A preparation method of ivocet

Abstract

The present invention relates to the technical field of chemical synthesis, and specifically discloses a preparation method of ivocasel. The present invention provides a new preparation method of ivocasel by designing a new synthetic route, using N-tert-butyloxycarbonyl-(R)-3-pyrrolidone as the starting material, activating the hydroxyl group through an acylation reaction, then reacting with (R)-1-(1-naphthyl)ethylamine with a nucleophilic substitution reaction, removing the Boc protecting group, reacting with 4-fluoro-3-nitrophenylethyl acetate with a nucleophilic substitution reaction, and then reducing, diazotizing, removing, and hydrolyzing to obtain ivocasel. The preparation method of ivocasel provided by the present invention has the advantages of reasonable process design, high product purity, and low production cost, the HPLC content of the prepared ivocasel is greater than 99.9%, and the raw materials are easily available, simple to operate, and mild reaction conditions, thereby realizing the industrialized production of ivocasel.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing evoked levocarbamide. Background Art

[0002] Chronic kidney disease (CKD) has become a common and frequently occurring disease in today's society, and secondary hyperparathyroidism (SHPT) is a serious complication of chronic kidney disease. When chronic kidney disease develops into mid-to-late stage renal failure, renal failure causes vitamin D deficiency, which reduces the efficiency of calcium absorption and utilization, and reduces phosphorus excretion, leading to metabolic disorders, which are often manifested as low calcium and high phosphorus in the early stages. The imbalance of calcium and phosphorus continuously stimulates the parathyroid glands to secrete parathyroid hormone (PTH), causing an abnormal increase in PTH, and ultimately triggering the occurrence of SHPT. In the mid-to-late stage of SHPT, high calcium, high phosphorus, and high PTH are more common. Calcium and phosphorus metabolism disorders can seriously threaten the life and health of patients, and are the top priority of chronic disease management in CKD patients.

[0003] Ivocasert is a third-generation oral calcimimetic developed by Mitsubishi Tanabe Pharma Co., Ltd. in Japan and launched in Japan in 2018. It is available in 1mg and 2mg dosage forms. Ivocasert acts on calcium receptors on the surface of parathyroid cells, inhibiting PTH secretion and reducing blood PTH concentrations, thereby alleviating symptoms. Ivocasert also regulates PTH biosynthesis and parathyroid cell proliferation, controlling PTH production.

[0004] The main synthetic route for ivocet is as follows: N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol is used as the starting material. The hydroxyl group is activated with o-nitrobenzenesulfonyl chloride, followed by nucleophilic substitution with (R)-1-(1-naphthyl)ethylamine. The Boc protecting group is removed in acetyl chloride isopropanol solution, followed by a Buchwald-Hartwig coupling reaction with ethyl 4-bromophenylacetate. Finally, ivocet is hydrolyzed to obtain ivocet. This route, adopted by the original manufacturer, has the following major drawbacks: the Buchwald-Hartwig coupling reaction conditions are relatively harsh, requiring anhydrous, oxygen-free conditions and a high temperature of 100°C. Furthermore, the product purity is relatively low, with a chemical purity of only approximately 85%. Even after multiple subsequent recrystallizations and purifications, the purity of the ivocet product remains low. Furthermore, the high cost of the palladium catalyst used in the reaction increases product costs, and there is also the risk of residual palladium in the product.

[0005] Summary of the Invention

[0006] In view of the problems that the existing process for preparing ivocate has, such as low product purity, harsh reaction conditions, high cost, and possible presence of metal palladium residue in the product, the present invention provides a method for preparing ivocate.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A preparation method of ivocet comprises the following steps:

[0009] S1, reacting compound I with ethyl 4-fluoro-3-nitrophenylacetate to obtain compound II;

[0010] S2, subjecting compound II to a reduction reaction to obtain compound III;

[0011] S3, subjecting compound III to diazotization reaction, elimination reaction and hydrolysis reaction in sequence to obtain ivocacet;

[0012]

[0013] Furthermore, as a specific embodiment of the present invention, the preparation method of compound I comprises the following steps:

[0014] After acylation reaction of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol with o-nitrosulfonyl chloride, a nucleophilic substitution reaction with (R)-1-(1-naphthyl)ethylamine is carried out, and then the Boc protecting group is removed to obtain a complex of compound I.

[0015] Compared with the prior art, the present invention provides a new method for preparing ivocet by designing a new synthetic route. The method uses N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol as the starting material, activates the hydroxyl group through an acylation reaction, then undergoes a nucleophilic substitution reaction with (R)-1-(1-naphthyl)ethylamine, removes the Boc protecting group, and undergoes a nucleophilic substitution reaction with ethyl 4-fluoro-3-nitrophenylacetate. The method then undergoes reduction, diazotization, removal, and hydrolysis to obtain ivocet. The method for preparing ivocet provided by the present invention has the advantages of reasonable process design, high product purity, and low production cost. The HPLC content of the prepared ivocet is greater than 99.9%. Furthermore, the raw materials are readily available, the operation is simple, and the reaction conditions are mild, thus realizing the industrial production of ivocet.

[0016] The present invention selects compound I and ethyl 4-fluoro-3-nitrophenylacetate to carry out a nucleophilic substitution reaction. Compared with the originally developed Buchwald-Hartwig coupling reaction, the reaction has higher selectivity and milder reaction conditions, and does not require a harsh anhydrous and oxygen-free environment. At the same time, it does not require an expensive palladium catalyst, which not only effectively reduces the production cost of ivocet, but also avoids the residual metal palladium in ivocet, providing a new process route for the production of ivocet and having high practical promotion value.

[0017] As a specific embodiment of the present invention, the preparation method of evoked seroquel specifically comprises the following steps:

[0018] Step 1: Acylation reaction of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol with o-nitrosulfonyl chloride in a first solvent and an organic base to obtain compound I (1);

[0019] Step 2: In a second solvent and an acid-binding agent, compound I (1) is subjected to a nucleophilic reaction with (R)-1-(1-naphthyl)ethylamine to obtain compound I (2);

[0020] Step 3: In a third solvent, compound I (2) and acetyl chloride are subjected to a deprotection reaction, and the reactant is added to an alkaline solution for dissociation to obtain compound I;

[0021] Step 4: In a fourth solvent, compound I is reacted with ethyl 4-fluoro-3-nitrophenylacetate in the presence of sodium cyanide to undergo a nucleophilic substitution reaction to obtain compound II;

[0022] Step 5: In a fifth solvent, compound II is subjected to a reduction reaction with a reducing agent to obtain compound III;

[0023] Step 6: Add compound III to the sixth solvent and acid solution, then add sodium nitrite aqueous solution to carry out diazotization reaction and elimination reaction, and hydrolyze the obtained product under alkaline conditions and the seventh solvent to obtain ivocacet.

[0024] The reaction equation of the above preparation process is as follows:

[0025]

[0026] Preferably, in step 1, the first solvent is at least one of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethyl sulfoxide, N,N-dimethylformamide or toluene.

[0027] Further preferably, in step 1, the first solvent is acetonitrile.

[0028] Preferably, in step 1, the organic base is one or both of triethylamine and diisopropylethylamine.

[0029] Further preferably, in step 1, the organic base is triethylamine.

[0030] Preferably, in step 1, the temperature of the acylation reaction is 0°C to 30°C.

[0031] Further preferably, in step 1, the temperature of the acylation reaction is 10°C to 20°C.

[0032] Preferably, in step 1, the molar ratio of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol to o-nitrosulfonyl chloride is 1:1.0 to 1:1.3.

[0033] Further preferably, in step 1, the molar ratio of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol to o-nitrosulfonyl chloride is 1:1.1.

[0034] The preferred reaction conditions in step 1 can promote the full reaction of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol with o-nitrosulfonyl chloride, and at the same time, are also conducive to increasing the reaction rate of the acylation reaction.

[0035] It should be noted that after the reaction of step 1 is completed, a post-treatment process is also included: purified water and dichloromethane are added to the reaction solution for extraction, and the extract is dried and concentrated to obtain compound I (1).

[0036] Preferably, in step 2, the second solvent is at least one of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethyl sulfoxide, N,N-dimethylformamide or toluene.

[0037] More preferably, in step 2, the second solvent is acetonitrile.

[0038] Preferably, in step 2, the acid binding agent is at least one of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine or diisopropylethylamine.

[0039] Further preferably, in step 2, the acid binding agent is potassium phosphate.

[0040] Preferably, in step 2, the temperature of the nucleophilic reaction is 70°C to 82°C.

[0041] Furthermore, in step 2, the temperature of the nucleophilic reaction is 82° C. (acetonitrile reflux temperature).

[0042] Preferably, in step 2, the molar ratio of compound I (1) to (R)-1-(1-naphthyl)ethylamine is 1:0.7 to 1:1.0.

[0043] Further preferably, in step 2, the molar ratio of compound I (1) to (R)-1-(1-naphthyl)ethylamine is 1:0.8.

[0044] The preferred reaction conditions in step 2 can promote the full reaction of compound I (1) with (R)-1-(1-naphthyl)ethylamine, and at the same time, are also conducive to increasing the reaction rate of the nucleophilic substitution reaction.

[0045] It should be noted that after the reaction of step 2 is completed, a post-treatment process is also included: filtering the reaction solution, concentrating the filtrate, adding purified water and ethyl acetate for extraction, drying and concentrating to obtain compound I (2).

[0046] Preferably, in step three, the third solvent is at least one of isopropanol, methanol, ethanol or tetrahydrofuran.

[0047] Further preferably, in step three, the third solvent is isopropanol.

[0048] Preferably, in step 3, the temperature of the deprotection reaction is 50°C to 70°C.

[0049] Further preferably, in step 3, the temperature of the deprotection reaction is 60°C to 65°C.

[0050] Preferably, in step 3, the molar ratio of compound I (2) to acetyl chloride is 1:5 to 1:7.

[0051] Further preferably, in step 3, the molar ratio of compound I (2) to acetyl chloride is 1:6.

[0052] The preferred reaction conditions of step 3 can promote the complete reaction of compound I (2) with acetyl chloride and simultaneously increase the reaction rate of the deprotection reaction.

[0053] Specifically, after the deprotection reaction in step 3 is completed, the reaction solution is filtered and dried to obtain a complex of compound I, which is dissolved in purified water and dichloromethane, and then an alkaline solution is added for dissociation. After dissociation, the complex is extracted and concentrated to obtain compound I.

[0054] As a specific embodiment of the present invention, the alkaline solution used for the dissociation can be a sodium hydroxide solution.

[0055] Preferably, in step 4, the fourth solvent is at least one of N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide or N-methylpyrrolidone.

[0056] Further preferably, in step 4, the fourth solvent is N,N-dimethylformamide.

[0057] The preferred solvent is conducive to the full mixing of the reaction raw materials, improves the utilization rate of the raw materials, and reduces the occurrence of side reactions. More importantly, the preferred solvent can increase the reactivity of the reaction raw materials and increase the reaction rate of the nucleophilic substitution reaction.

[0058] Preferably, in step 4, the temperature of the nucleophilic substitution reaction is 15°C to 40°C.

[0059] Further preferably, in step 4, the temperature of the nucleophilic substitution reaction is 25°C to 30°C.

[0060] Preferably, in step 4, the molar ratio of compound I to ethyl 4-fluoro-3-nitrophenylacetate is 1:1.0 to 1:1.3.

[0061] Further preferably, in step 4, the molar ratio of compound I to ethyl 4-fluoro-3-nitrophenylacetate is 1:1.1.

[0062] The preferred reaction conditions of step 4 can promote the full reaction of compound I with ethyl 4-fluoro-3-nitrophenylacetate, while increasing the reaction rate and selectivity of the reaction.

[0063] It should be noted that after the reaction in step 4 is completed, a post-treatment process is also included: the reaction solution is added to water for crystallization, filtered, and dried to obtain compound II.

[0064] Preferably, in step five, the fifth solvent is an ethanol aqueous solution or a methanol aqueous solution.

[0065] Further preferably, in step 5, the fifth solvent is an ethanol-water solution, and the volume ratio of the ethanol to water is 4:1.

[0066] Furthermore, in step five, the reaction temperature is reflux temperature.

[0067] Preferably, in step five, the reducing agent is iron powder and ammonium chloride, and the molar ratio of compound II to iron powder and reducing agent is 1:4-6:9-11.

[0068] It should be noted that after the reaction in step 5 is completed, a post-treatment process is also included: filtering the reaction solution, concentrating the filtrate under reduced pressure to remove the solvent, then adding dichloromethane for extraction, concentrating the extract, and beating the extract to obtain compound III.

[0069] Preferably, in step six, the sixth solvent is one or both of methanol and isopropanol.

[0070] Further preferably, in step six, the sixth solvent is ethanol.

[0071] Preferably, in step six, the acid solution is a mixed solution of concentrated sulfuric acid and hypophosphorous acid.

[0072] Preferably, in step six, the temperature of the diazotization reaction and the elimination reaction is 10°C to 50°C.

[0073] Further preferably, in step six, the temperature of the diazotization reaction and the elimination reaction is 20°C to 30°C.

[0074] Preferably, in step six, the molar ratio of compound III to sodium nitrite is 1:2.0 to 1:4.0.

[0075] Further preferably, in step six, the molar ratio of compound III to sodium nitrite is 1:3.0.

[0076] It should be noted that in step six, after the diazotization and elimination reactions are completed, a post-treatment process is also included: the reaction solution is added to purified water, the pH is adjusted to alkaline, dichloromethane is added for extraction, concentration, salt formation, and then the product is added to the seventh solvent for hydrolysis reaction under alkaline conditions.

[0077] Preferably, in step six, the seventh solvent is a methanol aqueous solution or an ethanol aqueous solution.

[0078] Further preferably, in step 6, the seventh solvent is an ethanol-water solution, wherein the mass ratio of ethanol to water is 1:1.

[0079] Preferably, in step six, the temperature of the hydrolysis reaction is 0°C to 100°C.

[0080] Further preferably, in step six, the temperature of the hydrolysis reaction is 50°C to 70°C.

[0081] As a specific embodiment of the present invention, the alkaline environment for hydrolysis can be provided by an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate or potassium carbonate.

[0082] The preparation process of the key compound in the original research process is a Buchwald-Hartwig coupling reaction. The reaction conditions are relatively harsh, requiring anhydrous, oxygen-free conditions and a high temperature of 100°C. The chemical purity of the prepared ivocet is only about 85%. Even after multiple recrystallization and purification, the purity of the ivocet product is still low. In addition, the cost of the palladium catalyst in the Buchwald-Hartwig coupling reaction is high, resulting in increased product costs. The present invention replaces the raw material 4-bromophenylacetic acid ethyl ester used to prepare the key compound with 4-fluoro-3-nitrophenylacetic acid ethyl ester. The reaction mechanism of this process is replaced by a nucleophilic substitution reaction, which has high reaction selectivity and high product purity, eliminating the need for multiple refining processes and effectively simplifying the purification process. The reaction process does not require a palladium catalyst, saving material costs and avoiding the residual metal palladium in the ivocet. This provides a new process route for preparing high-purity ivocet and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 This is the mass spectrum of ivocet prepared in Example 1 of the present invention;

[0084] Figure 2 This is the H NMR spectrum of ivocasel prepared in Example 1 of the present invention;

[0085] Figure 3 This is the C NMR spectrum of ivocacet prepared in Example 1 of the present invention;

[0086] Figure 4This is a COSY graph of evoked iodide prepared in Example 1 of the present invention;

[0087] Figure 5 This is the DEPT diagram of ivocaset prepared in Example 1 of the present invention;

[0088] Figure 6 This is the HMBC chart of ivocacet prepared in Example 1 of the present invention;

[0089] Figure 7 HSQC chart of ivocacet prepared in Example 1 of the present invention;

[0090] Figure 8 This is the NOESY graph of ivocasel prepared in Example 1 of the present invention;

[0091] Figure 9 This is the HPLC detection spectrum of ivocet prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0092] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0093] Example 1

[0094] This embodiment provides a method for preparing evoked levodopa, comprising the following steps:

[0095] Step 1, preparation of compound I:

[0096] a. Preparation of Compound Ⅰ (1):

[0097] To a 2L three-necked flask, 100.00 g of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol, 9.19 g of methylamine hydrochloride and 400 mL of acetonitrile were added, and 70.27 g of triethylamine was added under stirring. The temperature was lowered, and a solution prepared by 130.20 g of o-nitrobenzenesulfonyl chloride and 432 mL of toluene was slowly added at 14-16°C. After the addition was completed, 56 mL of acetonitrile was added to rinse the reaction flask, and the rinse was added to the reaction solution. After the addition was completed, the temperature was controlled at 10-20°C and stirred for 4 h. The reaction was completed by TLC detection. 300 mL of purified water was added to the reaction solution, and a solution prepared by 20 mL of hydrochloric acid and 176 mL of purified water was added. The liquids were separated, and 400 mL of purified water and 400 mL of dichloromethane were added to the organic phase. The mixture was stirred and separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain a dark brown oil, namely compound I (1), which was directly used in the next step.

[0098] b. Preparation of Compound Ⅰ (2):

[0099] To a 1L reaction flask, 198.9 g of compound I (1), 90.64 g of potassium phosphate and 796 mL of acetonitrile were added, and 73.12 g of (R)-1-(1-naphthyl)ethylamine was added with stirring. The temperature was raised to reflux and the reaction was carried out for 12 h. After TLC detection, the reaction was completed, the heating was turned off, the temperature was cooled to room temperature, filtered, the filtrate was concentrated, and after distillation, 800 mL of ethyl acetate and 800 mL of saturated brine were added. The mixture was stirred for 15 min, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a dark brown oil, i.e., compound I (2), which was used directly in the next step.

[0100] c. Preparation of Compound Ⅰ:

[0101] Add 546 mL of isopropanol to a 2 L three-necked flask, stir, cool, and add 251.65 g of acetyl chloride dropwise at a temperature of 0°C to 15°C. After the addition is complete, control the temperature at 0°C to 15°C and keep stirring for 30 min. Control the temperature at 0°C to 15°C and add dropwise a solution prepared by adding 181.84 g of compound Ⅰ (2) and 364 mL of isopropanol. After the addition is complete, heat to 60°C to 65°C and keep the temperature to react for 4 h. After TLC detection, the reaction is complete, cool to 20°C to 30°C, stir and crystallize for 2 h, filter, rinse with isopropanol, and dry the filter cake in vacuo at 45°C to obtain compound Ⅰ. The total yield of the three-step reaction is 65.7%.

[0102]

[0103] Step 2, preparation of compound II:

[0104] To the reaction flask, 250 g of compound I, 2250 mL of dichloromethane, and 200 mL of purified water were added and stirred. 4 mol / L sodium hydroxide solution was added to adjust the pH to 14. After adjustment, the liquids were separated, and the aqueous phase was extracted once with 500 mL of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to dryness to obtain a yellow oil, which was used directly in the next step.

[0105] 1250 mL of DMF was added to the residue from the previous step, stirred and dissolved, and 167.34 g of ethyl 4-fluoro-3-nitrophenylacetate (1.1 eq) was added. Under nitrogen protection, 32.14 g of sodium hydride (1.2 eq) was added in batches while controlling the temperature below 25 ° C. The reaction was stirred at room temperature for 3 h. After TLC detection, the reaction solution was added to 5 L of purified water, stirred at room temperature for 1 h to crystallize, filtered, washed with purified water, and dried to obtain compound II with a yield of 87.2%.

[0106]

[0107] Step 3, preparation of compound III:

[0108] To the reaction flask, 150 g of compound II, 1800 mL of anhydrous ethanol, and 450 mL of purified water were added, stirred, and 93.59 g of iron powder and 179.28 g of ammonium chloride were added. After the addition was complete, the temperature was raised to reflux for 4 h. The reaction was completed by TLC detection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. 450 mL of dichloromethane was added and extracted three times. The organic phases were combined, dried, filtered, and concentrated. After concentration was complete, 600 mL of ethyl acetate was added, stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound III with a yield of 86.7%.

[0109]

[0110] Step 4: Preparation of Compound IV:

[0111] To the reaction flask, 100 g of compound III and 1000 mL of anhydrous ethanol were added dropwise, 200 mL of concentrated sulfuric acid and 200 mL of hypophosphorous acid were added dropwise while controlling the temperature below 20 ° C, and then an aqueous sodium nitrite solution (49.57 g of sodium nitrite dissolved in 198 mL of water) was added dropwise while controlling the temperature below 20 ° C. After the addition, the reaction was stirred at room temperature for 10 h. After TLC detection, the reaction was completed. The reaction solution was added to 2000 mL of purified water, sodium hydroxide solution was added to adjust the pH to 8.0-8.5, 500 mL of dichloromethane was added and extracted three times, the organic phases were combined, dried, filtered, and concentrated. After concentration, 600 mL of ethyl acetate was added and stirred to dissolve, and ethyl acetate / hydrogen chloride mixed solution was added to adjust the pH to 3.0-4.0. After adjustment, the mixture was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound IV with a yield of 85.2%.

[0112]

[0113] Step 5, preparation of compound V:

[0114] To the reaction flask, 33.87 g of sodium hydroxide and 496 mL of purified water were added, stirred and cooled to 20-30 ° C, 124 g of compound IV and 496 mL of anhydrous ethanol were added, the temperature was raised to 60 ° C and the reaction was carried out for 45 min, hot filtration was performed, the filtrate was transferred to a reaction flask, the temperature was raised to 60 ° C, 10% citric acid solution was slowly added until solid precipitated, and the mixture was stirred for 0.5 h. 10% citric acid solution was slowly added to adjust the pH to 6-7. After the adjustment, the mixture was stirred at 60 ° C for 1 h, the heating was turned off, the temperature was lowered to 20 ° C, and the crystallization was stirred for 2 h. The mixture was filtered, washed with 50% ethanol, and dried to obtain compound IV with a yield of 96.3% and a liquid purity of 99.934%.

[0115]

[0116] Example 2

[0117] This embodiment provides a method for preparing evoked levodopa, comprising the following steps:

[0118] Step 1, preparation of compound I:

[0119] a. Preparation of Compound Ⅰ (1):

[0120] To a 2L three-necked flask, 100.00 g of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol, 9.19 g of methylamine hydrochloride and 400 mL of acetonitrile were added, and 70.27 g of triethylamine was added under stirring. The temperature was lowered and a solution of 118.37 g of o-nitrobenzenesulfonyl chloride and 393 mL of toluene was slowly added at 10-15 °C. After the addition was completed, 56 mL of acetonitrile was added to rinse the reaction flask. The rinse solution was added to the reaction solution. After the addition was completed, the temperature was controlled at 10-2 The reaction was stirred at 0°C for 4 h. After TLC detection, the reaction was complete. 300 mL of purified water was added to the reaction solution, followed by a solution prepared by adding 20 mL of hydrochloric acid and 176 mL of purified water. The mixture was separated. 400 mL of purified water and 400 mL of dichloromethane were added to the organic phase, stirred, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain a dark brown oil, namely compound I (1), which was used directly in the next step.

[0121] b. Preparation of Compound Ⅰ (2):

[0122] To a 1L reaction flask, 198.9 g of compound I (1), 90.64 g of potassium phosphate and 796 mL of acetonitrile were added, and 64.08 g of (R)-1-(1-naphthyl)ethylamine was added with stirring. The temperature was raised to reflux and the reaction was carried out for 12 h. After TLC detection, the reaction was completed, the heating was turned off, the temperature was lowered to room temperature, filtered, the filtrate was concentrated, and after distillation, 800 mL of ethyl acetate and 800 mL of saturated brine were added. The mixture was stirred for 15 min, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a dark brown oil, i.e., compound I (2), which was used directly in the next step.

[0123] c. Preparation of Compound Ⅰ:

[0124] Add 546 mL of isopropanol to a 2L three-necked flask, stir, cool, and add 293.55 g of acetyl chloride dropwise at a temperature of 0°C to 15°C. After the addition is complete, control the temperature at 0°C to 15°C and keep stirring for 30 min. Control the temperature at 0°C to 15°C and add dropwise a solution prepared by mixing 181.84 g of compound Ⅰ (2) with 364 mL of isopropanol. After the addition is complete, heat to 50°C to 55°C and keep the temperature to react for 4 h. After TLC detection, the reaction is complete, cool to 20°C to 30°C, stir and crystallize for 2 h, filter, rinse with isopropanol, and dry the filter cake in vacuo at 45°C to obtain compound Ⅰ. The total yield of the three-step reaction is 56.7%.

[0125]

[0126] Step 2, preparation of compound II:

[0127] To the reaction flask, 250 g of compound I, 2250 mL of dichloromethane, and 200 mL of purified water were added and stirred. 4 mol / L sodium hydroxide solution was added to adjust the pH to 14. After adjustment, the liquids were separated, and the aqueous phase was extracted once with 500 mL of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to dryness to obtain a yellow oil, which was used directly in the next step.

[0128] 1250 mL of DMF was added to the residue from the previous step, stirred and dissolved, and 152.13 g of ethyl 4-fluoro-3-nitrophenylacetate (1.0 eq) was added. Under nitrogen protection, 32.14 g of sodium hydride (1.2 eq) was added in batches while controlling the temperature below 25 ° C. The reaction was stirred at room temperature for 3 h. After TLC detection, the reaction solution was added to 5 L of purified water, stirred at room temperature for 1 h to crystallize, filtered, washed with purified water, and dried to obtain compound II with a yield of 71.4%.

[0129]

[0130] Step 3, preparation of compound III:

[0131] To the reaction flask, 150 g of compound II, 1800 mL of anhydrous ethanol, and 450 mL of purified water were added, stirred, and 77.56 g of iron powder and 166.75 g of ammonium chloride were added. After the addition was complete, the temperature was raised to reflux for 4 h. The reaction was completed by TLC detection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. 450 mL of dichloromethane was added and extracted three times. The organic phases were combined, dried, filtered, and concentrated. After concentration was complete, 600 mL of ethyl acetate was added, stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound III with a yield of 74.6%.

[0132]

[0133] Step 4: Preparation of Compound IV:

[0134] To the reaction flask, 100 g of compound III and 1000 mL of anhydrous ethanol were added dropwise, 200 mL of concentrated sulfuric acid and 200 mL of hypophosphorous acid were added dropwise while controlling the temperature below 20 ° C, and then an aqueous sodium nitrite solution (34.26 g of sodium nitrite dissolved in 137 mL of water) was added dropwise while controlling the temperature below 20 ° C. After the addition, the reaction was stirred at room temperature for 10 h. After TLC detection, the reaction was completed, and the reaction solution was added to 2000 mL of purified water. Sodium hydroxide solution was added to adjust the pH to 8.0-8.5, and 500 mL of dichloromethane was added and extracted three times. The organic phases were combined, dried, filtered, and concentrated. After concentration, 600 mL of ethyl acetate was added and stirred to dissolve, and ethyl acetate / hydrogen chloride mixed solution was added to adjust the pH to 3.0-4.0. After adjustment, the mixture was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound IV with a yield of 74.6%.

[0135]

[0136] Step 5, preparation of compound V:

[0137] To the reaction flask, 33.87 g of sodium hydroxide and 496 mL of purified water were added, stirred and cooled to 20-30 ° C, 124 g of compound IV and 496 mL of anhydrous ethanol were added, the temperature was raised to 60 ° C and the reaction was carried out for 45 min. The filtrate was transferred to a reaction flask, the temperature was raised to 60 ° C, and 10% citric acid solution was slowly added until solid precipitated. The mixture was stirred for 0.5 h, and 10% citric acid solution was slowly added to adjust the pH to 6-7. After the adjustment, the mixture was stirred at 60 ° C for 1 h, the heating was turned off, the temperature was lowered to 20 ° C, and the crystallization was stirred for 2 h. The mixture was filtered, washed with 50% ethanol, and dried to obtain compound IV with a yield of 96.2% and a liquid purity of 99.929%.

[0138]

[0139] Example 3

[0140] This embodiment provides a method for preparing evoked levodopa, comprising the following steps:

[0141] Step 1, preparation of compound I:

[0142] a. Preparation of Compound Ⅰ (1):

[0143] To a 2L three-necked flask, 100.00 g of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol, 9.19 g of methylamine hydrochloride and 400 mL of acetonitrile were added, and 70.27 g of triethylamine was added under stirring. The temperature was lowered, and a solution prepared by 142.1 g of o-nitrobenzenesulfonyl chloride and 471 mL of toluene was slowly added at 15-20°C. After the addition was completed, 56 mL of acetonitrile was added to rinse the reaction flask, and the rinse was added to the reaction solution. After the addition was completed, the temperature was controlled at 10-20°C and stirred for 4 h. The reaction was completed by TLC detection. 300 mL of purified water was added to the reaction solution, and a solution prepared by 20 mL of hydrochloric acid and 176 mL of purified water was added. The liquids were separated, and 400 mL of purified water and 400 mL of dichloromethane were added to the organic phase. The mixture was stirred and separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain a dark brown oil, namely compound I (1), which was directly used in the next step.

[0144] b. Preparation of Compound Ⅰ (2):

[0145] To a 1L reaction flask, 198.9 g of compound I (1), 90.64 g of potassium phosphate and 796 mL of acetonitrile were added, and 91.58 g of (R)-1-(1-naphthyl)ethylamine was added with stirring. The temperature was raised to reflux and the reaction was carried out for 12 h. After TLC detection, the reaction was completed, the heating was turned off, the temperature was cooled to room temperature, filtered, the filtrate was concentrated, and after distillation, 800 mL of ethyl acetate and 800 mL of saturated brine were added. The mixture was stirred for 15 min, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a dark brown oil, i.e., compound I (2), which was used directly in the next step.

[0146] c. Preparation of Compound Ⅰ:

[0147] Add 546 mL of isopropanol to a 2 L three-necked flask, stir, cool, and add 209.6 g of acetyl chloride dropwise at a temperature of 0°C to 15°C. After the addition is complete, control the temperature at 0°C to 15°C and keep stirring for 30 min. Control the temperature at 0°C to 15°C and add dropwise a solution prepared by mixing 181.84 g of compound Ⅰ (2) with 364 mL of isopropanol. After the addition is complete, heat to 65°C to 70°C and keep the temperature to react for 4 h. After TLC detection, the reaction is complete, cool to 20°C to 30°C, stir and crystallize for 2 h, filter, rinse with isopropanol, and dry the filter cake in vacuo at 45°C to obtain compound Ⅰ. The total yield of the three-step reaction is 65.1%.

[0148]

[0149] Step 2, preparation of compound II:

[0150] To the reaction flask, 250 g of compound I, 2250 mL of dichloromethane, and 200 mL of purified water were added and stirred. 4 mol / L sodium hydroxide solution was added to adjust the pH to 14. After adjustment, the liquids were separated, and the aqueous phase was extracted once with 500 mL of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to dryness to obtain a yellow oil, which was used directly in the next step.

[0151] 1250 mL of DMF was added to the residue from the previous step, stirred and dissolved, and 197.77 g of ethyl 4-fluoro-3-nitrophenylacetate (1.3 eq) was added. Under nitrogen protection, 32.14 g of sodium hydride (1.2 eq) was added in batches while controlling the temperature below 25 ° C. The reaction was stirred at room temperature for 3 h. After TLC detection, the reaction solution was added to 5 L of purified water, stirred at room temperature for 1 h to crystallize, filtered, washed with purified water, and dried to obtain compound II in a yield of 86.9%.

[0152]

[0153] Step 3, preparation of compound III:

[0154] To the reaction flask, 150 g of compound II, 1800 mL of anhydrous ethanol, and 450 mL of purified water were added, stirred, and 116.45 g of iron powder and 203.65 g of ammonium chloride were added. After the addition was complete, the temperature was raised to reflux for 4 h. The reaction was completed by TLC detection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. 450 mL of dichloromethane was added and extracted three times. The organic phases were combined, dried, filtered, and concentrated. After concentration was complete, 600 mL of ethyl acetate was added, stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound III with a yield of 86.9%.

[0155]

[0156] Step 4: Preparation of Compound IV:

[0157] To the reaction flask, 100 g of compound III and 1000 mL of anhydrous ethanol were added dropwise, 200 mL of concentrated sulfuric acid and 200 mL of hypophosphorous acid were added dropwise while controlling the temperature below 20 ° C, and then an aqueous sodium nitrite solution (68.54 g of sodium nitrite dissolved in 274 mL of water) was added dropwise while controlling the temperature below 20 ° C. After the addition, the reaction was stirred at room temperature for 10 h. After TLC detection, the reaction was completed, and the reaction solution was added to 2000 mL of purified water. Sodium hydroxide solution was added to adjust the pH to 8.0-8.5, and 500 mL of dichloromethane was added and extracted three times. The organic phases were combined, dried, filtered, and concentrated. After concentration, 600 mL of ethyl acetate was added and stirred to dissolve, and ethyl acetate / hydrogen chloride mixed solution was added to adjust the pH to 3.0-4.0. After adjustment, the mixture was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried to obtain compound IV with a yield of 85.1%.

[0158]

[0159] Step 5, preparation of compound V:

[0160] To the reaction flask, 33.87 g of sodium hydroxide and 496 mL of purified water were added, stirred and cooled to 20-30 ° C, 124 g of compound IV and 496 mL of anhydrous ethanol were added, the temperature was raised to 60 ° C and the reaction was carried out for 45 min. The filtrate was transferred to a reaction flask, the temperature was raised to 60 ° C, and 10% citric acid solution was slowly added until solid precipitated. The mixture was stirred for 0.5 h, and 10% citric acid solution was slowly added to adjust the pH to 6-7. After the adjustment, the mixture was stirred at 60 ° C for 1 h, the heating was turned off, the temperature was lowered to 20 ° C, and the crystallization was stirred for 2 h. The mixture was filtered, washed with 50% ethanol, and dried to obtain compound IV with a yield of 96.4% and a liquid purity of 99.921%.

[0161]

[0162] Comparative Example 1

[0163] This comparative example provides a method for preparing evokase. The preparation method is the same as that in Example 1, except that ethyl 4-fluoro-3-nitrophenylacetate in step 2 of Example 1 is replaced with an equimolar equivalent of methyl 4-fluoro-3-nitroacetate. The remaining steps and reaction conditions are exactly the same as those in Example 1.

[0164] In this comparative example, the yield of compound II prepared in step 2 was 79.8%, the yield of compound III prepared in step 3 was 81.2%, the yield of compound IV prepared in step 4 was 82.4%, the yield of ivocasep prepared in step 5 was 95.8%, and the liquid phase purity was 99.685%.

[0165] Comparative Example 2

[0166] This comparative example provides a method for preparing evokase. The preparation method is the same as that in Example 1, except that ethyl 4-fluoro-3-nitrophenylacetate in step 2 of Example 1 is replaced with an equimolar equivalent of isopropyl 4-fluoro-3-nitroacetate. The remaining steps and reaction conditions are exactly the same as those in Example 1.

[0167] In this comparative example, the yield of compound II prepared in step 2 was 78.2%, the yield of compound III prepared in step 3 was 79.3%, the yield of compound IV prepared in step 4 was 77.6%, the yield of ivocasep prepared in step 5 was 95.3%, and the liquid phase purity was 99.606%.

[0168] Comparative Example 3

[0169] This comparative example provides a method for preparing evokase. The preparation method is the same as that in Example 1, except that ethyl 4-fluoro-3-nitrophenylacetate in step 2 of Example 1 is replaced with an equimolar equivalent of ethyl 4-bromo-3-nitroacetate. The remaining steps and reaction conditions are exactly the same as those in Example 1.

[0170] In this comparative example, the yield of compound II prepared in step 2 was 12.8%, the yield of compound III prepared in step 3 was 86.1%, the yield of compound IV prepared in step 4 was 85.4%, the yield of ivocasep prepared in step 5 was 96.2%, and the liquid phase purity was 99.433%.

[0171] The yield and purity data comparison of the intermediate products and evokase prepared in Example 1 and Comparative Examples 1-3 are shown in Table 1.

[0172] Table 1

[0173]

[0174] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing evoked levodopa, characterized in that: The steps include: Step 1: Acylation reaction of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol with o-nitrobenzenesulfonyl chloride in a first solvent and an organic base to obtain compound I (1); Step 2: In a second solvent and an acid-binding agent, compound I (1) is subjected to a nucleophilic reaction with (R)-1-(1-naphthyl)ethylamine to obtain compound I (2); Step 3: In a third solvent, compound I (2) and acetyl chloride are subjected to a deprotection reaction, and the reactant is added to an alkaline solution for dissociation to obtain compound I; Step 4: In a fourth solvent, compound I is reacted with ethyl 4-fluoro-3-nitrophenylacetate under the action of sodium hydride to undergo a nucleophilic substitution reaction to obtain compound II; Step 5: In a fifth solvent, compound II is subjected to a reduction reaction with a reducing agent to obtain compound III; Step 6: Add compound III to the sixth solvent and acid solution, then add sodium nitrite aqueous solution to carry out diazotization reaction and elimination reaction, and hydrolyze the obtained product under alkaline conditions and the seventh solvent to obtain ivocacet.

2. The method for preparing evokedib according to claim 1, wherein: In step 1, the first solvent is at least one of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethyl sulfoxide, N,N-dimethylformamide or toluene; and / or In step 1, the organic base is one or both of triethylamine and diisopropylethylamine; and / or In step 1, the temperature of the acylation reaction is 0°C to 30°C; and / or In step 1, the molar ratio of N-tert-butyloxycarbonyl-(R)-3-pyrrolidinol to o-nitrobenzenesulfonyl chloride is 1:1.0 to 1:1.

3.

3. The method for preparing evokedib according to claim 1, wherein: In step 2, the second solvent is at least one of acetonitrile, tetrahydrofuran, ethyl acetate, acetone, dimethyl sulfoxide, N,N-dimethylformamide or toluene; and / or In step 2, the acid binding agent is at least one of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine or diisopropylethylamine; and / or In step 2, the temperature of the nucleophilic reaction is 70° C. to 82° C.; and / or In step 2, the molar ratio of compound I (1) to (R)-1-(1-naphthyl)ethylamine is 1:0.7 to 1:1.

0.

4. The method for preparing evokedib according to claim 1, wherein: In step 3, the third solvent is at least one of isopropanol, methanol, ethanol or tetrahydrofuran; and / or In step 3, the temperature of the deprotection reaction is 50° C. to 70° C.; and / or In step 3, the molar ratio of compound I (2) to acetyl chloride is 1:5 to 1:

7.

5. The method for preparing evokedib according to claim 1, wherein: In step 4, the fourth solvent is at least one of N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide or N-methylpyrrolidone; and / or In step 4, the temperature of the nucleophilic substitution reaction is 15° C. to 40° C.; and / or In step 4, the molar ratio of compound I to ethyl 4-fluoro-3-nitrophenylacetate is 1:1.0 to 1:1.

3.

6. The method for preparing evokedib according to claim 1, wherein: In step 5, the fifth solvent is an ethanol aqueous solution or a methanol aqueous solution; and / or In step 5, the reducing agent is iron powder and ammonium chloride, and the molar ratio of compound II to iron powder and ammonium chloride is 1:4-6:9-11.

7. The method for preparing evokedib according to claim 1, wherein: In step six, the sixth solvent is one or both of methanol and isopropanol; and / or In step 6, the acid solution is a mixed solution of concentrated sulfuric acid and hypophosphorous acid; and / or In step 6, the temperature of the diazotization reaction and the elimination reaction is 10° C. to 50° C.; and / or In step six, the molar ratio of compound III to sodium nitrite is 1:2.0 to 1:4.

0.

8. The method for preparing evokedib according to claim 1, wherein: In step six, the seventh solvent is a methanol aqueous solution or an ethanol aqueous solution; and / or In step six, the temperature of the hydrolysis reaction is 0°C to 100°C.

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