A method for synthesizing a key intermediate, n-methyl-3-hydroxyphenylamine

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a key intermediate N-methyl-3-hydroxyphenylamine, which comprises the following steps: using N-methyl-N-trifluoroacetyl phenylamine as a starting material, esterifying the starting material with a carboxylic acid under the action of an oxidizing agent system, and further hydrolyzing the ester and trifluoroacetyl under alkaline conditions to obtain N-methyl-3-hydroxyphenylamine. Compared with the prior art, the scheme has the characteristics of high product yield, high purity, avoidance of the step of using a reducing agent for carbonyl reduction, and easy separation and purification of the reaction product, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of a key intermediate N-methyl-3-hydroxyphenylalanine. BACKGROUND

[0002] The structural formulas of fluoxetine hydrochloride, tomoxetine hydrochloride and nisoxetine are as follows:

[0003]

[0004] Fluoxetine, tomoxetine and nisoxetine have a 3-aryloxy-3-arylpropylamine structure, and the compounds have activity on the central nervous system, and become the most popular antidepressants due to significant curative effect and few adverse reactions.

[0005] At present, fluoxetine hydrochloride, tomoxetine hydrochloride and nisoxetine are mainly obtained by first obtaining an N-methyl-3-hydroxyphenylalanine intermediate, and then obtaining the intermediate after etherification and separation. The structural formula of the key intermediate N-methyl-3-hydroxyphenylalanine is as follows:

[0006]

[0007] The synthesis methods of the key intermediate N-methyl-3-hydroxyphenylalanine mainly include the following methods:

[0008] Route one: Chinese Journal of Pharmacy, 2010, 45(14): 1104-1106; Guangzhou Chemical Industry, 2015, (22): 51-53, etc.

[0009] Commercial acetophenone is used as a raw material, N-methyl-3-ketophenylalanine is generated through a Mannich reaction, and then N-methyl-3-hydroxyphenylalanine is generated through reduction. However, a large amount of by-products of tertiary Mannich base are generated in the process of generating N-methyl-3-ketophenylalanine through the Mannich reaction, which causes difficulty in separation and purification, and the yield is low, 62%, and the yield in the reduction step is only 42%. The reaction route is as follows:

[0010]

[0011] Route two: Chin. J. Chem, 2011, 29, 504-510; Letters in Drug Design&Discovery, 2011, 8, 268-275; WO2015001565A, etc.

[0012] The route is refluxed for 12 h in the halogen exchange process, which is time-consuming and has a low yield. In addition, the ammination reaction to prepare N-methyl-3-hydroxyphenylamine generates by-products, resulting in low product purity, which is difficult to separate and purify, and increases the cost. Moreover, the low-temperature ammination reaction requires a long time, and the high-temperature ammination reaction requires a high-pressure reaction device, which is not conducive to safe industrial production. Alternatively, WO2015001565A uses 3-chloro-1-phenyl-1-propanone as a starting material, which is directly reacted with an aqueous solution of methylamine after carbonyl reduction. The purity of this step is also low (the actual production yield is less than 85%).

[0013]

[0014] Route three: patent CN103664658A.

[0015] 1-phenyl-2-propyn-1-one is used as a raw material, which is reacted with methylamine and then reduced by two steps to obtain N-methyl-3-hydroxyphenylamine. However, in the reaction of 1-phenyl-2-propyn-1-one with methylamine, the carbonyl group is prone to condensation with the amine group to form an imine, and a by-product of Michael addition is also generated, which further reduces the purity of the product and is not conducive to the separation and purification of the product. In the carbonyl reduction step, Raney Ni is used for reduction, which is not conducive to industrial production. The reaction route is as follows:

[0016]

[0017] Route four: patent CN110194719A.

[0018] 1-phenyl-2-propyn-1-one is used as a raw material, which is reacted with methylamine and then reduced by two steps to obtain N-methyl-3-hydroxyphenylamine. However, in the reaction of 1-phenyl-2-propyn-1-one with methylamine, the carbonyl group is prone to condensation with the amine group to form an imine, and a by-product of Michael addition is also generated, which further reduces the purity of the product and is not conducive to the separation and purification of the product. In the carbonyl reduction step, Raney Ni is used for reduction, which is not conducive to industrial production. The reaction route is as follows:

[0019]

[0020] Through the prior art retrieval and the study of the above-mentioned information, there are some deficiencies in the synthesis of N-methyl-3-hydroxyphenylamine; in order to solve the problems existing in the prior art, the inventors have carried out a series of researches on the synthesis method of N-methyl-3-hydroxyphenylamine. A synthesis process route of N-methyl-3-hydroxyphenylamine is sought, which is simple in operation, relatively mild in reaction condition, high in product yield and purity, and suitable for large-scale industrial production. SUMMARY

[0021] In view of the many problems existing in the synthesis of N-methyl-3-hydroxyphenylamine at present, the present application provides a new synthesis method of N-methyl-3-hydroxyphenylamine. The method is simple in operation, relatively mild in reaction condition, high in product yield and purity.

[0022] The specific technical scheme of the present application is as follows:

[0023] A synthesis method of N-methyl-3-hydroxyphenylamine, specifically comprising the following steps: step 1: compound I, i.e. N-methyl-N-trifluoroacetylphenylamine, is reacted with a carboxylic acid under the action of an oxidation system to generate an ester (compound II), step 2: compound II is hydrolyzed under alkaline conditions to generate N-methyl-3-hydroxyphenylamine (compound III), and the target product is obtained after treatment; the reaction route is as follows:

[0024]

[0025] wherein R is a carboxyl substituent corresponding to the carboxylic acid.

[0026] In the above step 1:

[0027] Preferably, the oxidation system in the step 1 is one of tert-butyl hydroperoxide (TBHP) / tetrabutylammonium iodide, KBrO3 / cerium ammonium nitrate (CAN); further preferably tert-butyl hydroperoxide (TBHP) / tetrabutylammonium iodide. Among them, the tert-butyl hydroperoxide preferably uses 70% tert-butyl hydroperoxide aqueous solution.

[0028] Preferably, the amount of the oxidation system in the step 1 is: the molar ratio of compound I: tert-butyl hydroperoxide (TBHP): tetrabutylammonium iodide is 1:1.0-5.0:0.1-0.5, further preferably 1:2.0:0.2; the molar ratio of compound I: KBrO3: CAN is 1:0.5-2.0:0.1-2.0, further preferably 1:1.0:0.5.

[0029] Preferably, the carboxylic acid in step 1 is one of benzoic acid, acetic acid, propionic acid, n-butyric acid, acrylic acid, p-methylbenzoic acid, m-methylbenzoic acid, phenylpropionic acid, p-methoxybenzoic acid, o-chlorobenzoic acid, p-chlorobenzoic acid, and further preferably benzoic acid. The amount of carboxylic acid used in the step of the present application is sufficient to react with compound I to form an ester.

[0030] Preferably, the amount of carboxylic acid used in step 1 is: the molar ratio of compound I: carboxylic acid is 1:1-10; and further preferably 1:5.

[0031] Preferably, the reaction solvent in step 1 is one or a combination of chloroform, ethyl acetate, and benzene.

[0032] Preferably, the reaction temperature in step 1 is 55-90°C, and further preferably 60-80°C.

[0033] Preferably, the reaction time in step 1 is 5-12h.

[0034] During the reaction process of the present application, thin layer chromatography and HPLC can be used for reaction monitoring.

[0035] Preferably, the post-reaction processing step in step 1 is: after the reaction is completed, saturated NaHCO3 solution is added, and dichloromethane or chloroform is used for extraction, the organic phase is washed and dried, and compound II is obtained by concentrating to dryness.

[0036] During the hydrolysis process in step 2 of the above preparation method:

[0037] Preferably, the base in step 2 is one or a combination of K2CO3, NaOH, and KOH, and further preferably K2CO3.

[0038] Preferably, the amount of base used in step 2 is: the molar ratio of compound II: base is 1:1.0-4.0; the molar ratio of compound II: K2CO3 is further preferably 1:1.5, and the molar ratio of compound II: NaOH or KOH is further preferably 1:2.0.

[0039] Preferably, the hydrolysis reaction solvent in step 2 is one of MeOH / H2O and EtOH / H2O mixed solvents, and further preferably MeOH / H2O.

[0040] Preferably, the volume ratio of alcohol: H2O in step 2 is 1:0.1-10, and further preferably 7:1.

[0041] Preferably, the reaction temperature in step 2 is 0-40°C, and further preferably room temperature, wherein the room temperature in the scheme of the present application refers to 25°C.

[0042] Preferably, the hydrolysis reaction time in step 2 is 0.5-10h.

[0043] In the hydrolysis process of the present application, thin layer chromatography and HPLC can be used for reaction monitoring. After the reaction is completed, a quenching agent is added to quench the reaction, and an extraction agent is used for extraction. After washing, drying, and concentration, the target product is obtained.

[0044] Preferably, the extraction agent is one of ethyl acetate, dichloromethane, and chloroform.

[0045] Preferably, the quenching agent is purified water.

[0046] Compared with the prior art, the present application has the following beneficial effects:

[0047] When the inventors selected an oxidizing agent to oxidize the substrate N-methyl-N-trifluoroacetyl amphetamine to a ketone, they unexpectedly found that an ester was generated, and the yield was high. The inventors further added a base to perform hydrolysis, and obtained the key intermediate N-methyl-3-hydroxy amphetamine.

[0048] Through the method of the present application, N-methyl-N-trifluoroacetyl amphetamine can be used as a starting material, and N-methyl-3-hydroxy amphetamine can be quickly and efficiently obtained through oxidation and hydrolysis. This route has the advantages of high yield, high product purity, few by-products, and easy separation and purification. DETAILED DESCRIPTION

[0049] The present application will be further described below through examples. It should be correctly understood that the examples of the present application are only used to illustrate the present application, and are not a limitation of the present application. Therefore, simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0050] In the following examples, various processes and methods that are not described in detail are conventional methods known in the art.

[0051] Embodiment I

[0052] Example 1

[0053] Step 1: Synthesis of propyl 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)benzoate

[0054] 1L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (6.0 g, 16.3 mmol), TBHP (22.4 mL, 163.2 mmol, 70% aqueous tert-butyl hydroperoxide), benzoic acid (49.8 g, 408.0 mmol), 200 mL of ethyl acetate, and the reaction flask was warmed to 70°C and stirred for 8 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL of saturated NaHCO3solution, extracted with 400 mL of dichloromethane, and the organic phase was washed once with 200 mL of purified water and 200 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 28.4 g of compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate, with a yield of 95.3% and HPLC: 99.2%.

[0055] 1 H-NMR (400 MHz, CDC13) δ: 8.06-7.96 (m, 2H), 7.70-7.50 (m, 3H), 7.35-7.20 (m, 5H), 5.80-5.76 (m, 1H), 3.42 (t, J = 7.4 Hz, 2H), 3.14 (s, 3H), 2.43-2.38 (m, 2H).

[0056] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0057] 1L three-necked flask was charged with compound II (28.4 g, 77.7 mmol), a mixture of MeOH / H2O (400 mL, V MeOH :V H2O = 7:1), K2CO3(16.1 g, 116.6 mmol), and the reaction was stirred at room temperature for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL of purified water, extracted with 400 mL of ethyl acetate, and the organic phase was extracted with 400 mL of saturated NaCl once, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 12.6 g of compound III, N-methyl-3-hydroxyphenylalanine, with a yield of 98.1% and HPLC: 99.4%.

[0058] Example 2

[0059] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate

[0060] 1 L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (3.0 g, 8.2 mmol), TBHP (11.2 mL, 81.6 mmol, 70% aqueous solution of tert-butyl hydroperoxide), benzoic acid (49.8 g, 408.0 mmol), 200 mL of ethyl acetate, and the reaction flask was warmed to 77.0 °C and stirred for 9 hours. TLC and HPLC were used to monitor the reaction until it was complete. Then, 400 mL of saturated NaHCO3 solution was added to quench the reaction, and the reaction mixture was extracted with 400 mL of dichloromethane. The organic phase was washed once with 200 mL of purified water and 200 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 27.8 g of compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate, in a yield of 93.3%, HPLC: 98.6%.

[0061] 1 H-NMR (400 MHz, CDC13) data was consistent with that of Example 1 in Embodiment One.

[0062] Step 2: Synthesis of N-methyl-3-hydroxyphenylpropylamine

[0063] 1 L three-necked flask was charged with compound II (27.5 g, 75.3 mmol), a mixture of MeOH / H2O (400 mL, V MeOH :V H2O = 7:1), K2CO3 (15.6 g, 113.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. Then, 400 mL of purified water was added to quench the reaction, and the reaction mixture was extracted with 400 mL of ethyl acetate. The aqueous phase was extracted with 400 mL of ethyl acetate twice, and the organic phase was combined. The organic phase was washed once with 400 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 12.2 g of compound III, N-methyl-3-hydroxyphenylpropylamine, in a yield of 98.1%, HPLC: 99.5%.

[0064] Example 3

[0065] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate

[0066] 1 L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (15.1 g, 40.8 mmol), TBHP (56.0 mL, 408.0 mmol, 70% aqueous tert-butyl hydroperoxide), benzoic acid (49.8 g, 408.0 mmol), 200 mL chloroform, and the reaction flask was warmed to 55 °C and stirred for 7 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL saturated NaHCO3solution, and extracted with 400 mL dichloromethane. The organic phase was washed once with 200 mL purified water and 200 mL saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide)benzoic acid propyl ester, 27.4 g, yield 92.0%, HPLC: 98.3%.

[0067] 1 H-NMR (400 MHz, CDC13) data was consistent with Example 1 in the first embodiment.

[0068] Step 2: Synthesis of N-methyl-3-hydroxyphenylpropylamine

[0069] 1 L three-necked flask was charged with compound II (27.2 g, 74.5 mmol), MeOH / H2O mixture solution (400 mL, V MeOH :V H2O = 7:1), K2CO3(16.1 g, 116.6 mmol), and the reaction was stirred at 0 °C for 4 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL purified water, extracted with 400 mL ethyl acetate, and the aqueous phase was extracted with 400 mL ethyl acetate twice. The organic phase was washed once with 400 mL saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 12.0 g of compound III, N-methyl-3-hydroxyphenylpropylamine, yield 97.5%, HPLC: 99.1%.

[0070] Example 4

[0071] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide)benzoic acid propyl ester

[0072] 1L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (6.0 g, 16.3 mmol), TBHP (22.4 mL, 163.2 mmol, 70% aqueous solution of tert-butyl hydroperoxide), benzoic acid (10.0 g, 81.6 mmol), 200 mL of benzene, and the reaction flask was warmed to 80°C and stirred for 8 hours. The reaction was monitored by TLC and HPLC until completion. The reaction was quenched by adding 400 mL of saturated NaHCO3solution, and extracted with 400 mL of dichloromethane. The organic phase was washed once with 200 mL of purified water and 200 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 26.9 g of compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate, in a yield of 90.3%, HPLC: 98.7%.

[0073] 1 H-NMR (400 MHz, CDC13) data was consistent with that of Example 1 in the first embodiment.

[0074] Step 2: Synthesis of N-methyl-3-hydroxyphenylpropylamine

[0075] 1L three-necked flask was charged with compound II (26.0 g, 71.2 mmol), a mixture of MeOH / H2O (400 mL, V MeOH :V H2O = 7:1), K2CO3(9.8 g, 71.2 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was monitored by TLC and HPLC until completion. The reaction was quenched by adding 400 mL of purified water, and extracted with 400 mL of ethyl acetate. The aqueous phase was extracted with 400 mL of ethyl acetate twice, and the organic phase was combined. The organic phase was washed once with 400 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 11.4 g of compound III, N-methyl-3-hydroxyphenylpropylamine, in a yield of 97.0%, HPLC: 99.2%.

[0076] Example 5

[0077] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate

[0078] 1 L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (6.0 g, 16.3 mmol), TBHP (22.4 mL, 163.2 mmol, 70% aqueous tert-butyl hydroperoxide), benzoic acid (99.6 g, 816 mmol), 200 mL ethyl acetate, and the reaction flask was warmed to 80 °C and stirred for 8 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 800 mL saturated NaHCO3solution, and extracted with 400 mL dichloromethane. The organic phase was washed once with 200 mL purified water and 200 mL saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide)benzoic acid propyl ester, 28.3 g, yield 95.0%, HPLC: 98.9%.

[0079] 1 H-NMR (400 MHz, CDC13) data was consistent with Example 1 in the first embodiment.

[0080] Step 2: Synthesis of N-methyl-3-hydroxyphenylpropylamine

[0081] 1 L three-necked flask was charged with compound II (28.0 g, 76.7 mmol), a mixture of MeOH / H2O (400 mL, V MeOH :V H2O = 7:1), K2CO3(42.4 g, 306.8 mmol), and the reaction was stirred at 40 °C for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 600 mL purified water, and extracted with 400 mL ethyl acetate. The aqueous phase was extracted with 400 mL ethyl acetate twice, and the organic phase was washed once with 400 mL saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 12.2 g of compound III, N-methyl-3-hydroxyphenylpropylamine, yield 96.4%, HPLC: 98.5%.

[0082] Example 6

[0083] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide)benzoic acid propyl ester

[0084] Into a 500 mL three-necked flask, compound I (20 g, 81.6 mmol), KBrO3(10.2 g, 61.2 mmol), CAN (2.2 g, 4.1 mmol), benzoic acid (49.8 g, 408.0 mmol), 200 mL ethyl acetate were added successively, the reaction flask was heated to 77 °C and stirred for 8 hours, then TLC and HPLC were used to monitor the reaction until it was completed. Then 400 mL saturated NaHCO3solution was added to quench the reaction, and the reaction mixture was extracted with 400 mL dichloromethane. The organic phase was washed with 200 mL purified water and 200 mL saturated NaCl once respectively, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound II 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate 28.8 g, with a yield of 96.6%, HPLC: 98.5%.

[0085] 1 H-NMR (400 MHz, CDCl3) data was consistent with that of Example 1 in Embodiment One.

[0086] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0087] Into a 1 L three-necked flask, compound II (28.8 g, 78.8 mmol), a mixed solution of MeOH / H2O (400 mL, V MeOH : V H2O = 7:1), NaOH (7.9 g, 197 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours, then TLC and HPLC were used to monitor the reaction until it was completed. Then 400 mL purified water was added to quench the reaction, and the reaction mixture was extracted with 400 mL ethyl acetate. The aqueous phase was extracted with 400 mL ethyl acetate twice, and then the organic phase was washed with 400 mL saturated NaCl once, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound III N-methyl-3-hydroxyphenylalanine 12.4 g, with a yield of 95.2%, HPLC: 99.2%.

[0088] Embodiment Two

[0089] Example 1

[0090] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl benzoate

[0091] 1 L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (6.0 g, 16.3 mmol), TBHP (22.4 mL, 163.2 mmol, 70% aqueous solution of tert-butyl hydroperoxide), acetic acid (24.5 g, 408 mmol), 200 mL of ethyl acetate, and the reaction flask was warmed to 70 °C and stirred for 8 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched with 400 mL of saturated NaHCO3solution, and then extracted with 400 mL of dichloromethane. The organic phase was washed once with 200 mL of purified water and 200 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl acetate, 23.3 g, in a yield of 94.2%, HPLC: 98.3%.

[0092] 1 H-NMR (400 MHz, CDC13) δ: 7.32-7.25 (m, 5H), 5.83-5.79 (m, 1H), 3.37 (t, J = 7.4 Hz, 2H), 3.04 (s, 3H), 2.30-2.24 (m, 2H), 2.14 (s, 3H).

[0093] Step 2: Synthesis of N-methyl-3-hydroxyphenylpropylamine

[0094] 1 L three-necked flask was charged with compound II (23.3 g, 76.9 mmol), a mixture of MeOH / H2O (400 mL, V MeOH : V H2O = 7:1), K2CO3(15.9 g, 115.4 mmol), and the reaction was stirred at room temperature for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched with 400 mL of purified water, extracted with 400 mL of ethyl acetate, and the aqueous phase was extracted with 400 mL of ethyl acetate twice. The organic phase was washed once with 400 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound III, N-methyl-3-hydroxyphenylpropylamine, 12.1 g, in a yield of 95.3%, HPLC: 98.2%.

[0095] Example 2

[0096] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl acetate

[0097] A 500 mL three-necked flask was charged with compound I (20 g, 81.6 mmol), KBrO3(10.2 g, 61.2 mmol), CAN (2.2 g, 4.1 mmol), acetic acid (24.5 g, 408 mmol), and 200 mL of ethyl acetate. The reaction flask was heated to 70°C and stirred for 8 hours. TLC and HPLC were used to monitor the reaction until it was complete. Then, 400 mL of saturated NaHCO3solution was added to quench the reaction. The reaction mixture was extracted with 400 mL of dichloromethane. The organic phase was washed with 200 mL of purified water and 200 mL of saturated NaCl once, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl acetate, 23.4 g, in a yield of 94.7%, HPLC: 98.6%.

[0098] 1 H-NMR (400 MHz, CDCl3) data was consistent with that of Example 1 in Embodiment Two.

[0099] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0100] A 500 mL three-necked flask was charged with compound II (23.4 g, 77.3 mmol), a mixture of MeOH / H2O (400 mL, V MeOH : V H2O = 7:1), and KOH (10.8 g, 193.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. Then, 400 mL of purified water was added to quench the reaction. The reaction mixture was extracted with 400 mL of ethyl acetate. The aqueous phase was extracted with 400 mL of ethyl acetate twice. The organic phase was washed with 400 mL of saturated NaCl once, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound III, N-methyl-3-hydroxyphenylalanine, 12.1 g, in a yield of 94.9%, HPLC: 98.0%.

[0101] Embodiment Three

[0102] Example 1

[0103] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl acetate

[0104] 1 L three-necked flask was charged with compound I (20 g, 81.6 mmol), tetrabutylammonium iodide (6.0 g, 16.3 mmol), TBHP (22.4 mL, 163.2 mmol, 70% aqueous solution of tert-butyl hydroperoxide), propionic acid (119.6 mL, 1.6 mol), 200 mL of chloroform, and the reaction flask was warmed to 60 °C and stirred for 8 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL of saturated NaHCO3solution, extracted with 400 mL of dichloromethane, and the organic phase was washed once with 200 mL of purified water and 200 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl propionate, 23.9 g, yield 92.3%, HPLC: 97.6%.

[0105] 1 H-NMR (400 MHz, CDC13) δ: 7.34-7.26 (m, 5H), 5.88-5.782 (m, 1H), 3.32 (t, J = 7.4 Hz, 2H), 2.96 (s, 3H), 2.32-2.22 (m, 4H), 1.22 (t, J = 7.6 Hz, 3H).

[0106] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0107] 1 L three-necked flask was charged with compound II (23.9 g, 75.3 mmol), a mixture of MeOH / H2O (400 mL, V MeOH :V H2O = 7:1), K2CO3(15.6 g, 113.0 mmol), and the reaction was stirred at room temperature for 2 hours. TLC and HPLC were used to monitor the reaction until it was complete. The reaction was quenched by adding 400 mL of purified water, extracted with 400 mL of ethyl acetate, and the aqueous phase was extracted with 400 mL of ethyl acetate twice, and the organic phase was washed once with 400 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give compound III, N-methyl-3-hydroxyphenylalanine, 11.6 g, yield 93.4%, HPLC: 96.3%.

[0108] Example 2

[0109] Step 1: Synthesis of 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl propionate

[0110] Into a 500 mL three-necked flask, compound I (20 g, 81.6 mmol), KBrO3(10.2 g, 61.2 mmol), CAN (2.2 g, 4.1 mmol), propionic acid (30.2 g, 408 mmol), 200 mL ethyl acetate were added successively, the reaction flask was heated to 70 °C and stirred for 8 hours, then TLC and HPLC were used to monitor the reaction until it was completed. Then 400 mL saturated NaHCO3solution was added to quench the reaction, and the reaction mixture was extracted with 400 mL dichloromethane. The organic phase was washed with 200 mL purified water and 200 mL saturated NaCl once respectively, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound II, 1-phenyl-3-(2,2,2-trifluoro-N-methylacetamide) propyl propionate, 24.2 g, yield 93.5%, HPLC: 97.9%.

[0111] 1 H-NMR (400 MHz, CDCl3) data was consistent with that of Example 1 in Embodiment Three.

[0112] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0113] Into a 500 mL three-necked flask, compound II (24.2 g, 76.3 mmol), a mixture of EtOH / H2O (400 mL, V EtOH :V H2O = 7:1), NaOH (6.1 g, 152.5 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours, then TLC and HPLC were used to monitor the reaction until it was completed. Then 400 mL purified water was added to quench the reaction, and the reaction mixture was extracted with 400 mL ethyl acetate. The aqueous phase was extracted with 400 mL ethyl acetate twice, and then the organic phase was washed with 400 mL saturated NaCl once, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound III, N-methyl-3-hydroxyphenylalanine, 11.8 g, yield 93.7%, HPLC: 96.2%.

[0114] Embodiment Four

[0115] Example 1

[0116] Step 1:

[0117] The substrate benzoic acid in Example 1, Step 1 of Embodiment One was replaced with p-tolyl benzoic acid to obtain the corresponding compound II, yield 91.8%, HPLC: 99.0%.

[0118] Step 2: Synthesis of N-methyl-3-hydroxyphenylalanine

[0119] The product from Step 1 above was hydrolyzed using the procedure of Example 1, Step 2, to give N-methyl-3-hydroxyphenylalanine in 95.2% yield, HPLC: 99.2%.

Claims

1. A key intermediate N - a process for the synthesis of methy!-3-hydroxyphenylamine, characterized in that, Specifically, it includes the following steps: Step 1: Compound I, i.e. N -methyl- N - Trifluoroacetylphenylpropanol reacts with carboxylic acid in an oxidizing system to form an ester, namely compound II. Step 2: Compound II is hydrolyzed under alkaline conditions to produce... N- Methyl-3-hydroxypropylamine, i.e., compound III, was post-processed to obtain the target product; the reaction route is as follows: ； The carboxylic acid is RCOOH, and the RCOOH is one of benzoic acid, acetic acid, propionic acid, and p-methylbenzoic acid; The oxidation system in step 1 is one of t-butyl hydroperoxide / tetrabutylammonium iodide and KBrO3 / cerium ammonium nitrate; The amount of the oxidation system in step 1 is as follows: the molar ratio of compound I:t-butyl hydroperoxide:tetrabutylammonium iodide is 1:1.0-5.0:0.1-0.5; The molar ratio of compound I:KBrO3:cerium ammonium nitrate is 1:0.5-2.0:0.1-2.0; The reaction temperature in step 1 is 55-90 DEG C; The base in step 2 is one or a combination of K2CO3, NaOH and KOH; The hydrolysis reaction solvent in step 2 is one of MeOH / H2O and EtOH / H2O mixed solvents; The reaction temperature in step 2 is 0-40 DEG C.

2. The method of synthesis of claim 1, wherein, The RCOOH in step 1 is benzoic acid.

3. The method of synthesis of claim 1, wherein, The reaction solvent in step 1 is one or a combination of chloroform, ethyl acetate and benzene.

4. The method of synthesis of claim 1, wherein, The reaction temperature in step 1 is 60-80 DEG C.

5. The method of synthesis of claim 1, wherein, The base in step 2 is K2CO3.

6. The method of synthesis of claim 1, wherein, The amount of the base in step 2 is as follows: the molar ratio of compound II:base is 1:1.0-4.

0.

7. The method of synthesis of claim 1, wherein, The reaction temperature in step 2 is 25 DEG C.

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