Synthesis method and application of deuterated megestrol acetate

Abstract

The present invention discloses a synthesis method of deuterated megestrol acetate and its application. The synthesis method comprises: first, dehydrogenating 17α-hydroxyprogesterone-17-acetate I under the oxidative action of tetrachlorobenzoquinone to obtain a diene compound II; second, epoxidizing the diene compound II under the action of meta-chloroperbenzoic acid to obtain an epoxy compound III; third, brominating the epoxy compound III under the action of hydrobromic acid to obtain a brominated compound IV; and fourth, Suzuki coupling reaction of the brominated compound IV with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V. The synthesis method of the present invention is low in cost and mild in conditions. The chemical purity and stable isotope abundance of the obtained deuterated megestrol acetate can reach above 98%, meeting the requirements of a standard reagent for quantitative detection of megestrol acetate compounds and being suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of stable isotope labeled compound production; more specifically, the present invention relates to a synthesis method of deuterated megestrol acetate and its application. Background Art

[0002] Megestrol acetate is a synthetic progesterone drug and a representative progesterone derivative. It is widely used in gynecology and contraception to treat conditions such as irregular menstruation, endometriosis, uterine fibroids, and breast cancer. It can also be used in oral contraceptives and emergency contraceptives.

[0003] Deuterium-labeled megestrol acetate is of great significance to unlabeled megestrol acetate in medical research, particularly in the study of pharmacology, pharmacokinetics, and biosynthetic pathways. However, there are relatively few studies and reports on isotope labeling of megestrol acetate, especially deuterated megestrol acetate, which has not been reported in any patents or literature.

[0004] Although Chinese patent applications CN106866767A and CN107501375A respectively report a method for preparing megestrol acetate, these two preparation methods cannot introduce the isotope deuterium and cannot obtain deuterium-labeled megestrol acetate.

[0005] Therefore, there is an urgent need in the art to provide a method for synthesizing deuterium-labeled megestrol acetate with simple steps, mild reaction conditions, low cost, and suitability for large-scale production. Summary of the Invention

[0006] The present invention provides a method for synthesizing deuterated (deuterium-labeled) megestrol acetate. The target compound obtained by this method achieves a purity and stable isotope abundance exceeding 98%, meeting the requirements for use as a standard reagent for the quantitative detection of megestrol acetate and its application in medical research. Furthermore, the method features simple steps, mild reaction conditions, and low cost, making it suitable for fine chemical production.

[0007] The present invention solves the above-mentioned technical problems by providing a method for synthesizing deuterium-labeled megestrol acetate. The method comprises: using 17α-hydroxyprogesterone-17-acetate I as a raw material, and subjecting it to a dehydrogenation reaction to obtain a diene compound II; using the diene compound II as a raw material, and subjecting it to an epoxidation reaction to obtain an epoxide compound III; using the epoxide compound III as a raw material, and subjecting it to a bromination reaction to obtain a brominated compound IV; and using the brominated compound IV as a raw material and deuterated methylboronic acid as a deuterium source, and subjecting it to a Suzuki coupling reaction to obtain deuterated megestrol acetate (Compound V). The resulting target compound has a purity and stable isotope abundance exceeding 98%.

[0008] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for synthesizing deuterium-labeled megestrol acetate, characterized in that the method comprises the following steps:

[0009] Step 1: Using 17α-hydroxyprogesterone-17-acetate I as a raw material, dehydrogenating it under the oxidation action of chloranil and acetic acid to obtain diene compound II;

[0010]

[0011] Step 2: using the diene compound II described in step 1 as a raw material, subjecting it to an epoxidation reaction under the action of m-chloroperbenzoic acid to obtain an epoxy compound III;

[0012]

[0013] Step 3: Using the epoxy compound III described in step 2 as a raw material, a brominated compound IV is obtained by bromination reaction under the action of hydrobromic acid;

[0014]

[0015] Step 4: using the brominated compound IV described in step 3 as a raw material, reacting it with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V;

[0016]

[0017] In one or more preferred embodiments, the dehydrogenation reaction in step 1 comprises: placing 17α-hydroxyprogesterone-17-acetate I, chloranil, and acetic acid in a container (such as a reaction bottle), starting stirring, and heating to 140±10°C (preferably 140±5°C or 140±3°C or 140±2°C) for 6 to 8 hours.

[0018] In one or more preferred embodiments, after the dehydrogenation reaction is completed, the step of isolating and purifying the product is further included; more preferably, the step of isolating and purifying the product includes: standing and cooling, removing the solvent by vacuum rotary evaporation and sodium hydroxide solution neutralization (removing most of the solvent by vacuum rotary evaporation, and neutralizing the remaining part with sodium hydroxide solution), filtering to obtain a filter cake, washing the filter cake to remove impurities (preferably washing the filter cake with ethyl acetate to remove impurities), and drying to obtain the diene compound II.

[0019] In one or more preferred embodiments, the molar ratio of 17α-hydroxyprogesterone-17-acetate I, chloranil and acetic acid is 1:(1-1.5):(45-60), more preferably 1:(1.05-1.2):(50-55).

[0020] In one or more preferred embodiments, the solvent used in the dehydrogenation reaction is toluene.

[0021] In one or more preferred embodiments, the epoxidation reaction in step 2 comprises: placing the diene compound II and m-chloroperbenzoic acid (mCPBA) in a container (such as a reaction bottle), starting stirring, and reacting at 25-30° C. for 24±6 hours, preferably 24±4 hours, 24±2 hours, or 24±1 hour.

[0022] In one or more preferred embodiments, after the epoxidation reaction is completed, the step of isolating and purifying the product is further included; more preferably, the step of isolating and purifying the product comprises: filtering out the solid, extracting the filtrate with sodium thiosulfate solution and sodium bicarbonate solution, respectively, drying (preferably drying with anhydrous sodium sulfate), removing the solvent by rotary evaporation under reduced pressure, and recrystallizing using methanol to obtain white solid epoxide III.

[0023] In one or more preferred embodiments, the solvent used in the epoxidation reaction is chloroform; the molar ratio of the diene compound II to m-chloroperbenzoic acid (mCPBA) is 1:(1-5), more preferably 1:(2-3), for example 1:2.5.

[0024] In one or more preferred embodiments, the solvent used in the epoxidation reaction is chloroform or dichloromethane.

[0025] In one or more preferred embodiments, the bromination reaction in step 3 comprises: placing epoxide III and acetic acid in a container (such as a reaction bottle), starting stirring, and adding a solution of hydrobromic acid in acetic acid dropwise at a rate of 1 to 2 drops per second at 0 to 5° C. for 1 to 3 hours; after the addition is complete, reacting at 25 to 30° C. for 2±0.5 hours, preferably 2±0.3 hours or 2±0.2 hours.

[0026] In one or more preferred embodiments, after the bromination reaction is completed, the step of isolating and purifying the product is further included; more preferably, the step of isolating and purifying the product includes: neutralizing with sodium hydroxide solution, extracting with dichloromethane, drying, and removing the solvent by vacuum rotary evaporation to obtain a yellow solid, and separating by column chromatography to obtain brominated compound IV.

[0027] In one or more preferred embodiments, in the bromination reaction, the molar ratio of epoxide III to hydrobromic acid is 1:(2-6), preferably 1:(3-5).

[0028] In one or more preferred embodiments, in the bromination reaction, the final concentration of the hydrobromic acid in the reaction system is 1 to 50 mmol, preferably 2 to 40 mmol, more preferably 3 to 30 mmol (e.g., 4, 6, 8.8, 10, 12, 15, 18, 20, 25 mmol).

[0029] In one or more preferred embodiments, the hydrobromic acid is an acetic acid solution containing hydrobromic acid, and the concentration of hydrobromic acid in the dropwise addition liquid is 33±5 wt %, preferably 33±3 wt %, and more preferably 33±2 wt %.

[0030] In one or more preferred embodiments, the solvent used in the bromination reaction is acetic acid.

[0031] In one or more preferred embodiments, the Suzuki coupling reaction in step 4 comprises: subjecting the reaction vessel (preferably a Shrek flask) to anhydrous and oxygen-free treatment, sequentially adding brominated compound IV, potassium carbonate, tetrakistriphenylphosphine palladium and deuterated methylboronic acid, and reacting at 100° C. for 36 hours.

[0032] In one or more preferred embodiments, after the Suzuki coupling reaction is completed, the step of isolating and purifying the product is further included; more preferably, the step of isolating and purifying the product comprises: standing and cooling, quenching with water, extracting with dichloromethane, drying with anhydrous sodium sulfate, and column chromatography to obtain deuterated megestrol acetate V.

[0033] In one or more preferred embodiments, in the Suzuki coupling reaction, the molar ratio of the brominated compound IV, deuterated methylboronic acid and catalyst palladium is 1:(1-6):(0.01-0.1), preferably 1:(2-4):(0.02-0.05).

[0034] In one or more preferred embodiments, the solvent used in the Suzuki coupling reaction is dry anhydrous 1,4-dioxane.

[0035] In another aspect of the present invention, there is provided the use of any of the above methods for preparing stable deuterium-labeled deuterated megestrol acetate, wherein the chromatographic purity of the deuterated megestrol acetate is higher than 98% and the isotopic abundance is higher than 98%.

[0036] The method for synthesizing deuterated-labeled megestrol acetate provided by the present invention has the following major advantages:

[0037] (1) The solvents such as toluene, chloroform and acetic acid used in the synthesis method of the present invention are relatively easy to recycle and reuse, thereby reducing the treatment cost of chemical waste liquid.

[0038] (2) The reaction conditions in each step of the present invention are mild, there is no violent exothermic and outgassing phenomenon, the reaction safety is good, and the reaction steps are simple and efficient.

[0039] (3) In step 4, deuterated methylboronic acid is used as a direct deuterium source, and the method of directly adding deuterated methyl groups by Suzuki coupling reaction reduces the hydrogen-deuterium exchange step and effectively avoids the problem of reduced deuteration rate in the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The megestrol acetate-D3 obtained in Example 1 of the present invention 1 H NMR spectrum.

[0041] Figure 2 The megestrol acetate-D3 obtained in Example 1 of the present invention 13 C NMR spectrum.

[0042] Figure 3 This is a liquid chromatography-mass spectrometry diagram of megestrol acetate-D3 obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0043] In the present invention, the terms "deuterated" and "deuterium labeled" are used interchangeably.

[0044] Throughout this disclosure, all features, such as values, amounts, amounts, and concentrations, specified in numerical ranges or percentage ranges are provided for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges (including integers and fractions).

[0045] The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments can be combined in any combination. All features disclosed in this specification can be used in any combination form. As long as there is no contradiction in the combination of these features, all possible combinations should be considered to be within the scope of this specification. Each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0046] To make the objectives, technical solutions, and advantages of the present invention more clear, the technical solutions of the present invention will be clearly described below in conjunction with specific embodiments of the present invention and corresponding drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0047] Unless otherwise specified, technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art regarding the present invention. In the event of any conflict, the definitions in this specification shall prevail.

[0048] Example 1 1. Synthesis process of deuterium-labeled megestrol acetate

[0049] Step 1: Using 17α-hydroxyprogesterone-17-acetate I as raw material, dehydrogenate under the oxidation action of chloranil and acetic acid to obtain diene compound II:

[0050] 17α-Hydroxyprogesterone-17-acetate I (54 mmol), chloranil (59 mmol), 160 mL of acetic acid and 40 mL of toluene were added to the reaction flask in sequence, and the mixture was heated to 140°C for 7 h. After the reaction, most of the solvent was removed by rotary evaporation, and sodium hydroxide solution was added for neutralization. The filter cake was filtered to obtain the filter cake, which was washed with ethyl acetate to remove impurities and dried to obtain the diene compound II in a yield of 90%.

[0051] Step 2: Using the diene compound II described in step 1 as a raw material, an epoxy compound III is obtained by an epoxidation reaction under the action of m-chloroperbenzoic acid (mCPBA):

[0052] Diene compound II (14 mmol), mCPBA (28 mmol), and 100 mL of chloroform (or dichloromethane) were added sequentially to a reaction flask and reacted at 25-30°C for 24 hours. After completion of the reaction, the solid was filtered off, and the filtrate was extracted with sodium thiosulfate solution and sodium bicarbonate solution, respectively. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was recrystallized from methanol to obtain epoxide compound III as a white solid in approximately 70% yield.

[0053] Step 3: Using the epoxy compound III described in step 2 as a raw material, a brominated compound IV is obtained by bromination reaction under the action of hydrobromic acid:

[0054] Add epoxy compound III (2.2 mmol) and 10 mL of acetic acid to the reaction flask, and add a solution of hydrobromic acid (final concentration 8.8 mmol) in acetic acid dropwise at a rate of 1 to 2 drops per second at 0 to 5°C for more than 1 hour. After the addition is complete, react at 25 to 30°C for 2 hours. After the reaction is completed, neutralize with sodium hydroxide solution, extract with dichloromethane, dry, and spin-dry to obtain a yellow solid. Separate by column chromatography to obtain brominated compound IV with a yield of 85%.

[0055] Step 4: Using the brominated compound IV described in step 3 as a raw material, reacting it with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V:

[0056] After three evacuations and nitrogen replacements, the Shrek flask was sequentially added with brominated compound IV (0.5 mmol), potassium carbonate (1.25 mmol), tetrakistriphenylphosphine palladium (0.025 mmol), deuterated methylboronic acid (1.5 mmol), and 5 mL of anhydrous dioxane. The reaction was allowed to proceed at 100°C for 36 hours, then allowed to cool and quenched with water. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain deuterated megestrol acetate V in a 75% yield as a pale yellow solid with a melting point of 213.7°C to 214.5°C.1 H NMR(400MHz,Chloroform-d)δ5.96(s,1H),5.88(s,1H),3.06-2.94(m,1H),2.64-2.40(m,2H),2.24(d,J=12.2Hz, 1H),2.09(s,3H),2.06(s,3H),2.02-1.87(m,4H),1.81-1.55(m,4H),1.48-1.30(m,3H),1.10(s,3H),0.72(s,3H).

[0057] Prepared megestrol acetate-D3 1 H NMR spectrum Figure 1 As shown; 13 C NMR spectrum Figure 2 As shown; Liquid chromatography-mass spectrometry is shown Figure 3 shown.

[0058] Example 2 2. Synthesis process of deuterium-labeled megestrol acetate

[0059] Step 1: Using 17α-hydroxyprogesterone-17-acetate I as raw material, dehydrogenate under the oxidation action of chloranil and acetic acid to obtain diene compound II:

[0060] To a reaction flask, 17α-hydroxyprogesterone-17-acetate I (20 mmol), chloranil (22 mmol), 80 mL of acetic acid, and 40 mL of toluene were added sequentially. The reaction was heated to 140°C for 7 hours. After completion, the solvent was mostly removed by rotary evaporation, and sodium hydroxide solution was added for neutralization. The filter cake was filtered, washed with ethyl acetate to remove impurities, and dried to obtain diene compound II in an 87% yield.

[0061] Step 2: Using the diene compound II described in step 1 as a raw material, an epoxy compound III is obtained by an epoxidation reaction under the action of m-chloroperbenzoic acid (mCPBA):

[0062] Diene compound II (7 mmol), mCPBA (18 mmol), and 60 mL of chloroform (or dichloromethane) were added sequentially to a reaction flask and reacted at 25-30°C for 24 hours. After the reaction, the solid was filtered off, and the filtrate was extracted with sodium thiosulfate solution and sodium bicarbonate solution, respectively. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was recrystallized from methanol to obtain epoxide compound III as a white solid in a yield of approximately 75%.

[0063] Step 3: Using the epoxy compound III described in step 2 as a raw material, bromination reaction is carried out under the action of hydrobromic acid to obtain the brominated compound IV:

[0064] Add epoxy compound III (5 mmol) and 10 mL of acetic acid to the reaction flask, and add hydrobromic acid (final concentration 20 mmol) in acetic acid solution dropwise at a rate of 1 to 2 drops per second at 0 to 5°C for more than 2 hours. After the addition is complete, react at 25 to 30°C for 2 hours. After the reaction is completed, neutralize with sodium hydroxide solution, extract with dichloromethane, dry, and spin-dry to obtain a yellow solid. Separate by column chromatography to obtain brominated compound IV with a yield of 75%.

[0065] Step 4: Using the brominated compound IV described in step 3 as a raw material, reacting it with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V:

[0066] After three evacuations and nitrogen replacements, the Shrek flask was sequentially added with brominated compound IV (1 mmol), potassium carbonate (2.5 mmol), tetrakistriphenylphosphine palladium (0.025 mmol), deuterated methylboronic acid (3 mmol), and 10 mL of anhydrous dioxane. The reaction was allowed to proceed at 100°C for 36 hours, then allowed to cool and quenched with water. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain deuterated megestrol acetate V in an 85% yield as a pale yellow solid with a melting point of 211.7°C to 215.5°C. 1 H NMR(400MHz, CDCl3)δ5.95(s,1H),5.87(s,1H),3.05-2.94(m,1H),2.64-2.52 (m,1H),2.45(dd,J=17.8,3.6Hz,1H),2.24(t,J=10.2Hz,1H),2.09(s,3H),2.0 5(s,3H),2.00(d,J=2.7Hz,1H),1.98-1.88(m,2H),1.86-1.66(m,3H),1.59(dd ,J=9.0,3.2Hz,2H),1.44(m,2H),1.37-1.23(m,2H),1.09(s,3H),0.72(s,3H).

[0067] The analysis results showed that the chromatographic purity and isotope abundance both reached more than 98%.

[0068] Example 3 3. Synthesis process of deuterium-labeled megestrol acetate

[0069] Step 1: Using 17α-hydroxyprogesterone-17-acetate I as raw material, dehydrogenate under the oxidation action of chloranil and acetic acid to obtain diene compound II:

[0070] To a reaction flask, 17α-hydroxyprogesterone-17-acetate I (5 mmol), chloranil (7 mmol), 16 mL of acetic acid, and 40 mL of toluene were added sequentially. The reaction was heated to 140°C for 7 hours. After completion, the solvent was mostly removed by rotary evaporation, and sodium hydroxide solution was added for neutralization. The filter cake was filtered, washed with ethyl acetate to remove impurities, and dried to obtain diene compound II in a 95% yield.

[0071] Step 2: Using the diene compound II described in step 1 as a raw material, an epoxy compound III is obtained by an epoxidation reaction under the action of m-chloroperbenzoic acid (mCPBA):

[0072] Diene compound II (3 mmol), mCPBA (9 mmol), and 50 mL of chloroform (or dichloromethane) were added to a reaction flask in sequence and reacted at 25-30°C for 24 hours. After the reaction, the solid was filtered off, and the filtrate was extracted with sodium thiosulfate solution and sodium bicarbonate solution, respectively. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was recrystallized from methanol to obtain epoxide compound III as a white solid in an approximately 83% yield.

[0073] Step 3: Using the epoxy compound III described in step 2 as a raw material, a brominated compound IV is obtained by bromination reaction under the action of hydrobromic acid:

[0074] Add epoxy compound III (1 mmol) and 10 mL of acetic acid to the reaction flask, and add a solution of hydrobromic acid (final concentration 4 mmol) in acetic acid dropwise at a rate of 1 to 2 drops per second at 0 to 5°C for more than 1 hour. After the addition is complete, react at 25 to 30°C for 2 hours. After the reaction is completed, neutralize with sodium hydroxide solution, extract with dichloromethane, dry, and spin-dry to obtain a yellow solid. Separate by column chromatography to obtain brominated compound IV with a yield of 87%.

[0075] Step 4: Using the brominated compound IV described in step 3 as a raw material, reacting it with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V:

[0076] After three evacuations and nitrogen replacements, the Shrek flask was sequentially added with brominated compound IV (3 mmol), potassium carbonate (7.5 mmol), tetrakistriphenylphosphine palladium (0.1 mmol), deuterated methylboronic acid (9 mmol), and 50 mL of anhydrous dioxane. The reaction was allowed to proceed at 100°C for 36 hours, then allowed to cool and quenched with water. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. Finally, deuterated megestrol acetate V was obtained by column chromatography with a yield of 78% as a pale yellow solid with a melting point of 211.7°C to 215.5°C. 1H NMR(400MHz, CDCl3)δ5.96(s,1H),5.87(s,1H),3.05-2.94(m,1H),2.64-2.5 2(m,1H),2.45(dd,J=17.9,3.6Hz,1H),2.25(t,J=10.2Hz,1H),2.09(s,3H), 2.06(s,3H),2.02-1.99(m,1H),1.98-1.85(m,3H),1.84-1.66(m,3H),1.64- 1.58(m,1H),1.49-1.38(m,2H),1.36-1.23(m,2H),1.09(s,3H),0.72(s,3H).

[0077] The analysis results showed that the chromatographic purity and isotope abundance both reached more than 98%.

[0078] According to the concept of the present invention, those skilled in the art may make various changes and modifications thereto, but these changes and modifications shall fall within the scope of the claims of the present invention.

Claims

1. A method for synthesizing deuterated megestrol acetate, characterized in that: The method comprises the following steps: Step 1: Using 17α-hydroxyprogesterone-17-acetate I as a raw material, dehydrogenating it under the oxidation action of chloranil and acetic acid to obtain diene compound II; Step 2: using the diene compound II described in step 1 as a raw material, subjecting it to an epoxidation reaction under the action of m-chloroperbenzoic acid to obtain an epoxy compound III; Step 3: Using the epoxy compound III described in step 2 as a raw material, a brominated compound IV is obtained by bromination reaction under the action of hydrobromic acid; Step 4: using the brominated compound IV described in step 3 as a raw material, reacting it with deuterated methylboronic acid under the catalysis of palladium to obtain deuterated megestrol acetate V; 2. The method for synthesizing deuterated megestrol acetate according to claim 1, wherein: In step 1, the dehydrogenation reaction includes: Place 17α-hydroxyprogesterone-17-acetate I, chloranil, and acetic acid in a reaction vessel, start stirring, and heat to 140±10°C for 6-8 hours.

3. A method for synthesizing deuterated megestrol acetate according to claim 2, characterized in that: After the dehydrogenation reaction is completed, the method further includes a step of separating and purifying the product.

4. The method for synthesizing deuterated megestrol acetate according to claim 3, wherein: The steps of separating and purifying the product include: standing and cooling, removing the solvent by vacuum rotary evaporation and sodium hydroxide solution neutralization, filtering to obtain a filter cake, washing the filter cake to remove impurities, and drying to obtain the diene compound II.

5. A method for synthesizing deuterated megestrol acetate according to claim 1 or 2, characterized in that: The molar ratio of the 17α-hydroxyprogesterone-17-acetate I, chloranil and acetic acid is 1: (1-1.5): (45-60).

6. The method for synthesizing deuterated megestrol acetate according to claim 5, wherein: The molar ratio of the 17α-hydroxyprogesterone-17-acetate I, chloranil and acetic acid is 1: (1.05-1.2): (50-55).

7. The method for synthesizing deuterated megestrol acetate according to claim 6, wherein: The solvent used in the dehydrogenation reaction is toluene.

8. The method for synthesizing deuterated megestrol acetate according to claim 1, wherein: In step 2, the epoxidation reaction includes: Place diene compound II and m-chloroperbenzoic acid in a reaction vessel, start stirring, and react at 25-30°C for 24±6h.

9. The method for synthesizing deuterated megestrol acetate according to claim 8, wherein: After the epoxy reaction is completed, the method further includes a step of separating and purifying the product.

10. The method for synthesizing deuterated megestrol acetate according to claim 9, wherein: The steps of separating and purifying the product include: filtering out the solid, extracting the filtrate with sodium thiosulfate solution and sodium bicarbonate solution respectively, drying and removing the solvent by vacuum rotary evaporation, and recrystallizing with methanol to obtain white solid epoxide III.

11. A method for synthesizing deuterated megestrol acetate according to claim 1 or 8, characterized in that: The molar ratio of the diene compound II to m-chloroperbenzoic acid is 1:(1-5).

12. The method for synthesizing deuterated megestrol acetate according to claim 11, wherein: The molar ratio of the diene compound II to m-chloroperbenzoic acid is 1:(2-3).

13. The method for synthesizing deuterated megestrol acetate according to claim 12, wherein: The solvent used in the epoxidation reaction is chloroform or dichloromethane.

14. The method for synthesizing deuterated megestrol acetate according to claim 1, wherein: In step 3, the bromination reaction comprises: placing epoxide III and acetic acid in a reaction vessel, starting stirring, adding an acetic acid solution containing hydrobromic acid at a rate of 1 to 2 drops per second at 0 to 5° C. for 1 to 3 hours, and reacting at 25 to 30° C. for 2±0.5 hours after the addition is completed.

15. The method for synthesizing deuterated megestrol acetate according to claim 14, wherein: After the bromination reaction is completed, the method further includes a step of separating and purifying the product.

16. The method for synthesizing deuterated megestrol acetate according to claim 15, wherein: The steps of separating and purifying the product include: neutralizing with sodium hydroxide solution, extracting with dichloromethane, drying, and removing the solvent by vacuum rotary evaporation to obtain a yellow solid, and separating by column chromatography to obtain brominated compound IV.

17. The method for synthesizing deuterated megestrol acetate according to claim 1 or 14, wherein: The molar ratio of epoxide III to hydrobromic acid is 1:(2-6).

18. The method for synthesizing deuterated megestrol acetate according to claim 17, wherein: The molar ratio of epoxide III to hydrobromic acid is 1:(3-5).

19. The method for synthesizing deuterated megestrol acetate according to claim 18, wherein: The hydrobromic acid is an acetic acid solution containing hydrobromic acid, and the final concentration of the hydrobromic acid in the reaction system is 1 to 50 mmol.

20. The method for synthesizing deuterated megestrol acetate according to claim 19, wherein: The solvent used in the bromination reaction is acetic acid.

21. The method for synthesizing deuterated megestrol acetate according to claim 1, wherein: In step 4, the Suzuki coupling reaction comprises: subjecting the reaction vessel to anhydrous and oxygen-free treatment, sequentially adding brominated compound IV, potassium carbonate, tetrakistriphenylphosphine palladium and deuterated methylboronic acid, and reacting at 100° C. for 36 hours.

22. The method for synthesizing deuterated megestrol acetate according to claim 21, wherein: After the Suzuki coupling reaction is completed, the method further includes a step of separating and purifying the product.

23. The method for synthesizing deuterated megestrol acetate according to claim 22, wherein: The steps of separating and purifying the product include: standing and cooling, adding water to quench, extracting with dichloromethane, drying with anhydrous sodium sulfate, and performing column chromatography to obtain deuterated megestrol acetate V.

24. The method for synthesizing deuterated megestrol acetate according to claim 1 or 21, wherein: In step 4, the molar ratio of the brominated compound IV, deuterated methylboronic acid and catalyst palladium is 1:(1-6):(0.01-0.1).

25. The method for synthesizing deuterated megestrol acetate according to claim 24, wherein: The molar ratio of the brominated compound IV, deuterated methylboronic acid and catalyst palladium is 1:(2-4):(0.02-0.05).

26. The method for synthesizing deuterated megestrol acetate according to claim 25, wherein: The solvent used in the Suzuki coupling reaction is dry and anhydrous 1,4-dioxane.

27. Use of the method according to any one of claims 1 to 26 for preparing stable deuterium-labeled deuterated megestrol acetate, wherein the chromatographic purity of the deuterated megestrol acetate is higher than 98% and the isotopic abundance is higher than 98%.

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