阅读说明：本技术 一种氘代马来酸氟伏沙明及其合成方法 (Deuterated maleic acid fluvoxamine and synthesis method thereof ) 是由 仇中选 王东 赵美法 杨慧 方光静 黄龙江 于 2021-09-28 设计创作，主要内容包括：本发明属于马来酸氟伏沙明合成技术领域,公开了一种氘代马来酸氟伏沙明及其合成方法。该合成方法使用4-三氟甲基苯甲醛为原料与格氏试剂反应简洁高效制备出5-(甲氧基-d3)-1-(4-(三氟甲基)苯基)-1-戊醇(VII),经Dess-Martin氧化得到5-(甲氧基-d3)-1-(4-三氟甲基苯基)-1-戊酮(VIII)。该合成方法原料易得,合成方法简单易操作,重现性好,产品纯度和同位素丰度均大于99.0％。(The invention belongs to the technical field of synthesis of fluvoxamine maleate, and discloses deuterated fluvoxamine maleate and a synthesis method thereof. The synthesis method uses 4-trifluoromethylbenzaldehyde as a raw material to react with Grignard reagent to prepare 5- (methoxyl-d 3) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII) simply and efficiently, and 5- (methoxyl-d 3) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) is obtained by Dess-Martin oxidation. The synthesis method has the advantages of easily obtained raw materials, simple and easy operation, good reproducibility and product purity and isotope abundance of more than 99.0%.)

1. The deuterated fluorovoxamine maleate is characterized by having the following structural formula:

the synthesis method of the deuterated fluvoxamine maleate comprises the following steps:

(1) 4-benzyloxy-1-butanol is alkylated with deuterated iodomethane in an organic solvent under the action of sodium hydride to prepare ((4- (methoxyl-d)₃) Butoxy) methyl) benzene;

(2) the compound ((4- (methoxy-d)₃) Butoxy) methyl) benzene is subjected to debenzylation protecting group reaction in an organic solvent under hydrogen atmosphere to prepare 4- (methoxy-d)₃) Butan-1-ol;

(3) the 4- (methoxy-d)₃) The butan-1-ol and the phosphorus trihalide have halogenation reaction to prepare the 1-halogen-4- (methoxy-d)₃) Butane;

(4) the 1-halo-4- (methoxy-d)₃) Carrying out Grignard reaction on butane and magnesium chips in an organic solvent to prepare (4- (methoxyl-d 3) butyl) magnesium halide;

(5) the (4- (methoxy-d)₃) Butyl) magnesium halide and 4-trifluoromethylbenzaldehyde are subjected to nucleophilic substitution reaction to obtain 5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol;

(6) the 5- (methoxy-d)₃) The (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanol and the Dess-Martin reagent are subjected to oxidation reaction to prepare the 5- (methoxyl-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone;

finally, with said 5- (methoxy-d)₃) Preparing the deuterated maleic acid fluvoxamine by using (E) -1- (4-trifluoromethylphenyl) -1-pentanone as one of reactants.

2. The deuterated fluorovoxamine maleate according to claim 1, wherein in step (1) the organic solvent is selected from N, N-dimethylformamide, tetrahydrofuran or toluene.

3. The deuterated fluorovoxamine maleate according to claim 1, wherein in step (2) the organic solvent is selected from tetrahydrofuran, methanol or ethanol.

4. The deuterated fluorovoxamine maleate according to claim 1, wherein in step (4) the organic solvent is selected from tetrahydrofuran or diethyl ether.

5. The deuterated fluorovoxamine maleate according to claim 1, wherein the halogen atom of the phosphorus trihalide in step (3) is selected from chlorine or bromine.

6. The deuterated fluorovoxamine maleate according to claim 1, wherein the temperature of the nucleophilic reaction in step (5) is between-10 ℃ and 25 ℃.

7. The deuterated fluorovoxamine maleate according to claim 1, wherein in step (6) the 5- (methoxy-d) is present₃) The molar ratio of the (1) -1- (4- (trifluoromethyl) phenyl) -1-pentanol to the Dess-Martin reagent is 1 (1-2); the organic solvent is selected from dichloromethane, tetrahydrofuran or toluene.

8. The deuterated fluorovoxamine maleate according to claim 1, wherein the synthesis method further comprises the following steps:

(7) the 5- (methoxy-d)₃) Reacting (E) -5- (methoxy-d) with (4-trifluoromethyl phenyl) -1-pentanone and hydroxylamine hydrochloride under the action of alkali₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime;

(8) the (E) -5- (methoxy-d)₃) Nucleophilic substitution reaction of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime and 2-halogenated ethylamine hydrochloride to prepare (E) -5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime;

(9) the (E) -5- (methoxy-d)₃) Reacting (E) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime and maleic acid to form a salt, and preparing the deuterated maleic acid fluvoxamine.

9. The deuterated fluorovoxamine maleate according to claim 7, wherein in step (7) the base is selected from pyridine, triethylamine, potassium hydroxide or sodium acetate.

10. The deuterated fluorovoxamine maleate according to claim 7, wherein in step (8) the halogen atom of the hydrochloride salt of 2-haloethylamine is selected from chlorine or bromine.

Technical Field

The invention relates to the technical field of synthesis of fluvoxamine maleate, and particularly relates to deuterated fluvoxamine maleate and a synthesis method thereof.

Background

Depression (MDD) is a serious disabling neuropsychiatric disorder with the core symptoms of depressed mood, anhedonia, irritability, difficulty in concentrating, appetite, sleep disorder, etc. With the rapid development of global economy, the pace of life of people is increasing, the incidence of psychological diseases, particularly depression, is increasing year by year worldwide, and more than 3.5 million people worldwide suffer from depression as reported by the World Health Organization (WHO), and about 15% of serious patients choose suicide.

Fluvoxamine maleate is a medicament for treating depression and obsessive-compulsive disorder developed by yapei pharmacy, is the first antidepressant medicament of a selective 5-hydroxytryptamine reuptake inhibitor (SSRIs) type worldwide, and is also the only monocyclic SSRIs. Compared with the traditional antidepressant, fluvoxamine maleate has low adrenomimetic efficacy and is not easy to cause symptoms such as excitation, hyperhidrosis and the like; the anti-choline and anti-histamine effects are low, and the phenomena of weight gain, lethargy and the like rarely occur; small interaction among medicines, is beneficial to combined medication and the like. The medicine is widely applied in the world since the market comes, but is limited by patent protection and higher process difficulty, and only the Lizhu medicine in China obtains the approved literature of the medicine at present.

Deuterium is a stable form of nonradioactive isotope of hydrogen in nature and is designated as D. The deuterated labeled compound is a compound in which a hydrogen atom or a part of hydrogen atoms in the compound is replaced with a deuterium atom. The deuterium-substituted marker plays an important role in biomedicine and pharmacokinetics. For example, parameters of drug metabolism pathway, metabolism mechanism and dynamics can be obtained, and isotope labeling technology is necessary for drug metabolism safety evaluation in new drug research required in industrial guidelines promulgated by the U.S. Food and Drug Administration (FDA). Deuterium marks fluvoxamine maleate, so that the method is beneficial to comprehensively analyzing the metabolic process and pharmacokinetics of the fluvoxamine maleate in a human body, and has important application value.

In clinical tests, in order to ensure that the detection method of the biological sample is accurate and reliable, the internal standard substance is added during detection, the deuterated compound is the best internal standard substance, the research and production of the standard substance in China are relatively less, the standard substance is indispensable in analysis and detection, the deuterated internal standard substance sold in the domestic market mainly depends on import, the selling price is expensive, and the wide use of the standard substance in China is severely limited. At present, no literature report on the synthesis of deuterated maleic acid fluvoxamine exists.

Disclosure of Invention

In order to solve the problem that an effective method for synthesizing deuterated maleic acid fluvoxamine does not exist in the prior art, the invention provides deuterated maleic acid fluvoxamine and a preparation method thereof.

In order to solve the technical problems, the invention adopts the following technical scheme:

a deuterated fluorovoxamine maleate has the following structural formula:

the synthesis method of the deuterated fluvoxamine maleate comprises the following steps:

(1) 4-benzyloxy-1-butanol (I) is alkylated with deuteroiodomethane in organic solvent under the action of sodium hydride to prepare ((4- (methoxyl-d)₃) Butoxy) methyl) benzene (II);

(2) ((4- (methoxy-d)₃) Butoxy) methyl) benzene (II) is subjected to debenzylation protecting group reaction in organic solvent under hydrogen atmosphere to prepare 4- (methoxy-d)₃) Butan-1-ol (III);

(3)4- (methoxy-d)₃) The butan-1-ol (III) and phosphorus trihalide are subjected to halogenation to prepare the 1-halogen-4- (methoxy-d)₃) Butane (IV);

wherein, PX3,Wherein X is halogen selected from chlorine or bromine.

(4) 1-halo-4- (methoxy-d)₃) Butane (IV) and magnesium chips in organic solvent to prepare (4- (methoxyl-d)₃) Butyl) magnesium (V) halide;

(5) (4- (methoxy-d)₃) Butyl) magnesium halide (V) and 4-trifluoromethylbenzaldehyde (VI) undergo nucleophilic substitution reaction to prepare the 5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII);

wherein the content of the first and second substances,wherein X is halogen selected from chlorine or bromine.

(6) The 5- (methoxy-d)₃) Oxidation reaction of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII) and Dess-Martin reagent in organic solvent to prepare 5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII);

finally, the 5- (methoxy-d) obtained in the final preparation₃) Preparing the deuterated maleic acid fluvoxamine by using (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) as one of the reaction raw materials.

Further, the organic solvent in step (1) is selected from N, N-dimethylformamide, tetrahydrofuran or toluene. Further, the organic solvent is N, N-dimethylformamide;

further, the organic solvent in step (2) is selected from tetrahydrofuran, methanol or ethanol. Further, the organic solvent is methanol or ethanol.

Further, in the step (4), the organic solvent is selected from tetrahydrofuran or diethyl ether. Further, the organic solvent is tetrahydrofuran.

Further, in the step (3), the halogen atom of the phosphorus trihalide is selected from chlorine or bromine.

Further, the temperature of the nucleophilic reaction in the step (5) is-10-25 ℃. Further, the temperature of the nucleophilic reaction is preferably 0 to 5 ℃;

further, in the step (6), the 5- (methoxy-d)₃) The molar ratio of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanol to Dess-Martin reagent is 1 (1-2), and further, the 5- (methoxy-d)₃) The molar ratio of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanol to Dess-Martin reagent is 1: (1.2-1.5); the organic solvent is selected from dichloromethane, tetrahydrofuran or toluene, and further, the organic solvent is selected from dichloromethane.

The 5- (methoxy-d) prepared in the step (6)₃) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) as a reactant for preparing the deuterated fluorovoxamine maleate according to the invention specifically comprises the following steps:

(7)5- (methoxy-d)₃) Reacting (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) with hydroxylamine hydrochloride under the action of alkali to prepare (E) -5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX);

(8) (E) -5- (methoxy-d₃) Nucleophilic substitution reaction of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX) and 2-halogenated ethylamine hydrochloride to prepare (E) -5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime (X);

wherein, YCH₂CH₂NH₂Y in HCl is a halogen selected from chlorine or bromine;

(9) (E) -5- (methoxy-d₃) Reacting (E) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime (X) with maleic acid to form a salt, and preparing the deuterated maleic acid fluvoxamine (XI).

Further, in the step (7), the base is selected from pyridine, triethylamine, potassium hydroxide or sodium acetate. Further, the base is potassium hydroxide.

Further, in the step (8), the halogen atom in the 2-haloethylamine hydrochloride is selected from chlorine or bromine.

The general synthetic route of the deuterated fluorovoxamine maleate is as follows:

the invention aims to provide deuterated fluvoxamine maleate serving as an internal standard substance and a synthetic method thereof. The synthetic method takes common deuterated iodomethane as a deuterium source, and the 5- (methoxyl-d) is prepared by adopting a simple synthetic method₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII); and the deuterated maleic acid fluvoxamine is further synthesized by taking the deuterated maleic acid fluvoxamine as a raw material. The synthesis method has the advantages of easily obtained raw materials, simple and easy operation, good reproducibility and product purity and isotope abundance of more than 99.0%.

In particular 5- (methoxy-d)₃) The preparation of the (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) is one of the key steps for synthesizing the deuterated maleic acid fluvoxamine, and the 5- (methoxy-d) is prepared by simply and efficiently reacting 4-trifluoromethylbenzaldehyde serving as a raw material with a Grignard reagent for the first time₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII) oxidized by Dess-Martin to give 5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII). Compared with the traditional method, the method avoids the problems of long reaction period, poor repeatability, use of high-toxicity cyanogen compounds and the like.

The deuterated fluvoxamine maleate is used as an internal standard drug and can be applied to the research on clinical pharmacokinetics, so that the metabolic process and the action mechanism of the fluvoxamine maleate in a human body can be more accurately and conveniently understood, the comprehensive analysis of the pharmacokinetics of the fluvoxamine maleate in the human body is facilitated, and the application value is important.

Drawings

FIG. 1 is a diagram of the deuterated fluorovoxamine maleate provided in example 1¹H NMR chart;

FIG. 2 is a diagram of the deuterated fluorovoxamine maleate provided in example 1¹³C NMR chart;

FIG. 3 is an ESI-HRMS plot of deuterated fluvoxamine maleate provided in example 1.

Detailed Description

The invention discloses deuterated maleic acid fluvoxamine and a synthesis method thereof, and a person skilled in the art can realize the synthesis by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The following detailed description of the invention refers to specific embodiments thereof for better understanding by those skilled in the art.

Example 1

(1) In a 500mL three-necked flask, 4-benzyloxy-1-butanol (I, 18.0g, 100mmol) was dissolved in N, N-dimethylformamide (DMF, 200mL), the system was cooled to about 0 to 5 ℃, sodium hydride (60%, dispersed in liquid paraffin) (6.0g, 150mmol) was added under stirring, and after stirring for 10 minutes, deuterated iodomethane (29.0g, 200mmol) was added dropwise thereto. After the addition, the reaction system is naturally raised to the room temperature, stirred for 12 hours, the reaction is stopped, the system is poured into ice water, ethyl acetate (200mL) is added for extraction and liquid separation, the organic phase obtained by extraction is respectively washed by water (200mL) and saturated saline (200mL), dried by anhydrous sodium sulfate, filtered, decompressed and concentrated, and separated by column chromatography to obtain ((4- (methoxyl-d)₃) Butoxy) methyl) benzene (II)19.3g, yield 98%A colorless liquid.

(2) In a 500mL three-necked flask, ((4- (methoxy-d)₃) Butoxy) methyl) benzene (II, 17.7g, 90mmol) was dissolved in anhydrous methanol (180mL), added with a palladium on carbon catalyst (1.77g, palladium content in palladium on carbon catalyst is 10 wt%), and stirred rapidly under hydrogen atmosphere at room temperature for 12 hours. Stopping reaction, filtering, washing filter cake with anhydrous methanol (10mL), and concentrating filtrate under reduced pressure to constant weight to obtain 4- (methoxyl-d)₃) Butan-1-ol (III)9.5g, yield 98%, colorless liquid.

(3) Phosphorus tribromide (24.6g, 91mmol) is slowly added dropwise to a solution of 4- (methoxy-d 3) butan-1-ol (III, 7.5g, 70mmol) in tetrahydrofuran (140mL) in a 500mL three-necked flask under the protection of argon at about 0-5 ℃, and after the addition is finished, the temperature is naturally raised to room temperature and stirred for 12 h. Adding saturated sodium bicarbonate solution to adjust the pH value to 7-8, extracting and separating by ethyl acetate (150mL), washing the organic phase by water (100mL) and saturated saline (100mL) successively, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain 9.9g of 1-bromo-4- (methoxy-d 3) butane (IV), wherein the yield is 83%, and the colorless liquid is obtained.

(4) Under the protection of argon, magnesium chips (1.44g, 60mmol), small iodine particles and anhydrous tetrahydrofuran (30mL) are added into a 250mL three-necked bottle, the mixture is heated to slight boiling, the brown color of the system is faded, and 1-bromine-4- (methoxyl-d) is dripped₃) A solution of butane (IV, 8.5g, 50mmol) in dry tetrahydrofuran (30mL) was kept slightly boiling and stirred for 1h after addition to give a solution of (4- (methoxy-d 3) butyl) magnesium bromide (V) in tetrahydrofuran.

(5) Under the protection of argon, at the temperature of 0-5 ℃, a solution of 4-trifluoromethylbenzaldehyde (VI, 8.7g and 50mmol) in anhydrous tetrahydrofuran (20mL) is added dropwise to the (4- (methoxy-d) prepared in the previous step₃) After the addition, naturally heating to raise the temperature and stirring for 3 hours, adding 1mol/L hydrochloric acid (10mL) to quench the reaction, adding water (100mL) and ethyl acetate (100mL) to extract and separate liquid, washing an organic phase with saturated saline solution (100mL), drying with anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate under reduced pressure, and performing column chromatography to obtain the 5- (methoxy-d) magnesium bromide (V)₃)11.1g of (E) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII) in 84% yield in two steps as a white solid.

(6) 5- (methoxy-d) is added into a 500mL reaction bottle₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII, 10.6g, 40mmol), Dess-Martin reagent (25.4g, 60mmol) and dichloromethane (100mL) are stirred at room temperature for 2h, saturated sodium bicarbonate solution (100mL) is added, stirring is carried out for 10min, extraction and liquid separation are carried out, the aqueous phase is extracted by dichloromethane (100mL), the organic phase is combined, saturated saline solution (100mL) is used for washing, anhydrous sodium sulfate is used for drying, suction filtration is carried out, the filtrate is decompressed, concentrated and dried to obtain 5- (methoxy-d)₃)10.1g of (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII), yield 96%, white solid.

(7) A250 mL reaction flask was charged with hydroxylamine hydrochloride (3.1g, 45mmol), potassium hydroxide (5.1g, 90mmol) and absolute ethanol (100mL), stirred at room temperature for 30min, and added with 5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII, 7.9g, 30mmol), refluxing for 3 h. The reaction was stopped, the temperature was reduced to room temperature, water (100mL) and methylene chloride (100mL) were added to extract the separated liquid, and the aqueous phase was extracted with methylene chlorideExtracting (50mL), mixing organic phases, washing with saturated saline (100mL), drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate under reduced pressure, and performing column chromatography to obtain (E) -5- (methoxyl-d)₃)7.8g of 1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX), yield 94%, white solid; (Z) -5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime 0.3g, yield 4%, white solid.

(8) A250 mL reaction flask was charged with (E) -5- (methoxy-d 3) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX, 7.0g, 25mmol), 2-chloroethylamine hydrochloride (2.9g, 25mmol), potassium hydroxide (3.1g, 55mmol), and N, N-dimethylformamide (80mL) and stirred at room temperature for 6 h. The reaction was stopped, concentrated under reduced pressure, the pH of the residue was adjusted to about 1-2 by the addition of 2mol/L hydrochloric acid, the mixture was extracted with water (100mL) and methylene chloride (100mL) to obtain a liquid, the aqueous phase was adjusted to about 11-13 by the addition of 10% aqueous sodium hydroxide solution, the aqueous phase was extracted with methylene chloride (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to a constant weight to give (E) -5- (methoxy-d 3) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime (X)7.8g, yield 97%, colorless liquid.

(9) A250 mL reaction flask was charged with (E) -5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime (X, 6.4g, 20mmol), maleic acid (2.3g, 20mmol) and absolute ethyl alcohol (60mL), stirring at room temperature for 2h, concentrating the filtrate under reduced pressure to obtain a crude product of deuterated fluvoxamine maleate, adding a mixed solution (40mL, wherein the volume ratio of ethyl acetate to n-hexane is 1:9), pulping for 1 hour, performing suction filtration, washing the filter cake with n-hexane (20mL), and drying to obtain 8.4g of deuterated fluvoxamine (XI), wherein the yield is 96%, the purity is 99.3%, the isotopic abundance is 99.6%, and the structural characterization data of a white solid of deuterated fluvoxamine (XI) are shown in FIGS. 1-3.

Example 2

(1) In a 500mL three-necked flask, 4-benzyloxy-1-butanol (I, 18.0g, 100mmol) was dissolved in tetrahydrofuran (THF, 200mL), the system was cooled to about 0-5 ℃, sodium hydride (60%, dispersed in liquid paraffin) (6.0g, 150mmol) was added under stirring, and after stirring for 10 minutes, deuterated iodomethane (29.0g, 200mmol) was added dropwise thereto. After the addition, the reaction system is naturally raised to the room temperature, stirred for 12 hours, the reaction is stopped, the system is poured into ice water, ethyl acetate (200mL) is added for extraction and liquid separation, the organic phase obtained by extraction is respectively washed by water (200mL) and saturated saline (200mL), dried by anhydrous sodium sulfate, filtered, decompressed and concentrated, and separated by column chromatography to obtain ((4- (methoxyl-d)₃) Butoxy) methyl) benzene (II)18.5g, yield 94%, colorless liquid.

(2) In a 500mL three-necked flask, ((4- (methoxy-d 3) butoxy) methyl) benzene (II, 17.7g, 90mmol) was dissolved in absolute ethanol (180mL), and palladium on carbon catalyst (1.77g, palladium content 10 wt% in palladium on carbon catalyst) was added, followed by rapid stirring under hydrogen atmosphere at room temperature for 12 hours. Stopping reaction, filtering, washing filter cake with anhydrous ethanol (10mL), and concentrating filtrate under reduced pressure to constant weight to obtain 4- (methoxyl-d)₃) Butan-1-ol (III)9.4g, 97% yield, colorless liquid.

(3) In a 500mL three-neck flask, under the protection of argon, phosphorus trichloride (12.5g, 91mmol) is slowly dripped into 4- (methoxyl-d) at the temperature of about 0-5 DEG C₃) After adding the solution of butan-1-ol (III, 7.5g, 70mmol) in tetrahydrofuran (140mL), the solution was allowed to warm to room temperature and stirred for 12 h. Adding saturated sodium bicarbonateAdjusting pH of the solution to 7-8, extracting with ethyl acetate (150mL), separating, washing organic phase with water (100mL) and saturated saline (100mL), drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain 1-bromo-4- (methoxyl-d)₃) Butane (IV)6.9g, yield 79%, colorless liquid.

(4) Under the protection of argon, magnesium chips (1.44g, 60mmol), small iodine particles and anhydrous ether (30mL) are added into a 250mL three-necked bottle, the mixture is heated to slight boiling, the brown color of the system is faded, and 1-chlorine-4- (methoxyl-d) is dripped₃) Dissolving butane (IV, 6.28g, 50mmol) in anhydrous ether (30mL), maintaining slightly boiling state, stirring for 1h to obtain (4- (methoxyl-d)₃) Butyl) magnesium (V) chloride in ether.

(5) Under the protection of argon, at a temperature of-10 to-5 ℃, a solution of 4-trifluoromethylbenzaldehyde (VI, 8.7g and 50mmol) in anhydrous ether (20mL) is added dropwise to the (4- (methoxy-d) prepared in the previous step₃) After the addition, the solution is naturally raised to the temperature and stirred for 3 hours, 1mol/L hydrochloric acid (10mL) is added to quench the reaction, water (100mL) and ethyl acetate (100mL) are added to extract and separate the solution, the organic phase is washed by saturated saline solution (100mL), anhydrous sodium sulfate is dried, the solution is filtered, the filtrate is decompressed and concentrated, and the column chromatography separation is carried out to obtain 10.3g of 5- (methoxy-d 3) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII), the yield of the two steps is 78%, and the white solid is obtained.

(6) 5- (methoxy-d) is added into a 500mL reaction bottle₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII, 10.6g, 40mmol), Dess-Martin reagent (17.0g, 40mmol) and tetrahydrofuran (100mL) stirred at room temperature for 2h, addAdding saturated sodium bicarbonate solution (100mL), stirring for 10min, extracting, separating, extracting the water phase with dichloromethane (100mL), mixing the organic phases, washing with saturated saline (100mL), drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate under reduced pressure, and drying to obtain 5- (methoxyl-d)₃)9.1g of (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII), yield 86%, white solid.

(7) A250 mL reaction flask was charged with hydroxylamine hydrochloride (3.1g, 45mmol), pyridine (7.1g, 90mmol) and absolute ethanol (100mL), stirred at room temperature for 30min, added with 5- (methoxy-d 3) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII, 7.9g, 30mmol) and refluxed for 3 h. Stopping reaction, cooling to room temperature, adding water (100mL) and dichloromethane (100mL), extracting, separating the aqueous phase with dichloromethane (50mL), mixing the organic phases, washing with saturated saline (100mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing column chromatography to obtain (E) -5- (methoxy-d)₃)7.4g of 1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX), yield 89%, white solid; (Z) -5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime 0.7g, yield 8%, white solid.

(8) A250 mL reaction flask was charged with (E) -5- (methoxy-d)₃) -1- (4- (trifluoromethyl) phenyl) -1-pentanone oxime (IX, 7.0g, 25mmol), 2-bromoethylamine hydrochloride (4.0g, 25mmol), potassium hydroxide (3.1g, 55mmol) and N, N-dimethylformamide (80mL) stirring at room temperature for 6 h. Stopping reaction, concentrating under reduced pressure, adjusting pH of the residue to 1-2 with 2mol/L hydrochloric acid, extracting with water (100mL) and dichloromethane (100mL), adjusting pH of the aqueous phase to 11-13 with 10% sodium hydroxide aqueous solution, extracting with dichloromethane (100mL), drying the organic phase with anhydrous sodium sulfate, vacuum filtering, and concentrating the filtrate under reduced pressure to constant weight to obtain (E) -5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime(X)7.5g, yield 94%, colorless liquid.

(9) A250 mL reaction flask was charged with (E) -5- (methoxy-d)₃) -1- (4-trifluoromethylphenyl) -1-pentanone-O- (2-aminoethyl) oxime (X, 6.4g, 20mmol), maleic acid (2.3g, 20mmol) and absolute ethyl alcohol (60mL), stirring at room temperature for 2h, concentrating the filtrate under reduced pressure to obtain a crude product of deuterated fluvoxamine maleate, adding a mixed solution (40mL, wherein the volume ratio of ethyl acetate to n-hexane is 1:9), pulping for 1 hour, performing suction filtration, washing a filter cake with n-hexane (20mL), and drying to obtain 8.3g of deuterated fluvoxamine maleate (XI), wherein the yield is 95%, the purity is 99.5%, the isotopic abundance is 99.6%, and the product is a white solid.

Example 3

The reaction temperature of the step (5) in the example 2 is adjusted to 20-25 ℃, and then the reaction process of the step (5) is as follows: under the protection of argon, the temperature is adjusted to about 20-25 ℃, and a solution of 4-trifluoromethylbenzaldehyde (VI, 8.7g and 50mmol) in anhydrous tetrahydrofuran (20mL) is added dropwise to the (4- (methoxy-d) prepared in the previous step₃) Butyl) magnesium bromide (V), stirring for 3h, adding 1mol/L hydrochloric acid (10mL) to quench the reaction, adding water (100mL) and ethyl acetate (100mL) to extract and separate, washing the organic phase with saturated saline solution (100mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain 5- (methoxyl-d) magnesium bromide (V)₃)8.5g of-1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII) in 64% yield in two steps as a white solid;

and the organic solvent in step (6) in example 2 was replaced with toluene, 5- (methoxy-d)₃) The molar ratio of the (VII) -1- (4- (trifluoromethyl) phenyl) -1-pentanol to the Dess-Martin reagent is 1:2, the reaction process of the step (6) is as follows: adding 5- (methoxy-d 3) -1- (4- (trifluoromethyl) phenyl) -1-pentanol (VII, 10.6g, 40mmol), Dess-Martin reagent (34.0g, 80mmol) and toluene (100mL) into a 500mL reaction bottle, stirring at room temperature for 2h, adding saturated sodium bicarbonate solution (100mL), stirring for 10min, extracting, separating, extracting the aqueous phase with toluene (50mL), combining the organic phases, washing with saturated saline (100mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and drying to obtain 5- (methoxy-d) pentanol₃)9.5g of (E) -1- (4-trifluoromethylphenyl) -1-pentanone (VIII) in 90% yield as a white solid.

The other reaction procedures were the same as in example 2, and 8.2g of deuterated fluvoxamine maleate (XI) was finally obtained in 94% yield, 99.1% purity and 99.6% isotopic abundance as a white solid.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.