Method for synthesizing (R)-3-methylheptanoic acid

Abstract

The invention relates to a method for synthesizing (R)-3-methylheptanoic acid. According to the method, the application range of steroid sapogenin degradation waste is further expanded. According to the method disclosed by the invention, the (R)-3-methyl-heptanoic acid can be conveniently obtained by taking the (R)-4-methyl-gamma-butyric acid lactone obtained by degrading steroid sapogenin as a raw material. According to the method provided by the invention, the use of highly toxic and controlled reagents is avoided, high-risk reactions such as hydrogenation in the prior art are avoided, and the method is mild in reaction condition and low in synthesis cost. Meanwhile, the utilization rate of steroid sapogenin resources is increased, and waste generated in the utilization process of the steroid sapogenin resources is reduced.

Description

Technical Field

[0001] This invention relates to a novel method for synthesizing (R)-3-methylheptanoic acid. Background Technology

[0002] (R)-3-methylheptanoic acid is a sex pheromone of the scarab beetle (Kheper nigroaeneus), a member of the genus Kheper in the family Scarabaeidae. Extensive literature has reported its role as an important chiral synthetic intermediate, playing a unique role in the synthesis of various drugs and in constructing complex chiral molecular structures. Furthermore, it can serve as a probe material in biological research and as a biopesticide for controlling insect pests.

[0003] Since 2002, numerous studies have reported on the synthesis of (R)-3-methylheptanoic acid, but the methods are generally complex and yields are not guaranteed. For example, the BVBurger group at Stellenbosch University in South Africa synthesized (R)-3-methylheptanoic acid from natural chiral (R)-citronellol. The Sergio Pinheiro group in Brazil developed an asymmetric conjugated addition reaction using (-)-pinenediol as a chiral cofactor to obtain (R)-3-methylheptanoic acid. The Bruce H. Lipshutz group at the University of California obtained (R)-3-methylheptanoic acid through the asymmetric reduction of unsaturated ketones catalyzed by copper hydride. The Xumu Zhang group at the University of Pennsylvania developed a rhodium complex-catalyzed highly enantioselective reduction synthesis of (R)-3-methylheptanoic acid. Furthermore, the Tian Weisheng group at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, prepared (R)-3-methylheptanoic acid using 4-(R)-methylvalerol lactone as a starting material.

[0004] Although various methods for preparing (R)-3-methylheptanoic acid have been reported in this field, existing methods still suffer from drawbacks such as complex synthesis processes, difficulty in obtaining raw materials, and low efficiency. Furthermore, the group led by Tian Weisheng at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, prepared (R)-3-methylheptanoic acid using 4-(R)-methylvalerolactone as a starting material. However, 4-(R)-methylvalerolactone is a mixture, making it difficult to separate and purify. Therefore, the starting material for this synthetic route is a mixture containing many impurities, which poses difficulties for subsequent synthesis, separation, and purification.

[0005] Given the significant potential applications of this chiral fragment in the pharmaceutical industry and complex molecular design, the more economical and environmentally friendly synthesis of (R)-3-methylheptanoic acid remains a technical challenge that needs to be addressed. Summary of the Invention

[0006] Through in-depth research and creative work, the inventors have discovered a method for synthesizing (R)-3-methylheptanoic acid using steroidal saponin degradation waste as raw material.

[0007] This invention provides a method for synthesizing (R)-3-methylheptanoic acid, which can conveniently synthesize (R)-3-methylheptanoic acid from (R)-4-methyl-γ-butyrate lactone obtained by the degradation of steroidal saponins.

[0008] The method provided by this invention does not use expensive catalysts or highly toxic and controlled reagents, and involves no high-risk reactions such as hydrogenation. All post-processing steps can be purified by distillation, eliminating the need for column chromatography. It is milder, more environmentally friendly, and easier to mass-produce than existing technologies. Simultaneously, it helps improve the utilization rate of steroidal saponin resources and reduces waste generated during their utilization, thus being more environmentally friendly.

[0009] This invention provides a method for preparing (R)-3-methyl-heptanoic acid, comprising:

[0010] 1) Compound 2 is reduced to give compound 3;

[0011]

[0012] R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl.

[0013] 2) Compound 3 was protected with methoxymethyl ether (mom) to obtain compound 4;

[0014]

[0015] 3) Compound 4 reacts with magnesium to give compound 5;

[0016]

[0017] 4) Compound 5 undergoes a carboxylation reaction to yield compound 6;

[0018]

[0019] 5) Compound 6 was deprotected by the mom protecting group under acidic conditions and simultaneously methylated with carboxylic acid to give compound 7;

[0020]

[0021] 6) Compound 7 undergoes bromination to give compound 8;

[0022]

[0023] 7) Compound 8 undergoes a coupling reaction with Grignard reagent in the presence of an auxiliary reagent to generate compound 9;

[0024]

[0025] 8) Compound 10 undergoes a hydrolysis reaction.

[0026]

[0027] Preferably, compound 2 is obtained by reacting compound 1 with a hydrobromic acid-acetic acid solution and an alcohol solvent.

[0028]

[0029] More preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl.

[0030] More preferably, compound 1 is (R)-4-methyl-γ-butyric acid lactone produced by the degradation of steroidal saponins.

[0031] More preferably, the alcohol solvent is selected from one or more of ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, or benzyl alcohol.

[0032] Preferably, the reducing agent in step 1) is selected from one or more of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), potassium borohydride (KBH4), lithium borohydride (LiBH4), zinc borohydride (ZnBH4), lithium aluminum hydride (LiAlH4), or diisobutylaluminum hydride (DIBALH).

[0033] Preferably, the molar ratio of compound 2 and reducing agent in step 1) is 1:0.5 to 1:15.

[0034] Preferably, in step 2), the methoxymethyl ether protecting agent is selected from one or more of bromomethyl methyl ether, chloromethyl methyl ether, or dimethoxymethane, and the organic base is selected from one or more of N,N-diisopropylethylamine, triethylamine, and pyridine.

[0035] Preferably, the brominating agent in step 6) is selected from CBr4, HBr, or N-bromosuccinimide (NBS).

[0036] Preferably, the activating agent in step 6) is selected from Ph3P, Me3P, Bu3P or (MeO)3P.

[0037] Preferably, the Grignard reagent in step 7) is selected from ethyl magnesium bromide or ethyl magnesium iodide.

[0038] More preferably, the Grignard reagent in step 7) is ethyl magnesium bromide.

[0039] More preferably, in step 7), ethyl magnesium bromide is a Grignard reagent formed by ethyl bromide and magnesium shavings.

[0040] Preferably, the auxiliary reagent in step 7) is selected from tetrahydrofuran or diethyl ether solution of CuCl, CuBr, CuI, CuCN, LiCl, LiBr, Li2CuCl4, N-methylpyrrolidone, or mixtures thereof.

[0041] More preferably, the auxiliary reagent in step 7) is selected from a tetrahydrofuran or diethyl ether solution of lithium tetrachlorocubic acid, N-methylpyrrolidone, or a mixture thereof.

[0042] Preferably, in step 7), the molar ratio of compound 8 to Grignard reagent and auxiliary reagent is 1:1 to 10, or 1:0.01 to 10.

[0043] More preferably, in step 7), the molar ratio of compound 8 to Grignard reagent and auxiliary reagent is 1:2.4, 1:0.1 to 4.

[0044] As a preferred embodiment, the present invention relates to a method for preparing (R)-3-methyl-heptanoic acid, the method route of which is as follows:

[0045]

[0046] Preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl.

[0047] More preferably, R is a methyl group. Attached Figure Description Figure 1 (R)-3-methyl-heptanoic acid was synthesized from (R)-4-methyl-γ-butyric acid lactone. Detailed Implementation

[0048] The following specific implementation methods will help to understand the present invention, but do not limit the scope of the present invention.

[0049] The method for synthesizing compound 2 is described in patent application (WO2020084300A1).

[0050]

[0051] Add 6.0 g (60 mmol) of (R)-4-methyl-γ-butyric acid lactone to a 250 ml round-bottom flask, followed by adding...

[0052] 44 mL of a 33% hydrobromic acid-acetic acid solution was heated to 80 °C and refluxed for 4 h. After cooling to room temperature, 68 mL of methanol was added to the system and the reaction was carried out at room temperature for 24 h. The methanol was then removed by concentration. The solution was adjusted to a weakly alkaline state with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting product was purified by distillation to give 6.87 g of compound 2, with a yield of 59%.

[0053] Example 1: Synthesis of Compound 3

[0054]

[0055] Under nitrogen protection, 50 mL of anhydrous tetrahydrofuran and 0.456 g (4 mmol) of lithium aluminum hydride were added to the reaction flask. The mixture was cooled to -10 °C, and 2.328 g (12 mmol) of compound 2 was added to the system. The reaction was maintained at low temperature for 3 h. TLC showed that the reaction was complete. The reaction was quenched, and the mixture was filtered. The solid was washed with ethyl acetate, and the filtrates were combined and concentrated under reduced pressure to give 1.73 g of compound 3, in 87% yield.

[0056] Example 2 Synthesis of Compound 4

[0057]

[0058] Under argon protection, 1.66 g (10 mmol) of compound 3 and 15 mL of dry dichloromethane were added to a reaction flask, followed by 3.67 mL of N,N-diisopropylethylamine and 1.6 mL of bromomethyl methyl ether. The reaction was carried out at room temperature for 2 hours. TLC showed that the reaction was complete. Saturated NaHCO3 solution was added, and the mixture was separated. The aqueous phase was extracted three times with methyl tert-butyl ether. The organic phases were combined, dried and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.99 g of a colorless oily compound 4, with a yield of 95%.

[0059] Example 3 Synthesis of Compound 5

[0060]

[0061] Under argon protection at 60°C, 1.05 g (5 mmol) of compound 4 was added dropwise to a tetrahydrofuran suspension containing 0.15 g (6 mmol) of magnesium chips. After the addition was complete, the mixture was stirred for 1 h to obtain a tetrahydrofuran solution of compound 5.

[0062] Example 4: Synthesis of Compound 6

[0063]

[0064] Dry CO2 was bubbled into a tetrahydrofuran solution of compound 5 under an ice-water bath, and the reaction was allowed to proceed at room temperature. TLC showed the reaction was complete. Then, HCl (1.2 mol / L) was slowly added under an ice-water bath, and the mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 6.

[0065] 0.69g, yield 78%.

[0066] Example 5 Synthesis of Compound 7

[0067]

[0068] Compound 6 obtained in Example 5 was dissolved in methanol, and 1.33 mL of 6N dilute hydrochloric acid was added. The reaction was heated in an oil bath at 50°C. TLC showed that the reaction was complete. The mixture was quenched with water, separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.51 g of compound 7, with a yield of 90%.

[0069] Example 6 Synthesis of Compound 8

[0070]

[0071] Compound 7 was dissolved in anhydrous dichloromethane. Under ice-water bath conditions, 1.38 g (5.29 mmol, 1.5 eq) of triphenylphosphine and 1.70 g (5.29 mmol, 1.5 eq) of carbon tetrabromide were added. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was quenched with water, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2. The organic phases were combined and evaporated to dryness under reduced pressure. The residue solid was washed several times with n-hexane to remove a large amount of salt. The mother liquor was concentrated and purified by vacuum distillation to obtain 0.55 g of colorless liquid of compound 8, with a yield of 80%.

[0072] Example 7 Synthesis of Compound 9

[0073]

[0074] Weigh 0.17 g (7 mmol) of metallic magnesium into a dry three-necked flask, add 5.8 mL of freshly distilled tetrahydrofuran under argon protection, and then add 0.616 mL (6.72 mmol, 2.4 eq) of bromoethane in 5.8 mL of tetrahydrofuran solution under reflux. After the addition is complete, stir for 1 h to obtain a tetrahydrofuran solution of ethyl magnesium bromide, and cool to room temperature for later use.

[0075] Under argon protection, anhydrous tetrahydrofuran, compound 8 (0.55 g, 2.8 mmol), N-methyl-2-pyrrolidone (1.07 mL, 11.2 mmol, 4 eq), and a THF solution of Li₂CuCl₄ (0.56 mL, 0.5 mol / L) were added to a reaction flask. The prepared ethyl magnesium bromide solution was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed for 0.5 h. The reaction was then quenched by adding saturated ammonium chloride solution. The mixture was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was then distilled to give compound 9 (0.28 g), with a yield of 70%.

[0076] Example 8 Synthesis of Compound 10

[0077]

[0078] Compound 9 (0.24 g, 1.5 mmol) was diluted with 6 ml of methanol, and 0.36 g of sodium hydroxide was dissolved in 4 ml of water and added to the reaction flask. The reaction was carried out at room temperature for 3 h. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the pH was adjusted to 3 with dilute hydrochloric acid. The mixture was extracted with dichloromethane and concentrated under reduced pressure to give 0.194 g, with a yield of 90%.

[0079] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of this invention. The full scope of this invention is given by the appended claims and any equivalents thereof.

Claims

1. A method for preparing (R)-3-methyl-heptanoic acid, comprising the following steps: 1) Compound 2 reacts in the presence of a reducing agent to give compound 3; in, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl; 2) Compound 3 was protected with methoxymethyl (mom) to obtain compound 4; 3) Compound 4 reacts with magnesium to give compound 5; 4) Compound 5 undergoes a carboxylation reaction to yield compound 6; 5) Compound 6 was deprotected by the mom protecting group under acidic conditions, and then methylated to give compound 7; 6) Compound 7 reacts with a brominating reagent to give compound 8; 7) Compound 8 undergoes a coupling reaction with Grignard reagent in the presence of an auxiliary reagent to generate compound 9; 8) Compound 9 undergoes a hydrolysis reaction to give compound 10.

2. The method according to claim 1, wherein compound 2 is obtained by reacting compound 1 with a hydrobromic acid-acetic acid solution and an alcohol solvent. in, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl.

3. The method according to claim 2, wherein compound 1 is (R)-4-methyl-γ-butyric acid lactone produced by the degradation of steroidal saponins, and the alcohol solvent is selected from one or more of ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol or benzyl alcohol.

4. The method according to claim 1, wherein the reducing agent in step 1) is selected from sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), potassium borohydride (KBH4), lithium borohydride (LiBH4), etc. 4， One or more of zinc borohydride (ZnBH4), lithium aluminum hydride (LiAlH4), or diisobutylaluminum hydride (DIBALH).

5. The method according to claim 1, wherein the molar ratio of compound 2 and reducing agent in step 1) is 1:0.5 to 1:

15.

6. The method according to claim 1, wherein the methoxymethyl ether protecting agent in step 2) is selected from one or more of bromomethyl methyl ether, chloromethyl methyl ether or dimethoxymethane, and the organic base is selected from one or more of N,N-diisopropylethylamine, triethylamine and pyridine.

7. The method according to claim 1, wherein the brominating agent in step 6) is selected from Br2, CBr4, HBr or N-bromosuccinimide (NBS); and the activating agent is selected from Ph3P, Me3P, Bu3P or (MeO)3P.

8. The method according to claim 1, wherein the Grignard reagent in step 7) is selected from ethyl magnesium bromide or ethyl magnesium iodide.

9. The method according to claim 8, wherein the Grignard reagent in step 7) is ethyl magnesium bromide.

10. The method according to claim 9, wherein the ethyl magnesium bromide in step 7) is a Grignard reagent formed by ethyl bromide and magnesium shavings.

11. The method according to claim 1, wherein the auxiliary reagent in step 7) is selected from CuCl, CuBr, CuI, CuCN, LiCl, LiBr, Li2CuCl4, N-methylpyrrolidone or mixtures thereof.

12. The method according to claim 1, wherein the auxiliary reagent in step 7) is selected from Li2CuCl4, N-methylpyrrolidone, or a mixture thereof.

13. The method according to claim 1, wherein the molar ratio of compound 8 in step 7) to Grignard reagent and auxiliary reagent is 1:1 to 10, or 1:0.01 to 10.

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