A method for synthesizing 4-hydroxyphenethyl((3,5,6-trimethylpyrazin-2-yl)methyl) carbonate

Abstract

The application relates to the technical field of medicine synthesis, and provides a synthesis method of 4-hydroxyphenethyl((3,5,6-trimethylpyrazin-2-yl)methyl) carbonate. The synthesis method provided by the application adopts Boc as a hydroxyl protecting group, and does not need to use highly toxic hydrofluoric acid when a protecting group is removed, so that the synthesis process is safer, and the product yield is high. Furthermore, in the synthesis method provided by the application, product separation of each step is simple, and silica gel column chromatography purification is not needed, so that the cost is effectively reduced, and industrial production is easy. The results of examples show that the total yield of four-step reaction of 4-hydroxyphenethyl((3,5,6-trimethylpyrazin-2-yl)methyl) carbonate synthesized by the method is 53.3%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate. Background Technology

[0002] 4-Hydroxyphenethyl ((3,5,6-trimethylpyrazine-2-yl)methyl)carbonate has preventive and therapeutic effects on aging-related or mitochondrial-related diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedrich's cerebellar ataxia, Duchenne muscular dystrophy, diabetes, and diabetic nephropathy. It also has advantages such as multi-target effects, low toxicity, and good synergistic effects. The molecular formula of 4-hydroxyphenethyl ((3,5,6-trimethylpyrazine-2-yl)methyl)carbonate is C2 17 H 20 N₂O₄, with a molecular weight of 316.36, has the following structural formula:

[0003]

[0004] In the existing technology for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate, tetramethylpyrazine and p-hydroxyphenylethanol are usually used as starting materials. The target product is obtained through protection, esterification, and deprotection. In this process, tert-butyldimethylsilyl (TBS) is used as the hydroxyl protecting group. Finally, the highly corrosive and toxic hydrofluoric acid is required for deprotection. Moreover, the overall product yield is low (only about 16%), which is not suitable for industrial production. Summary of the Invention

[0005] In view of this, the present invention provides a method for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate. The synthetic method provided by the present invention uses Boc as the hydroxyl protecting group, eliminating the need for deprotection with highly toxic hydrofluoric acid, and yields a high product yield.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] A method for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate, comprising the following steps:

[0008] (1) A substitution reaction was carried out by mixing p-hydroxyphenylethanol, di-tert-butyl dicarbonate and a basic reagent to obtain tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate;

[0009] (2) The tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxyl tetrazine, basic reagent and triphosgene are mixed and subjected to condensation reaction to obtain tert-butyl benzoate of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate;

[0010] (3) The tert-butyl benzoate of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate was deprotected in an organic solvent solution of hydrogen chloride to obtain 4-hydroxyphenylethyl((3,5,6-trimethylpyrazine-2-yl)methyl)carbonate.

[0011] Preferably, in step (1), the molar ratio of p-hydroxyphenylethanol, ditert-butyl dicarbonate and alkaline reagent is 1:(1.2-2):2;

[0012] The alkaline reagent in step (1) includes one or more of triethylamine, N,N-diisopropylethylamine and sodium hydroxide.

[0013] Preferably, after the substitution reaction, the reaction solution is further subjected to post-treatment, which includes the following steps: concentrating the reaction solution to obtain a residue; mixing the residue with an organic solvent and then washing, drying and concentrating it sequentially to obtain tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate.

[0014] Preferably, the preparation method of the hydroxytetracycline includes the following steps:

[0015] The tebufenozide and an oxidant were mixed and subjected to an oxidation reaction to obtain tebufenozide nitrogen oxides;

[0016] The tebufenozide nitrogen oxide and acid anhydride were mixed and heated for rearrangement. The resulting product was then hydrolyzed under alkaline conditions to obtain hydroxytebufenozide.

[0017] Preferably, after the hydrolysis reaction is completed, the process further includes extracting, drying and concentrating the obtained reaction solution in sequence to obtain a crude product, and recrystallizing the crude product to obtain hydroxytetracycline.

[0018] Preferably, in step (2), the molar ratio of tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxyl tetrazine, and triphosgene is 1:1:1;

[0019] The alkaline reagent in step (2) includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and N,N-diisopropylethylamine.

[0020] Preferably, step (2) specifically includes: mixing tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, triphosgene, alkaline reagent and organic solvent to carry out a first esterification reaction to obtain a reaction solution; concentrating the obtained reaction solution and mixing it with hydroxyl tetrazine, organic solvent and alkali to carry out a second esterification reaction to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate.

[0021] Preferably, after the second esterification reaction is completed, the reaction solution is further subjected to post-treatment, which includes the following steps: washing, drying and concentrating the reaction solution in sequence to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate.

[0022] Preferably, the organic solvent solution of hydrogen chloride includes one or more of the following: methanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, and dioxane solution of hydrogen chloride; the deprotection reaction is carried out at room temperature for more than 3 hours.

[0023] Preferably, after the deprotection reaction is completed, the reaction solution is further subjected to post-treatment; the post-treatment includes the following steps: mixing the obtained reaction solution with an organic solvent, then adding a saturated sodium bicarbonate solution and stirring and separating the solution sequentially, and washing, drying and concentrating the obtained organic layer sequentially to obtain 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate.

[0024] This invention provides a method for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate. The method uses Boc as the hydroxyl protecting group, eliminating the need for highly toxic hydrofluoric acid during deprotection, making the synthesis safer and achieving a high product yield. Furthermore, the method simplifies product separation at each step, eliminating the need for silica gel column chromatography purification during post-processing, thus effectively reducing costs and facilitating industrial production. Example results show that, using the method of this invention, the yield of hydroxytetramethylbenzylbenzyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate is 77.6%; the yield of p-hydroxyphenylethanol protected with Boc is 98.7%; the yield of Boc-protected p-hydroxyphenylethanol reacting with hydroxytetramethylbenzyl ... Detailed Implementation

[0025] This invention provides a method for synthesizing 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate, comprising the following steps:

[0026] (1) A substitution reaction was carried out by mixing p-hydroxyphenylethanol, di-tert-butyl dicarbonate, basic reagent and solvent to obtain tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate;

[0027] (2) Tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxyl tetrazine, basic reagent and triphosgene were mixed and subjected to condensation reaction to obtain tert-butyl benzoate (4-2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate;

[0028] (3) The tert-butyl benzoate of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate was deprotected in an organic solvent solution of hydrogen chloride to obtain 4-hydroxyphenylethyl((3,5,6-trimethylpyrazine-2-yl)methyl)carbonate.

[0029] This invention involves a substitution reaction of p-hydroxyphenylethanol, di-tert-butyl dicarbonate, a basic reagent, and a solvent to obtain tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate. In this invention, the molar ratio of p-hydroxyphenylethanol, di-tert-butyl dicarbonate, and the basic reagent is preferably 1:(1.2-2):2; the basic reagent preferably includes one or more of triethylamine, N,N-diisopropylethylamine, and sodium hydroxide, more preferably triethylamine; the solvent preferably includes one or more of dichloromethane, tetrahydrofuran, acetone, dioxane, and water, more preferably tetrahydrofuran; this invention does not have special requirements for the amount of solvent used, as long as it allows the substitution reaction to proceed smoothly.

[0030] In this invention, the temperature of the substitution reaction is preferably room temperature, and the time is preferably 4 hours or more, more preferably 4 to 6 hours.

[0031] In a specific embodiment of the present invention, hydroxyphenylethanol is preferably dissolved in a solvent, and then di-tert-butyl dicarbonate and an alkaline reagent are added, and a substitution reaction is carried out under stirring conditions.

[0032] In this invention, the reaction formula of the substitution reaction is shown in Formula I, in which compound 2-0 is p-hydroxyphenylethanol and compound 2-A is tert-butyl(4-(2-hydroxyethyl)phenyl) carbonate.

[0033]

[0034] After the substitution reaction is completed, the present invention preferably concentrates the resulting reaction solution to obtain a residue; the residue is then mixed with an organic solvent and sequentially washed, dried, and concentrated to obtain tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate. In the present invention, the organic solvent is preferably dichloromethane; the washing is preferably performed sequentially with water and saturated brine, after which an organic layer is obtained; the drying agent is preferably anhydrous sodium sulfate, and after drying, the desiccant is preferably removed by filtration.

[0035] After obtaining tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, the present invention involves mixing the tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxytetracycline, a basic reagent, and triphosgene for a condensation reaction to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate. In the present invention, the preferred method for preparing the hydroxytetracycline includes the following steps:

[0036] The tebufenozide and an oxidant were mixed and subjected to an oxidation reaction to obtain tebufenozide nitrogen oxides;

[0037] The tebufenozide nitrogen oxide and acid anhydride were mixed and heated for rearrangement. The resulting product was then hydrolyzed under alkaline conditions to obtain hydroxytebufenozide.

[0038] In this invention, the reaction formula for preparing hydroxytetracycline from tetracycline is shown in Formula II, where compound 1-0 is tetracycline and compound 1-1 is hydroxytetracycline:

[0039]

[0040] This invention involves mixing tebufenozide and an oxidant to undergo an oxidation reaction, yielding tebufenozide nitrogen oxides. In this invention, the oxidant is preferably one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, peracetic acid, urea peroxide, and sodium perborate, more preferably hydrogen peroxide or m-chloroperoxybenzoic acid; the hydrogen peroxide is preferably used in the form of hydrogen peroxide solution, and the mass fraction of the hydrogen peroxide solution is preferably 30%. In this invention, the solvent used for the oxidation reaction is preferably glacial acetic acid; the molar ratio of tebufenozide to the oxidant is preferably 1:1 to 1:3, more preferably 1:2; the temperature of the oxidation reaction is preferably 50 to 100°C, more preferably 70 to 80°C; the time of the oxidation reaction is preferably 4 hours or more; in a specific embodiment of this invention, TLC monitoring is preferably used until the raw material disappears.

[0041] After the oxidation reaction is complete, the present invention preferably places the resulting reaction solution in an ice bath, then adjusts the pH value of the reaction solution to 9-10.5, preferably to 10, and then extracts with dichloromethane. The resulting organic layer is then dried and concentrated sequentially to obtain crude tetracycline nitrogen oxides. This crude product does not require further purification and can be directly used for the next reaction. In the present invention, the extraction is preferably performed twice, and the drying agent is preferably anhydrous sodium sulfate. After drying, the drying agent is preferably removed by filtration.

[0042] To obtain tebufenozide nitrogen oxides, the present invention involves mixing the tebufenozide nitrogen oxides with an acid anhydride and subjecting them to heating rearrangement. The resulting product is then hydrolyzed under alkaline conditions to obtain hydroxytebufenozide. In the present invention, the acid anhydride is preferably one or more of acetic anhydride, trifluoroacetic anhydride, propionic anhydride, and n-butyric anhydride, more preferably acetic anhydride; the molar ratio of the tebufenozide nitrogen oxides to the acid anhydride is preferably 1:1.5 to 1:2; the heating rearrangement is preferably carried out under reflux conditions, and when the acid anhydride is acetic anhydride, the reflux temperature is preferably 120 to 130°C, more preferably 125°C; the heating rearrangement time is preferably 10 to 12 hours; in a specific embodiment of the present invention, TLC monitoring is preferably used until the raw material disappears.

[0043] Taking acetic anhydride as an example, the structure of the product obtained by the heating rearrangement is as follows:

[0044]

[0045] After heating and rearrangement, no further treatment is required; the resulting oxidation reaction solution is directly subjected to a hydrolysis reaction. Preferably, the resulting oxidation reaction solution is cooled to room temperature, then the pH is adjusted to 12 before the hydrolysis reaction is carried out. The hydrolysis reaction is preferably carried out at room temperature for 5 hours. The pH adjustment agent used to adjust the oxidation reaction solution is preferably a sodium hydroxide solution, with a preferred mass fraction of 30%.

[0046] After the hydrolysis reaction is completed, the present invention preferably extracts, dries, and concentrates the obtained reaction solution sequentially to obtain a crude product, which is then recrystallized to obtain hydroxytetracycline. In the present invention, the extractant used for extraction is preferably dichloromethane, and the number of extractions is preferably three. The present invention preferably combines the organic layers from the three extractions. The drying agent used for drying is preferably anhydrous sodium sulfate, and after drying, the drying agent is preferably removed by filtration. The present invention does not have special requirements for concentration; it is sufficient to completely remove the organic solvent from the dried organic layer. The brown oily substance obtained after concentration is the crude product. In the present invention, the solvent used for recrystallization is preferably petroleum ether, n-hexane, or n-heptane, more preferably n-hexane. The present invention preferably adds the crude product to the solvent and heats it to reflux, then filters to remove insoluble matter, cools the filtrate to 0-10°C, and stirs to crystallize for 2 hours.

[0047] After obtaining hydroxytetracycline, the present invention involves a condensation reaction of tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxytetracycline, a basic reagent, and triphosgene to obtain tert-butyl benzoate of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate. In the present invention, the reaction formula for the condensation reaction is shown in Formula III, where compound 3 is tert-butyl benzoate of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate:

[0048]

[0049] In this invention, the molar ratio of tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, hydroxyl tetrazine, and triphosgene is preferably 1:1:1; the basic reagent preferably includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (TEA), and N,N-diisopropylethylamine (DIEA), more preferably N,N-diisopropylethylamine; the organic solvent is preferably dichloromethane; this invention does not have special requirements on the amount of solvent used, as long as it is sufficient to allow the reaction to proceed smoothly.

[0050] In this invention, it is preferable to first mix tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, triphosgene, a basic reagent, and an organic solvent to carry out a first esterification reaction to obtain a reaction solution; after concentrating the obtained reaction solution, it is mixed with hydroxyl tetrazine, an organic solvent, and a base to carry out a second esterification reaction to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate. In this invention, the preferred temperature for the first esterification reaction is room temperature, and the preferred time is 1 hour. Preferably, tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, triphosgene, and an organic solvent are first mixed, then the mixture is cooled to -5 to 5°C, followed by the dropwise addition of an alkaline reagent. After the addition is complete, the temperature is raised to room temperature to carry out the first esterification reaction. The alkaline reagent used in the second esterification reaction is preferably 2 to 4 times the molar amount of tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate, preferably 3 times. The preferred temperature for the second esterification reaction is room temperature, and the preferred time is 1 hour. Preferably, the residue is dissolved in an organic solvent, and then hydroxyl tetracycline and an alkaline reagent are added, and the reaction is carried out at room temperature.

[0051] After the second esterification reaction is completed, the present invention preferably washes, dries, and concentrates the resulting reaction solution sequentially to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate. In the present invention, the washing is preferably performed sequentially using hydrochloric acid solution and saturated brine; the concentration of the hydrochloric acid solution is preferably 1 mol / L; the drying agent is preferably anhydrous sodium sulfate; after drying, the desiccant is removed by filtration.

[0052] After obtaining tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate, the present invention deprotects the tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate in an organic solvent solution of hydrogen chloride to obtain 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl)carbonate. In this invention, the organic solvent solution of hydrogen chloride includes one or more of the following: a methanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, and a dioxane solution of hydrogen chloride, preferably an ethyl acetate solution of hydrogen chloride; the concentration of hydrogen chloride in the organic solvent solution of hydrogen chloride is preferably 1-3 mol / L, more preferably 2 mol / L; the volume ratio of tert-butyl 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate to the organic solvent solution of hydrogen chloride is preferably 1:10-1:15; this invention does not have special requirements on the source of the organic solvent solution of hydrogen chloride, and commercially available solutions can be used, or hydrogen chloride gas can be passed into an organic solvent for preparation.

[0053] In this invention, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 3 hours or more, more preferably 3 to 5 hours.

[0054] In this invention, the reaction formula for the deprotection reaction is shown in Formula IV, where OLB-1 is 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate.

[0055]

[0056] After the deprotection reaction is completed, the present invention preferably mixes the obtained reaction solution with an organic solvent, then adds a saturated sodium bicarbonate solution, and stirs and separates the mixture sequentially. The resulting organic layer is then washed, dried, and concentrated to obtain 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate. In the present invention, the type of organic solvent is preferably the same as that in the organic solvent solution of hydrogen chloride; the washing agent is preferably saturated brine; the drying agent is preferably anhydrous sodium sulfate; after drying, the drying agent is preferably removed by filtration.

[0057] The synthesis method provided by this invention has mild reaction conditions, uses environmentally friendly reagents, and does not require silica gel column chromatography purification in the post-processing of each step, thereby effectively reducing costs, facilitating industrial production, and offering greater advantages.

[0058] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments thereof.

[0059] Example 1

[0060] (1) Synthesis of hydroxytetracycline (1-1)

[0061] 13.6 g (100 mmol) of tetramethylpyrazine was dissolved in glacial acetic acid (20 mL), and 10.2 mL (100 mmol) of 30% hydrogen peroxide was added. The mixture was heated to 75 ± 5 °C and reacted for 4 h. The reaction was monitored by TLC until the starting material spot disappeared. The reaction solution was placed in an ice bath, and 10% sodium hydroxide solution was added to adjust the pH to 10. The mixture was extracted twice with 100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 13.4 g of crude tetramethylpyrazine nitrogen oxide, a white solid. The crude tetramethylpyrazine nitrogen oxide was added to acetic anhydride (14.3 mL), heated to 125 ± 5 °C, and refluxed until the starting material was completely reacted. The reaction solution was cooled to room temperature, and 30% sodium hydroxide solution was added to adjust the pH to 12. The mixture was stirred at room temperature for 5 h. The mixture was extracted three times with 100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oily substance. Add 150 mL of n-hexane to the oily substance, heat to reflux, stir for 30 min, filter off the insoluble matter, cool the filtrate to 5 ± 5 °C, and stir to crystallize for 2 h. Filter and dry to obtain 11.8 g of pale yellow solid hydroxytetracycline (1-1), yield 77.6%. 1 HNMR (400MHz, DMSO-d6) δ5.38(s,1H),3.80(s,2H),2.43(s,6H),2.40(s,3H).

[0062] (2) Synthesis of tert-butyl (4-(2-hydroxyethyl)phenyl) carbonate (2-A)

[0063] p-Hydroxyphenylethanol (2-O, 13.8 g, 100 mmol) was dissolved in 150 mL of tetrahydrofuran, and TEA (27.7 mL, 200 mmol) and (Boc)₂O (27.6 mL, 120 mmol) were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until the starting material disappeared. The reaction solution was concentrated, and 200 mL of dichloromethane was added to the residue. The residue was washed with 50 mL of water and saturated brine, respectively. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give 23.5 g of colorless oily substance 2-A, with a yield of 98.7%. 1 HNMR (400MHz, CDCl3) δ7.24(m,2H),7.11(d,2H),3.84(t,2H),2.85(t,2H),1.56(s,9H).

[0064] (3) Synthesis of tert-butyl benzoate (3) of 4-(2-((((3,5,6-trimethylpyrazine-2-yl)methoxy)carbonyl)oxy)ethyl)benzoate

[0065] 23.4 g of compound 2-A was dissolved in 200 mL of dichloromethane, and triphosgene (29.7 g, 100 mmol) was added. The reaction solution was cooled to 0-5 °C, and DIEA (49.5 mL, 300 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reactants had completely reacted. The mixture was concentrated, and the residue was dissolved in 200 mL of dichloromethane. Hydroxytetracycline (15.2 g, 100 mmol) and DIEA (49.5 mL, 300 mmol) were added. The mixture was stirred at room temperature for 1 h, washed twice with 50 mL of 1 N hydrochloric acid each time, and once with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 30.3 g of brown oily compound 3, with a yield of 74%. 1 HNMR (400MHz, CDCl3) δ7.22(d,2H),7.09(d,2H),5.23(s,2H),4.35(t,2H),2.98(t,2H),2.53(s,3H),2.51(s,3H),2.49(s,3H),1.55(s,9H).

[0066] (4) Synthesis of 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate (OLB-1)

[0067] 30 g of compound 3 was dissolved in 150 mL of ethyl acetate solution (2 mol / L HCl). The mixture was stirred at room temperature until complete, and then filtered to obtain a pale yellow solid. 300 mL of ethyl acetate was added to the solid, followed by 200 mL of saturated sodium bicarbonate solution. The mixture was stirred to dissolve, and the layers were separated. The organic layer was washed with 50 mL of water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 21.4 g of 4-hydroxyphenylethyl ((3,5,6-trimethylpyrazine-2-yl)methyl) carbonate (OLB-1) with an HPLC purity of 99.2% and a yield of 94.1%. 1 HNMR(400MHz, DMSO-d6)δ7.02(d,J=8.4Hz,2H),6.67(d,J=8.4Hz,2H),5.20(s,2H), 4.23(t,J=6.8Hz,2H),2.80(t,J=6.8Hz,2H),2.45(s,3H),2.44(s,3H),2.42(s,3H).

[0068] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for the synthesis of 4-hydroxyphenethyl((3,5,6-trimethylpyrazin-2- yl)methyl) carbonate, characterized in that, The method comprises the following steps: (1) substituting p-hydroxyphenethyl alcohol, di-tert-butyl dicarbonate and a basic reagent to obtain tert-butyl (4-(2-hydroxyethyl) phenyl) carbonate; the temperature of the substitution reaction is room temperature, and the time is 4-6 hours; the basic reagent in step (1) is triethylamine; (2) condensing tert-butyl (4-(2-hydroxyethyl) phenyl) carbonate, hydroxychavicine, a basic reagent and triphosgene to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazin-2-yl) methoxy) carbonyl) oxy) ethyl) benzoate; the basic reagent in step (2) is N,N-diisopropylethylamine; and step (2) specifically comprises: mixing tert-butyl (4-(2-hydroxyethyl) phenyl) carbonate, triphosgene, a basic reagent and an organic solvent to perform a first esterification reaction to obtain a reaction solution; and mixing the obtained reaction solution, hydroxychavicine, an organic solvent and a base to perform a second esterification reaction to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazin-2-yl) methoxy) carbonyl) oxy) ethyl) benzoate; (3) performing a deprotection reaction on tert-butyl 4-(2-((((3,5,6-trimethylpyrazin-2-yl) methoxy) carbonyl) oxy) ethyl) benzoate in a hydrogen chloride organic solvent solution to obtain 4-hydroxyphenethyl ((3,5,6-trimethylpyrazin-2-yl) methyl) carbonate; the temperature of the deprotection reaction is room temperature, and the time is more than 3 hours.

2. The method of synthesis of claim 1, wherein, The molar ratio of p-hydroxyphenethyl alcohol, di-tert-butyl dicarbonate and a basic reagent in step (1) is 1:(1.2-2):

2.

3. The method of synthesis of claim 1, wherein, After the substitution reaction, the obtained reaction solution is further treated, and the treatment comprises the following steps: concentrating the obtained reaction solution to obtain a residue; and mixing the residue and an organic solvent, and then sequentially performing washing, drying and concentration to obtain tert-butyl (4-(2-hydroxyethyl) phenyl) carbonate.

4. The method of synthesis of claim 1, wherein, The preparation method of hydroxychavicine comprises the following steps: mixing chavicine and an oxidizing agent to perform an oxidation reaction to obtain chavicine nitroxide; mixing the chavicine nitroxide and an anhydride to perform a heating rearrangement, and hydrolyzing the obtained product under alkaline conditions to obtain hydroxychavicine.

5. The method of synthesis of claim 4, wherein, After the hydrolysis reaction is completed, the obtained reaction solution is sequentially extracted, dried and concentrated to obtain a crude product, and the crude product is recrystallized to obtain hydroxychavicine.

6. The method of synthesis of claim 1, wherein, The molar ratio of tert-butyl (4-(2-hydroxyethyl) phenyl) carbonate, hydroxychavicine and triphosgene in step (2) is 1:1:

1.

7. The method of synthesis of claim 1, wherein, After the second esterification reaction is completed, the obtained reaction solution is further treated, and the treatment comprises the following steps: sequentially performing washing, drying and concentration on the obtained reaction solution to obtain tert-butyl 4-(2-((((3,5,6-trimethylpyrazin-2-yl) methoxy) carbonyl) oxy) ethyl) benzoate.

8. The method of synthesis of claim 1, wherein, The hydrogen chloride organic solvent solution comprises one or more of a hydrogen chloride methanol solution, a hydrogen chloride ethyl acetate solution and a hydrogen chloride dioxane solution.

9. The method according to claim 1 or 8, characterized in that, After the deprotection reaction is completed, the obtained reaction solution is subjected to post-treatment; the post-treatment comprises the following steps: The obtained reaction solution is mixed with an organic solvent, then saturated sodium bicarbonate solution is added, and stirring and liquid separation are sequentially performed on the mixture, the obtained organic layer is sequentially subjected to washing, drying and concentration, and 4-hydroxyphenethyl((3,5,6-trimethylpyrazin-2-yl)methyl) carbonate is obtained.

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