introduced, heating and stirring were started, and the reaction system was heated to 80 °C and reacted for 1 hour. Keeping the nitrogen atmosphere, the reaction system was cooled to 20 °C, then 4 g of zinc powder was added, and hydrogen peroxide with a mass fraction of 20% (total mass of hydrogen peroxide was 216.7 g) was added dropwise within 20 minutes, and the reaction was continued at 20 °C for 2 h. Keeping the nitrogen atmosphere, the reaction solution was cooled to 0 °C for crystallization (3 h), and filtered under nitrogen atmosphere to obtain 180.6 g of crude 5,6 - dihydroxyindole (equivalent to a product yield of 89%). The melting point of the crude 5,6 - dihydroxyindole was detected by a melting point apparatus to be 140.8 °C, which was consistent with the melting point of the 5,6 - dihydroxyindole standard product of 140 °C, and the purity was detected by HPLC to be 90.3%.

[0026] Example 2: 197 g (1 mol) of L - dopa, 200 g of 36 wt% (2 mol) hydrochloric acid, and 1000 g of water were added into a reactor. Nitrogen was continuously introduced, heating and stirring were started, and the reaction system was heated to 80 °C and reacted for 1.6 hours. Keeping the nitrogen atmosphere, the reaction system was cooled to 20 °C, then 6 g of copper powder was added, and hydrogen peroxide with a mass fraction of 20% (total mass of hydrogen peroxide was 295.5 g) was added dropwise within 20 minutes, and the reaction was continued at 20 °C for 2 h. Keeping the nitrogen atmosphere, the reaction solution was cooled to 0 °C for crystallization (3 h), and filtered under nitrogen atmosphere to obtain 180.4 g of crude 5,6 - dihydroxyindole. The melting point of the crude 5,6 - dihydroxyindole was detected by a melting point apparatus to be 140.9 °C, and the purity was detected by HPLC to be 89.5%.

[0027] Example 3: 197 g (1 mol) of L - dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 1500 g of water were added into a reactor. Nitrogen was continuously introduced, heating and stirring were started, and the reaction system was heated to 85 °C and reacted for 1 hour. Keeping the nitrogen atmosphere, the reaction system was cooled to 35 °C, then 4 g of zinc powder was added, and hydrogen peroxide with a mass fraction of 20% (total mass of hydrogen peroxide was 591 g) was added dropwise within 20 minutes, and the reaction was continued at 20 °C for 2 h. Keeping the nitrogen atmosphere, the reaction solution was cooled to 0 °C for crystallization (2 h), and filtered under nitrogen atmosphere to obtain 180.2 g of crude 5,6 - dihydroxyindole. The melting point of the crude 5,6 - dihydroxyindole was detected by a melting point apparatus to be 140.9 °C, and the purity was detected by HPLC to be 90.6%.

[0028] Example 4 Add 197 g (1 mol) of L-dopa, 150 g of 36 wt% (1 mol) hydrochloric acid, and 1500 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 90 °C, and continuously react for 1.5 hours. Maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 7 g of aluminum powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 394 g) within 30 minutes, and continue to keep the temperature at 30 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 2 °C for crystallization (cooling time is 3 h, the same meaning in other examples), and filter under nitrogen atmosphere to obtain 180.7 g of crude 5,6-dihydroxyindole. Under nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.5 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point instrument is 140.2 °C, which is consistent with the melting point of the standard product of 140 °C.

[0029] Example 5: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 1000 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 88 °C, and continuously react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 6 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 236.4 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization, and filter under nitrogen atmosphere to obtain 180.9 g of crude 5,6-dihydroxyindole. Under nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 60 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.3 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point instrument is 140.2 °C, which is consistent with the melting point of the standard product of 140 °C.

[0030] Example 6: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 3000 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 80 °C, and continuously react for 2 hours. Maintain the nitrogen atmosphere, cool the reaction system to 30 °C, then add 8 g of zinc powder, and dropwise add hydrogen peroxide with a mass fraction of 20% (total mass of hydrogen peroxide is 400 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2.5 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 1440 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 3 h, and filter to obtain 160.5 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point apparatus is 140.3 °C.

[0031] Example 7: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2500 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 80 °C, and continuously react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of zinc powder, and dropwise add hydrogen peroxide with a mass fraction of 30% (total mass of hydrogen peroxide is 400 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.7 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 1200 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 3 h, and filter to obtain 160.5 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point apparatus is 140.6 °C.

[0032] Example 8: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 1000 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 80 °C, and react continuously for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 400 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 4 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 700 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.6 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%, and the melting point of the finished product detected by a melting point apparatus is 140.5 °C.

[0033] Example 9: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2000 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 80 °C, and react continuously for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of copper powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 550 g) within 50 minutes, and continue to keep the temperature at 35 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 5 °C for crystallization (2 h), and filter under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 800 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.2 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point apparatus is 140.6 °C.

[0034] Example 10: Add 197 g (1 mol) of levodopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 80 °C, and continuously react for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to hold the reaction at 20 °C for 2 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.5 g of the finished product of 5,6-dihydroxyindole. The purity is detected by HPLC to be 99%, and the melting point of the finished product is detected by a melting point apparatus to be 140.4 °C.

[0035] Example 11: Add 197 g (1 mol) of levodopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 3000 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 80 °C, and continuously react for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to hold the reaction at 20 °C for 2 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.1 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.6 g of the finished product of 5,6-dihydroxyindole. The purity is detected by HPLC to be 99%. The melting point of the finished product is detected by a melting point apparatus to be 140.8 °C.

[0036] Example 12: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react continuously for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 20 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.8 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.7 °C.

[0037] Example 13: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react continuously for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 30 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.6 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.4 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.5 °C.

[0038] Example 14: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 95 °C, and continuously react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 4 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.2 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.3 °C.

[0039] Example 15: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 95 °C, and continuously react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 3.96 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (2 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.7 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.5 °C.

[0040] Example 16: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 20 minutes, and continue to hold the reaction at 20 °C for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.5 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point apparatus is 140.1 °C.

[0041] Example 17: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 30 minutes, and continue to hold the reaction at 20 °C for 2 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.5 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole into 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 0 °C for crystallization in 2 h, and filter to obtain 160.7 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point apparatus is 140.4 °C.

[0042] Example 18: 197 g (1 mol) of levodopa, 100 g of 36 wt% (1 mol) hydrochloric acid and 2400 g of water were added into a reactor. Nitrogen was continuously introduced, heating and stirring were started, and the reaction system was heated to 95 °C and reacted for 1 hour. Keeping the nitrogen atmosphere, the reaction system was cooled to 40 °C, then 19.7 g of zinc powder was added, and 20% hydrogen peroxide (total mass of hydrogen peroxide was 350 g) was added dropwise within 40 minutes, and the reaction was continued to be kept warm at 20 °C for 2 h. Keeping the nitrogen atmosphere, the reaction solution was cooled to 0 °C for crystallization (3 h), and filtered under the nitrogen atmosphere to obtain 180.4 g of 5,6-dihydroxyindole crude product. Under the nitrogen atmosphere, 180 g of the 5,6-dihydroxyindole crude product was added into 540 g of water, heated to 70 °C for dissolution, stirred for 10 minutes, cooled to 0 °C for crystallization in 2 h, and filtered to obtain 160.3 g of 5,6-dihydroxyindole finished product, and the purity detected by HPLC was 99%. The melting point of the finished product was detected by a melting point instrument to be 140.4 °C.

[0043] Example 19: 197 g (1 mol) of levodopa, 100 g of 36 wt% (1 mol) hydrochloric acid and 2400 g of water were added into a reactor. Nitrogen was continuously introduced, heating and stirring were started, and the reaction system was heated to 95 °C and reacted for 1 hour. Keeping the nitrogen atmosphere, the reaction system was cooled to 40 °C, then 19.7 g of zinc powder was added, and 20% hydrogen peroxide (total mass of hydrogen peroxide was 350 g) was added dropwise within 50 minutes, and the reaction was continued to be kept warm at 20 °C for 2 h. Keeping the nitrogen atmosphere, the reaction solution was cooled to 0 °C for crystallization (3 h), and filtered under the nitrogen atmosphere to obtain 180.2 g of 5,6-dihydroxyindole crude product. Under the nitrogen atmosphere, 180 g of the 5,6-dihydroxyindole crude product was added into 540 g of water, heated to 70 °C for dissolution, stirred for 10 minutes, cooled to 0 °C for crystallization in 2 h, and filtered to obtain 160.2 g of 5,6-dihydroxyindole finished product, and the purity detected by HPLC was 99%. The melting point of the finished product was detected by a melting point instrument to be 140.1 °C.

[0044] Example 20: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and continuously react for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue to keep the temperature at 20 °C for reaction for 2 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.3 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 5 °C for crystallization in 2 h, and filter to obtain 160.2 g of 5,6-dihydroxyindole finished product, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.3 °C.

[0045] Example 21: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and continuously react for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue to keep the temperature at 20 °C for reaction for 3 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.4 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 5 °C for crystallization in 2 h, and filter to obtain 160.2 g of 5,6-dihydroxyindole finished product, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.8 °C.

[0046] Example 22: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react continuously for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue to hold the reaction at 30 °C for 3 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and filter under the nitrogen atmosphere to obtain 180.6 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 5 °C for crystallization in 2 h, and filter to obtain 160.2 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.2 °C.

[0047] Example 23: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, heat the reaction system to 95 °C, and react continuously for 1 hour; maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue to hold the reaction at 40 °C for 3 h; maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (2 h), and filter under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole; under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat to 70 °C for dissolution, stir for 10 minutes, cool to 5 °C for crystallization in 2 h, and filter to obtain 160.7 g of the finished product of 5,6-dihydroxyindole, and the purity detected by HPLC is 99%. The melting point of the finished product is detected by a melting point instrument to be 140.2 °C.

[0048] Example 24: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 95 °C, and continue the reaction for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue the insulation reaction at 40 °C for 3 h. Maintain the nitrogen atmosphere, cool the reaction solution to 0 °C for crystallization (3 h), and perform suction filtration under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat it to 60 °C for dissolution, stir for 10 minutes, cool it to 5 °C for crystallization in 2 h, and perform suction filtration to obtain 160.7 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point instrument is 140.5 °C.

[0049] Example 25: Add 197 g (1 mol) of L-dopa, 100 g of 36 wt% (1 mol) hydrochloric acid, and 2400 g of water into the reactor. Continuously introduce nitrogen, turn on heating and stirring, raise the temperature of the reaction system to 95 °C, and continue the reaction for 1 hour. Maintain the nitrogen atmosphere, cool the reaction system to 40 °C, then add 19.7 g of zinc powder, and dropwise add 20% hydrogen peroxide (total mass of hydrogen peroxide is 350 g) within 50 minutes, and continue the insulation reaction at 40 °C for 3 h. Maintain the nitrogen atmosphere, cool the reaction solution to 10 °C for crystallization (3 h), and perform suction filtration under the nitrogen atmosphere to obtain 180.2 g of crude 5,6-dihydroxyindole. Under the nitrogen atmosphere, add 180 g of the crude 5,6-dihydroxyindole to 540 g of water, heat it to 60 °C for dissolution, stir for 10 minutes, cool it to 5 °C for crystallization in 2 h, and perform suction filtration to obtain 160.7 g of the finished product of 5,6-dihydroxyindole. The purity detected by HPLC is 99%. The melting point of the finished product detected by a melting point instrument is 140.2 °C.

[0050] In summary, when synthesizing 5,6-dihydroxyindole by the method of the present invention, the yield is as high as 80% (calculated based on L-dopa), the product color is light, the purity is as high as 99%, the reaction time is short, the by-products are few, the emission of three wastes is reduced, and it has good industrial application value.

Claims

1. A method for preparing 5,6-dihydroxyindole, characterized in that: The following steps are involved: Mixing levodopa, hydrochloric acid and water to obtain a first solution; wherein the molar ratio of levodopa to hydrochloric acid is 1:(1-2), and the mass ratio of levodopa to water is 197:(1000-3000); The first solution is heated to 80-95° C. and reacted for 1-2 hours to obtain a second solution; The second solution is cooled to 20-40° C., an inert metal powder is added to the second solution and hydrogen peroxide is added dropwise, and the mixture is kept warm until the reaction is complete to obtain a third solution; wherein the mass ratio of the inert metal powder to levodopa is (4-10):197, the mass ratio of the hydrogen peroxide to levodopa is (1.1-3):1, and the dropping time is 20-50 min; The third solution is cooled and crystallized and filtered to obtain a crude 5,6-dihydroxyindole; wherein the cooling and crystallization time is 2-3 hours and the cooling cut-off temperature is 0-5°C; Wherein, all the above steps are carried out under a protective gas atmosphere.

2. The method for preparing 5,6-dihydroxyindole according to claim 1, characterized in that: After obtaining the crude 5,6-dihydroxyindole, the following steps are also included: The crude 5,6-dihydroxyindole product is dissolved in water for recrystallization to obtain a finished 5,6-dihydroxyindole product.

3. The method for preparing 5,6-dihydroxyindole according to claim 2, characterized in that: When water is used as the solvent for the recrystallization, the mass ratio of crude 5,6-dihydroxyindole to water is 1:(3-8), the heating temperature is 60-70°C, the cooling temperature is 0-10°C, and the cooling time is 2-3h.

4. A method for preparing 5,6-dihydroxyindole as claimed in claim 2 or 3, characterized in that: The reaction is complete when the solution changes from dark red to light yellow.

5. A method for preparing 5,6-dihydroxyindole as claimed in claim 2 or 3, characterized in that: The insulation time until the reaction is complete is 2-4 hours.

6. The method for preparing 5,6-dihydroxyindole according to claim 5, characterized in that: After the levodopa and hydrochloric acid are mixed and reacted, racemic dopa hydrochloride is obtained.

7. A method for preparing 5,6-dihydroxyindole as claimed in claim 2 or 3, characterized in that: The mass ratio of the inert metal powder to levodopa is (4-6):

197.

8. A method for preparing 5,6-dihydroxyindole as claimed in claim 2 or 3, characterized in that: The mass fraction of the hydrogen peroxide is 20-30%.