A process for the preparation of N-methyl-3-hydroxyphenylamine

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of N-methyl-3-hydroxyphenylalanine, which comprises the following steps: using N-methyl phenylalanine as a starting material, and oxidizing a benzene ring benzyl methylene under the action of CeO2 to obtain a compound II; and reducing the compound II by a reducing agent to obtain N-methyl-3-hydroxyphenylalanine. Compared with the prior art, the scheme has the characteristics of high product yield, high purity and easy separation and purification, and can effectively reduce the production cost and improve the efficiency, so that the scheme has a good application prospect and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of N-methyl-3-hydroxyphenylpropylamine. BACKGROUND

[0002] Some compounds with the structure of 3-aryloxy-3-arylpropylamine have activity on the central nervous system, such as fluoxetine, tomoxetine and nisoxetine, etc. Because of significant curative effect and less adverse reactions, they have become the most popular antidepressants.

[0003] Fluoxetine hydrochloride, the chemical name of which is N-methyl-3-(4-trifluoromethylphenyl)-3-phenyl-1-propanamine hydrochloride, is a new type of antidepressant developed by Lilly Company of the United States, and is commercially available as Prozac. It was listed in the United States in 1988. In addition, it can also be used for the treatment of obsessive-compulsive disorder, panic disorder, binge eating disorder and premenstrual dysphoric disorder. Fluoxetine is the first selective serotonin reuptake inhibitor (SSRI) listed in the United States, which can increase the concentration of 5-hydroxytryptamine in the synaptic cleft, thereby improving the mood of patients. Compared with tricyclic antidepressants, fluoxetine shows stronger efficacy, less anti-M cholinergic receptor side effects and less cardiotoxicity. The listing of fluoxetine is a major breakthrough in the history of depression treatment.

[0004] Atomoxetine hydrochloride, the chemical name of which is (R)-N-methyl-3-(2-methylphenoxy)-3-phenyl-1-propanamine hydrochloride, is a drug molecule developed by Lilly Company for treating attention deficit hyperactivity disorder (ADHD) in children and adolescents. It has been approved by the US FDA for listing on November 26, 2002. Atomoxetine hydrochloride is a highly selective norepinephrine reuptake inhibitor (SNRI), which can bind to and inhibit the reuptake of norepinephrine (NE) on the presynaptic membrane with high selectivity. At present, the drug has been recommended as a first-line drug for the treatment of ADHD, and has a broad market prospect.

[0005] Nisoxetine is a selective norepinephrine reuptake inhibitor (SNRI) developed in the 1970s. It was initially studied as an antidepressant, but it has no other clinical applications except as a standard SNRI for research. It has been used to study obesity and energy balance, and has played some local analgesic effect.

[0006] The structural formulas of fluoxetine hydrochloride, atomoxetine hydrochloride and nisoxetine are as follows:

[0007]

[0008] The preparation of fluoxetine hydrochloride is disclosed in patents GB 2060618, US 5,166,437, US 5,225,585, WO 94 / 00416: fluoxetine is prepared by reacting N-methyl-3-hydroxyphenylamine with p-fluoro (or chloro) trifluoromethylbenzene in NaH, DMSO at high temperature. A method for the synthesis of fluoxetine hydrochloride is disclosed in Synthetic Chemistry, 2008, Vol. 16, No. 3, p354-355 (Sun Wenqian, Li Aijun et al.): 3-methylamino-1-phenylpropanone hydrochloride is prepared by Mannich reaction of acetophenone with methylamine hydrochloride and paraformaldehyde, and then 3-methylamino-1-phenylpropanol is prepared by using potassium borohydride as a reducing agent in methanol, and fluoxetine hydrochloride is synthesized by etherification and salification, and part of the reaction route is as follows:

[0009]

[0010] The preparation of nisoxetine is disclosed in patent CN 1891682A: nisoxetine is prepared by using N-methyl-3-hydroxyphenylamine as a raw material, and reacting at 100℃ for 12 hours in KOH, DMSO, and the reaction route is as follows:

[0011]

[0012] At present, there are many methods for the preparation of tomoxetine hydrochloride, which can be mainly divided into chemical synthesis and biological synthesis, and the chemical synthesis can be further divided into racemate resolution and asymmetric synthesis. Biological synthesis is to obtain chiral benzyl alcohol by lipase resolution, whole cell transformation and other methods, and then to obtain by etherification or other chemical methods. However, biological synthesis is still in the basic research stage, and there are still many problems to be solved in large-scale industrial production; in the chemical synthesis, asymmetric synthesis method has some problems such as expensive chiral catalyst and exceeding of isomer impurities due to racemization of part of the products, which makes this method still have some deficiencies in industrial production. Therefore, the method of chiral resolution is still the main way to obtain the drug molecules on a large scale at present.

[0013] At present, the methods for preparing tomoxetine hydrochloride from the key intermediate N-methyl-3-hydroxyphenylamine mainly include the following:

[0014] Route one: Chin. J. Chem, 2011, 29, 504-510; Letters in Drug Design & Discovery, 2011, 8, 268-275, etc.

[0015] The route is as follows: Route 1: Chinese Journal of Pharmaceuticals, 2010, 45(14): 1104-1106; Guangzhou Chemical Industry, 2015, (22): 51-53, etc.

[0016]

[0017] Route 2: Chinese Journal of Pharmaceuticals, 2010, 45(14): 1104-1106; Guangzhou Chemical Industry, 2015, (22): 51-53, etc.

[0018] The route is as follows: Route 1: Chinese Journal of Pharmaceuticals, 2010, 45(14): 1104-1106; Guangzhou Chemical Industry, 2015, (22): 51-53, etc.

[0019]

[0020] Route 3: Chinese Patent CN103664658A.

[0021] The route is as follows: Route 1: Chinese Journal of Pharmaceuticals, 2010, 45(14): 1104-1106; Guangzhou Chemical Industry, 2015, (22): 51-53, etc.

[0022]

[0023] Route 4: Chinese Patent CN110194719A.

[0024] N-methyl-3-hydroxyphenylalanine is obtained by Michael addition reaction of 1-phenyl-2-propenyl-1-ketone with methylamine, and then reduction with sodium borohydride, and then etherification and resolution. However, 1-phenyl-2-propenyl-1-ketone is prone to condensation to form imine in the reaction with methylamine, and then reduction with sodium borohydride to form impurities, resulting in reduced purity of the product, which is not conducive to the separation and purification of the product, and the reaction route is as follows:

[0025]

[0026] It can be seen that the main way to obtain fluoxetine hydrochloride, tomoxetine hydrochloride and nisoxetine is to first obtain the N-methyl-3-hydroxyphenylalanine intermediate, and then to obtain it by etherification and resolution. The structural formula of the key intermediate N-methyl-3-hydroxyphenylalanine is as follows:

[0027]

[0028] Through the research on the prior art and the above information, there are some deficiencies in the preparation of N-methyl-3-hydroxyphenylalanine, therefore, it is of great significance to study a new synthetic process of N-methyl-3-hydroxyphenylalanine which is simple in operation, relatively mild in reaction conditions, high in product yield and purity, and suitable for large-scale industrial production, for reducing the production cost of fluoxetine, tomoxetine and nisoxetine, expanding the source of them, and further developing and tapping the medical potential of these drug molecules. SUMMARY

[0029] In view of the many problems existing in the preparation of N-methyl-3-hydroxyphenylalanine at present, the present application provides a new preparation method of N-methyl-3-hydroxyphenylalanine. The method is simple in operation, relatively mild in reaction conditions, and high in product yield and purity.

[0030] The specific technical scheme of the present application is as follows:

[0031] A preparation method of N-methyl-3-hydroxyphenylalanine, specifically comprising the following steps: step 1: compound I, i.e. N-methylphenylalanine, is oxidized with an oxidizing agent under the action of a catalyst, and compound II is obtained after treatment; step 2: compound II is reduced to form N-methyl-3-hydroxyphenylalanine (compound III) under the action of a reducing agent, and the target product is obtained after treatment; the reaction route is as follows:

[0032]

[0033] In the above step 1 oxidation process:

[0034] Preferably, the oxidizing agent in step 1 is one of KBrO3 and KMnO4.

[0035] Preferably, the amount of oxidant used in step 1 is: the molar ratio of compound I: KBrO3 is 1:1.0-2.0, further preferably 1:1.0; the molar ratio of compound I: KMnO4 is 1:3.0-8.0, further preferably 1:5.0.

[0036] Preferably, the catalyst in step 1 is CeO2, and the amount used is: the molar ratio of compound I: CeO2 is 1:0.001-0.01, further preferably 1:0.003.

[0037] Preferably, the reaction solvent in step 1 is an H2O / organic solvent / acetic acid mixed solvent, and the corresponding volume ratio of H2O / organic solvent / acetic acid is 1:0-1:0.1-1, preferably the volume ratio of the solvents is 1:0.2:0.2; the organic solvent is one of 1,4-dioxane, DMF, and DMSO; and the preferred solvent is an H2O / 1,4-dioxane / acetic acid mixed solvent.

[0038] Preferably, the reaction temperature in step 1 is 70-110°C, further preferably 90-95°C.

[0039] During the oxidation process, thin layer chromatography (TLC) and HPLC can be used for reaction monitoring.

[0040] Preferably, the post-reaction treatment step after step 1 is: after the reaction is completed, filtration is performed, extraction is performed with dichloromethane or chloroform, the organic phase is washed and dried, and compound II is obtained by concentrating to dryness.

[0041] During the reduction process in step 2 of the above preparation method:

[0042] Preferably, the reducing agent in step 2 is one of LiAlH4, red aluminum, borane dimethyl sulfide, NaBH4-AlCl3, and DIBAL-H, further preferably LiAlH4.

[0043] Preferably, the amount of reducing agent used in step 2 is: the molar ratio of compound II: reducing agent is 1:3.0-6.0.

[0044] Preferably, the solvent for the reduction reaction in step 2 is one or more of tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, toluene, methanol, and 1,4-dioxane, further preferably tetrahydrofuran.

[0045] Preferably, the temperature for the reduction reaction in step 2 is 0-100°C, further preferably 25-70°C.

[0046] Preferably, the reaction time for the reduction reaction in step 2 is 0.5-10h, further preferably 4-6h.

[0047] The present application can adopt thin layer chromatography and HPLC to monitor the reaction during the reduction process, and after the reaction is completed, a quenching agent is added to quench the reaction, filtration is performed, the filtrate is extracted with an extraction agent, and after washing, drying and concentration, the target product is obtained.

[0048] Preferably, the extraction agent is one of ethyl acetate, dichloromethane and chloroform.

[0049] In a preferred embodiment, the quenching agent is a sodium hydroxide aqueous solution, preferably 1-5 mol / L.

[0050] In another preferred embodiment, the quenching agent is a potassium sodium tartrate solution.

[0051] Compared with the prior art, the present application has the following beneficial effects:

[0052] By the method of the present application, N-methyl-3-hydroxyphenylamine can be quickly and efficiently obtained from N-methyl phenylalanine as a starting material through oxidation and reduction, and the route has the advantages of high yield, high product purity, less by-products, easy separation and purification, etc. DETAILED DESCRIPTION

[0053] The present application will be further described by the following examples, which should be correctly understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that the simple improvement of the present application under the premise of the method of the present application is within the scope of the present application.

[0054] In the following examples, various processes and methods not described in detail are conventional methods known in the art.

[0055] Example 1

[0056] A 500ml three-necked flask was sequentially added KBrO3(10.2g, 61.3mmol), a mixed solution of H2O / 1,4-dioxane / glacial acetic acid (V H2O :V 1,4-二氧六环 :V 冰乙酸 =1:0.2:0.2, 184ml), cerium dioxide (31.7mg, 0.18mmol), and stirred at room temperature for 5 minutes, then compound I (10.0g, 61.3mmol) was added to the reaction flask and heated to 95℃ and stirred for 1 hour, then thin layer chromatography and HPLC were used to monitor the reaction until the reaction was completed, filtration was performed, the filtrate was extracted with dichloromethane 200ml x 3, and then the organic phase was washed with 200ml saturated NaHCO3 solution once, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound II, with a yield of 97.2%, HPLC: 99.3%.

[0057] Example 2

[0058] 500ml three-necked flask was added KBrO3(20.5g, 122.6mmol), a mixture of H2O / DMF / ice acetic acid (V H2O :V DMF :V 冰乙酸 =1:0.2:0.2, 184ml), cerium dioxide (31.7mg, 0.18mmol) and stirred for 5 minutes at room temperature. Compound I (10.0g, 61.3mmol) was added to the flask and stirred for 1 hour at 95°C. The reaction was monitored by TLC and HPLC until it was completed. The filtrate was extracted with dichloromethane (200ml x 3) and the organic phase was washed with 200ml saturated NaHCO3solution once and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give compound II with a yield of 94.1% and HPLC: 97.7%.

[0059] Example 3

[0060] 500ml three-necked flask was added KBrO3(9.7g, 58.2mmol), a mixture of H2O / DMF / ice acetic acid (V H2O :V DMF :V 冰乙酸 =1:0.2:0.2, 184ml), cerium dioxide (31.7mg, 0.18mmol) and stirred for 5 minutes at room temperature. Compound I (10.0g, 61.3mmol) was added to the flask and stirred for 1 hour at 95°C. The reaction was monitored by TLC and HPLC until it was completed. The filtrate was extracted with dichloromethane (200ml x 3) and the organic phase was washed with 200ml saturated NaHCO3solution once and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give compound II with a yield of 89.0% and HPLC: 98.7%.

[0061] Example 4

[0062] 500ml three-necked flask was added KBrO3(10.2g, 61.3mmol), a mixture of H2O / DMSO / ice acetic acid (V H2O :V DMSO :V 冰乙酸= 1 : 1 : 1, 184 ml), cerium dioxide (105.5 mg, 0.61 mmol) after stirring for 5 minutes at room temperature, compound I (10.0 g, 61.3 mmol) was added to the reaction bottle and stirred for 1 hour after warming to 70°C, reaction monitoring began to be performed using thin layer chromatography and HPLC until the reaction was complete, suction filtration was performed, the filtrate was extracted with dichloromethane 200 ml x 3, the organic phase was combined, the organic phase was washed once with 200 ml of saturated NaHCO3solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound II, the yield was 95.9%, HPLC: 98.3%.

[0063] Example 5

[0064] 500 ml of a three-necked bottle were sequentially added KBrO3(10.2 g, 61.3 mmol), a mixed solution of H2O / 1,4-dioxane / ice acetic acid (V H2O :V 1,4-二氧六环 :V 冰乙酸 = 1 : 1 : 1, 184 ml), cerium dioxide (105.5 mg, 0.61 mmol) after stirring for 5 minutes at room temperature, compound I (10.0 g, 61.3 mmol) was added to the reaction bottle and stirred for 1 hour after warming to 70°C, reaction monitoring began to be performed using thin layer chromatography and HPLC until the reaction was complete, suction filtration was performed, the filtrate was extracted with dichloromethane 200 ml x 3, the organic phase was combined, the organic phase was washed once with 200 ml of saturated NaHCO3solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound II, the yield was 95.9%, HPLC: 98.3%.

[0065] Example 6

[0066] 500 ml of a three-necked bottle were sequentially added KMnO4(48.4 g, 306.3 mmol), a mixed solution of H2O / 1,4-dioxane / ice acetic acid (V H2O :V 1,4-二氧六环 :V 冰乙酸 = 1 : 1 : 1, 184 ml), cerium dioxide (105.5 mg, 0.61 mmol) after stirring for 5 minutes at room temperature, compound I (10.0 g, 61.3 mmol) was added to the reaction bottle and stirred for 1 hour after warming to 70°C, reaction monitoring began to be performed using thin layer chromatography and HPLC until the reaction was complete, suction filtration was performed, the filtrate was extracted with dichloromethane 200 ml x 3, the organic phase was combined, the organic phase was washed once with 200 ml of saturated NaHCO3solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound II, the yield was 95.9%, HPLC: 98.3%.

[0067] Example 7

[0068] A 500ml flask was charged with KMnO4(29.0g, 183.8mmol), H2O / ice acetic acid (V H2O :V 冰乙酸 =1:0.2, 184ml), cerium dioxide (31.7mg, 0.18mmol) and stirred for 5 minutes at room temperature. Compound I (10.0g, 61.3mmol) was added to the flask and stirred for 1 hour at 100°C. The reaction was monitored by TLC and HPLC until completion. The reaction was filtered and the filtrate was extracted with 200ml x 3 dichloromethane. The organic phase was washed once with 200ml saturated NaHCO3solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give compound II in 92.1% yield, HPLC: 98.2%.

[0069] Example 8

[0070] A 500ml flask was charged with KMnO4(77.5g, 490.4mmol), H2O / DMSO / ice acetic acid (V H2O :V DMSO :V 冰乙酸 =1:0.2:0.2, 184ml), cerium dioxide (31.7mg, 0.18mmol) and stirred for 5 minutes at room temperature. Compound I (10.0g, 61.3mmol) was added to the flask and stirred for 1 hour at 70°C. The reaction was monitored by TLC and HPLC until completion. The reaction was filtered and the filtrate was extracted with 200ml x 3 dichloromethane. The organic phase was washed once with 200ml saturated NaHCO3solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give compound II in 94.2% yield, HPLC: 97.6%.

[0071] Example 9

[0072] A 250ml flask was charged with compound II (10.3g, 58.1mmol) and dissolved in 100ml tetrahydrofuran. Lithium aluminum hydride (6.6g, 174.4mmol) was added portionwise. The reaction was stirred for 6 hours at 68°C. The reaction was monitored by TLC and HPLC until completion. The reaction was quenched by adding 10ml 1mol / L NaOH solution in an ice water bath. The suspension was filtered through celite and the filter cake was washed with 50ml tetrahydrofuran. The filtrate was extracted with 200ml x 3 dichloromethane after adding 100ml saturated ammonium chloride solution. The organic phase was washed until pH=8.0 with saturated NaCl solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound III in 95.7% yield, HPLC: 98.5%.

[0073] Example 10

[0074] Into a 250ml three-necked flask, compound II (10.3g, 58.1mmol) was dissolved in 100ml tetrahydrofuran under argon protection, then lithium aluminum hydride (13.2g, 348.8mmol) was added portionwise, the reaction was heated to 68℃ and stirred for 4 hours, TLC and HPLC were used to monitor the reaction, the reaction was complete, the reaction solution was moved into an ice water bath, 20ml 1mol / L NaOH solution was added to quench the reaction, the suspension was filtered through celite, the filter cake was washed with 100ml tetrahydrofuran, the filtrate was added with 100ml saturated ammonium chloride solution, then extracted with 200ml dichloromethane for 3 times, the organic phase was combined, washed with saturated NaCl solution until pH=8.0, the organic phase was dried over anhydrous sodium sulfate, concentrated to give compound III, yield: 93.4%, HPLC: 97.7%.

[0075] Example 11

[0076] Into a 500ml three-necked flask, compound II (10.6g, 59.8mmol) was dissolved in 100ml tetrahydrofuran under argon protection, then the reaction was cooled to 0℃ and stirred, 86.4g red aluminum toluene solution (70% toluene solution, 299.1mmol) was added dropwise, after the addition was completed, the reaction was heated to 45℃ and stirred for 6 hours, TLC and HPLC were used to monitor the reaction, the reaction was complete, the reaction solution was cooled to 0℃ and 200ml 1mol / L NaOH solution was added dropwise to quench the reaction, after the addition was completed, the reaction solution was stirred at room temperature for 1 hour, filtered, the filtrate was allowed to stand and separated, the aqueous phase was extracted with 200ml ethyl acetate for 3 times, the organic phase was combined, washed with saturated NaCl solution until pH=8.0, the organic phase was dried over anhydrous sodium sulfate, concentrated to give compound III, yield: 89.5%, HPLC: 98.2%.

[0077] Example 12

[0078] Into a 500ml three-necked flask, compound II (10.2g, 57.6mmol) was dissolved in 100ml tetrahydrofuran under argon protection, then borane dimethyl sulfide complex (21.9g, 287.8mmol) was added dropwise, the reaction was heated to 68℃ and stirred for 5 hours, TLC and HPLC were used to monitor the reaction, the reaction was complete, the reaction solution was cooled to 0℃ and stirred, 100ml tetrahydrofuran and water mixed solvent (V 四氢呋喃 :V 水= 1 : 1) 200 ml of 5 mol / L NaOH solution was added to quench the reaction, filtered, and the aqueous phase was extracted with 200 ml of ethyl acetate three times. The combined organic phase was washed with saturated NaCl solution until pH = 8.0, dried over anhydrous sodium sulfate, and concentrated to obtain compound III, yield: 87.9%, HPLC: 98.0%.

[0079] Example 13

[0080] Compound II (10.4 g, 58.7 mmol) was added to a 250 ml three-necked flask, and dissolved in 100 ml of ethylene glycol dimethyl ether under argon protection. After 31.3 g of AICI3(234.8 mmol) was added to the reaction solution, it was stirred at room temperature for half an hour. Then 8.9 g of NaBH4(234.8 mmol) was added in batches within half an hour, and stirred at room temperature for 6 hours. The reaction was monitored by thin layer chromatography and HPLC. After the reaction was completed, the temperature was lowered to 0°C, 100 ml of ice water was added, and 1 mol / L NaOH solution was added to the reaction solution to adjust the pH to about 8.5 to quench the reaction. Then 100 ml of ethyl acetate was added to the reaction solution, and filtered. The filter cake was washed with 50 ml of ethyl acetate, and the filtrate was separated. The aqueous phase was extracted with 200 ml of ethyl acetate three times, and the combined organic phase was washed with saturated NaCl solution until pH = 8.0, dried over anhydrous sodium sulfate, and concentrated to obtain compound III, yield: 93.4%, HPLC: 98.2%.

[0081] Example 14

[0082] Compound II (10.2 g, 57.6 mmol) was added to a 500 ml three-necked flask, and dissolved in 100 ml of dichloromethane under argon protection. After the reaction solution was cooled to 0°C, DIBAL-H (1 M toluene solution, 287.8 ml, 287.8 mmol) was added dropwise. The reaction solution was stirred at 0°C for 1 hour, and then warmed to room temperature and stirred for 6 hours. The reaction was monitored by thin layer chromatography and HPLC. After the reaction was completed, 200 ml of potassium sodium tartrate solution was added to quench the reaction, filtered, and the filtrate was separated. The aqueous phase was extracted with 200 ml of dichloromethane three times, and the combined organic phase was washed with saturated NaCl solution until pH = 8.0, dried over anhydrous sodium sulfate, and concentrated to obtain compound III, yield: 87.5%, HPLC: 97.6%.

Claims

1. A kind N The method for preparing methyl-3-hydroxyphenylpropanol is characterized by, Specifically, it includes the following steps: Step 1: Compound I, i.e. N -Methylphenylpropionamide is oxidized by an oxidant in the presence of a catalyst, and after post-treatment, compound II is obtained; Step 2: Compound II is converted to... N- Methyl-3-hydroxypropylamine, i.e., compound III, was post-processed to obtain the target product; the reaction route is as follows: ； The oxidant in step 1 is one of KBrO3 and KMnO4; The amounts of oxidant used in step 1 are as follows: the molar ratio of compound I to KBrO3 is 1:1.0 to 2.0; the molar ratio of compound I to KMnO4 is 1:3.0 to 8.

0. The catalyst in step 1 is CeO2; In step 1, the amount of catalyst CeO2 used is: the molar ratio of compound I to CeO2 is 1:0.001 to 0.01; In step 1, the reaction solvent is a mixed solvent of H2O / organic solvent / acetic acid, and the corresponding volume ratio of H2O / organic solvent / acetic acid is 1:0 to 1:0.1 to 1; the organic solvent is one of 1,4-dioxane, DMF, and DMSO. The reducing agent in step 2 is one of LiAlH4, red aluminum, boron dimethyl sulfide, NaBH4-AlCl3, and DIBAL-H.

2. The preparation method according to claim 1, characterized in that, The amounts of oxidant used in step 1 are as follows: the molar ratio of compound I to KBrO3 is 1:1.0; the molar ratio of compound I to KMnO4 is 1:5.

0.

3. The preparation method according to claim 1, characterized in that, In step 1, the amount of catalyst CeO2 used is: the molar ratio of compound I to CeO2 is 1:0.

003.

4. The preparation method according to claim 1, characterized in that, In step 1, the reaction solvent is a mixture of H2O / organic solvent / acetic acid, and the corresponding volume ratio of H2O / organic solvent / acetic acid is 1:0.2:0.

2.

5. The preparation method according to claim 1, characterized in that, The reaction solvent in step 1 is a mixed solvent of H2O / 1,4-dioxane / acetic acid.

6. The preparation method according to claim 1, characterized in that, The reaction temperature in step 1 is 70–110°C.

7. The preparation method according to claim 1, characterized in that, The reaction temperature in step 1 is 90–95°C.

8. The preparation method according to claim 1, characterized in that, The reducing agent in step 2 is LiAlH4.

9. The preparation method according to claim 1, characterized in that, In step 2, the amount of reducing agent used is: the molar ratio of compound II to reducing agent is 1:3.0 to 6.

0.

10. The preparation method according to claim 1, characterized in that, The solvent for the reduction reaction in step 2 is one or more of tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, toluene, methanol, and 1,4-dioxane.

11. The preparation method according to claim 1, characterized in that, The solvent for the reduction reaction in step 2 is tetrahydrofuran.

12. The preparation method according to claim 1, characterized in that, The temperature of the reduction reaction in step 2 is 0–100°C.

13. The preparation method according to claim 1, characterized in that, The temperature of the reduction reaction in step 2 is 25–70°C.

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