Preparation method of 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one

Abstract

The present invention provides a method for preparing 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one, the preparation method comprising the following steps: (1) reacting 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one with p-nitrobenzenesulfonyl chloride to obtain compound INT-1, and performing iodination reaction of compound INT-1 with potassium iodide and iodine to obtain 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one. In the present invention, by utilizing p-nitrobenzenesulfonyl chloride which is cheap and readily available, an intermediate INT-1 of a disubstituted sulfonylamino group is obtained by sulfonylation reaction, an excellent leaving group is formed, and the process conditions of the iodination reaction are milder, the occurrence of side reactions is reduced, and it is beneficial to control product quality.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of thioctic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one. Background Art

[0002] α-lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble, and can assist coenzymes in physiological metabolism that is beneficial to the body's immunity. It is a universal antioxidant drug. α-lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumors, nervous system degeneration, radiation damage, arsenic, mercury, cadmium and other heavy metal poisoning. For example, it can assist in the treatment of type II diabetes, improve pancreatic function and glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage, etc.

[0003] There are many α-lipoic acid synthesis routes published in literature and patents, each with its own characteristics, but most of them are costly, with complicated synthesis steps, harsh process conditions, and are prone to produce polymer impurities and other process impurities, which are difficult to separate and affect product quality. The main existing synthesis methods are as follows:

[0004] (1) Adipic acid method: Using adipic acid as the starting material, α-lipoic acid is obtained through six steps of monomethyl esterification, chlorination, ethylene addition, reduction, chlorination, cyclization, and ester hydrolysis. The total yield of this method is 34.6%, which is low and easily forms lipoic acid polymers, which are difficult to separate, resulting in low purity.

[0005] (2) Cyclohexanone and vinyl ether method: Cyclohexanone and vinyl ether are used as raw materials, and α-lipoic acid can be obtained through four steps of free radical addition, Baeyer-Villiger oxidation, lactone hydrolysis, nucleophilic substitution, and air oxidation. This method has low raw material cost, but the yield is only 45%, which is low, and the conditions are relatively harsh, the reaction is complex, and there are many by-products, which is not conducive to industrialization.

[0006] (3) 4-Chloroformylvaleric acid ethyl ester method: 6,8-dichlorooctanoic acid ethyl ester is used as the raw material, reacted with sodium benzyl mercaptan, hydrolyzed with potassium hydroxide, and then reduced to 6,8-dimercaptooctanoic acid with metallic sodium in liquid ammonia, and then oxidized to obtain α-lipoic acid. The yield of the three steps is 53%. This method has many steps and cumbersome operation. The use of liquid ammonia and sodium is not conducive to industrial production.

[0007] The existing methods for synthesizing α-lipoic acid, including the three methods mentioned above, all have the disadvantages of high cost, low yield and high raw material consumption and cannot meet the requirements of industrialized production. In addition, they do not meet the requirements of green and environmentally friendly production due to high waste emissions.

[0008] CN113754630A discloses a method for synthesizing α-lipoic acid, wherein the key intermediate involved is 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (Formula 1). The process is simple, the operation is safe and controllable, and the cost is low, so it is suitable for industrial production. The disclosed synthetic route is:

[0009]

[0010]

[0011] However, the iodination reaction involved in CN113754630A uses 2,4,6-triphenylpyran tetrafluoroborate to pre-prepare the iodination reagent. Based on considerations such as molecular structure, molecular weight and reaction equivalent, its atomic economic utilization rate is not high enough. At the same time, due to the steric hindrance of the molecular structure, the reaction time is long and the risk of impurity generation is also increased. Summary of the invention

[0012] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one.

[0013] To achieve this object, the present invention adopts the following technical solutions:

[0014] In one aspect, the present invention provides a method for preparing 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one, the preparation method comprising the following steps:

[0015] (1) 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one reacts with p-nitrobenzenesulfonyl chloride to obtain compound INT-1. The reaction formula is as follows:

[0016]

[0017] (2) Compound INT-1 is subjected to iodination reaction with potassium iodide and iodine to obtain 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one. The reaction formula is as follows:

[0018]

[0019] In the present invention, by utilizing cheap and readily available p-nitrobenzenesulfonyl chloride, a disubstituted sulfonylamino intermediate INT-1 is obtained through a sulfonylation reaction to form an excellent leaving group. The iodination reaction process conditions are mild and no side reactions occur, which is greatly beneficial to controlling product quality.

[0020] Preferably, the molar ratio of 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one to p-nitrobenzenesulfonyl chloride in step (1) is 1:2-4, for example 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8 or 1:4.

[0021] Preferably, the reaction in step (1) is carried out in the presence of an alkaline substance.

[0022] Preferably, the alkaline substance is any one of triethylamine, N,N-diisopropylethylamine or pyridine, or a combination of at least two thereof.

[0023] Preferably, the molar ratio of the alkaline substance to 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one is 4-6:1, for example 4:1, 4.3:1, 4.5:1, 4.8:1, 5:1, 5.3:1, 5.5:1, 5.8:1 or 6:1.

[0024] Preferably, the p-nitrobenzenesulfonyl chloride in step (1) is added to the reaction system at 0-10°C (0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C or 10°C).

[0025] Preferably, the solvent for the reaction in step (1) is any one of dichloromethane, methyl tert-butyl ether or tetrahydrofuran, or a combination of at least two thereof.

[0026] Preferably, the reaction temperature in step (1) is 50-90°C (e.g., 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or 90°C), and the reaction time is 5-48 hours (e.g., 5 hours, 8 hours, 10 hours, 13 hours, 15 hours, 20 hours, 25 hours, 28 hours, 30 hours, 35 hours, 38 hours, 40 hours, 45 hours or 48 hours).

[0027] Preferably, the molar ratio of the compound INT-1 to potassium iodide in step (2) is 1:2-3, for example 1:2, 1:2.5, 1:2.8, 1:3.

[0028] Preferably, in step (2), the molar ratio of the compound INT-1 to iodine is 1:2-3, for example, 1:2, 1:2.5, 1:2.8, 1:3.

[0029] Preferably, the solvent for the iodination reaction in step (2) is N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0030] Preferably, the temperature of the iodination reaction in step (2) is 50-80°C (e.g., 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C), and the reaction time is 3-8 hours (e.g., 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours).

[0031] As a preferred technical solution, the preparation method of 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one of the present invention comprises the following steps:

[0032] (1) In the presence of an alkaline substance, 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one and p-nitrobenzenesulfonyl chloride are reacted at a molar ratio of 1:2-4 at 50-90° C. for 5-48 hours to obtain compound INT-1;

[0033] (2) Compound INT-1 is subjected to iodination reaction with potassium iodide and iodine at 50-80° C. for 3-8 hours, wherein the molar ratio of compound INT-1 to potassium iodide is 1:2-3, and the molar ratio of compound INT-1 to iodine is 1:2-3, to obtain 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] In the present invention, by utilizing cheap and readily available p-nitrobenzenesulfonyl chloride, a disubstituted sulfonylamino intermediate INT-1 is obtained through a sulfonylation reaction to form an excellent leaving group. The iodination reaction process conditions are milder, the occurrence of side reactions is reduced, and it is beneficial to control product quality. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0037] Example 1

[0038] (1) Preparation of intermediate INT-1:

[0039] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (7.5 g, 27.2 mmol) and triethylamine (13.0 g, 0.13 mol) were dissolved in dichloromethane (200 mL), cooled to 10°C, and p-nitrobenzenesulfonyl chloride (18.5 g, 83.5 mmol) was slowly added. The temperature was raised to 50°C for reaction for 24 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The solution was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the intermediate INT-1 (16.0 g) with a yield of 91%. The reaction formula is as follows:

[0040]

[0041] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0042] The intermediate INT-1 (16.0 g, 24.8 mmol) was dissolved in N, N-dimethylformamide (200 mL), potassium iodide (8.5 g, 51.2 mmol) and iodine (12.5 g, 49.2 mmol) were added, the temperature was raised to 50 ° C for reaction for 8 h, the temperature was lowered to room temperature, the organic solvent was removed by concentration under reduced pressure, dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the finished product (8.9 g) with a yield of 93%. The reaction formula is as follows:

[0043]

[0044] Example 2

[0045] (1) Preparation of intermediate INT-1:

[0046] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (10.0 g, 36.3 mmol) and N,N-diisopropylethylamine (25.0 g, 0.19 mol) were dissolved in methyl tert-butyl ether (300 mL), cooled to 10°C, and p-nitrobenzenesulfonyl chloride (28.0 g, 0.13 mol) was slowly added. The temperature was raised to 90°C for reaction for 12 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the intermediate INT-1 (21.0 g) with a yield of 90%.

[0047] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0048] The intermediate INT-1 (21.0 g, 32.5 mmol) was dissolved in N,N-dimethylformamide (300 mL), potassium iodide (16.0 g, 96.4 mmol) and iodine (24.0 g, 94.6 mmol) were added, the temperature was raised to 80 ° C for reaction for 3 h, the temperature was lowered to room temperature, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the finished product (11.5 g) with a yield of 92%.

[0049] Example 3

[0050] (1) Preparation of intermediate INT-1:

[0051] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (18.0 g, 65.3 mmol) and pyridine (25.0 g, 0.32 mol) were dissolved in tetrahydrofuran (500 mL), cooled to 10°C, and p-nitrobenzenesulfonyl chloride (47.0 g, 0.21 mol) was slowly added. The temperature was raised to 70°C for reaction for 18 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The solution was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the intermediate INT-1 (38.8 g) with a yield of 92%.

[0052] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0053] The intermediate INT-1 (38.0 g, 58.8 mmol) was dissolved in N,N-dimethylacetamide (500 mL), potassium iodide (24.0 g, 0.14 mol) and iodine (37.0 g, 0.15 mol) were added, the temperature was raised to 70 ° C for reaction for 5 h, the temperature was lowered to room temperature, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the finished product (21.6 g) with a yield of 95%.

[0054] Example 4

[0055] (1) Preparation of intermediate INT-1:

[0056] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (12 g, 43.6 mmol) and triethylamine (18.0 g, 0.18 mol) were dissolved in methyl tert-butyl ether (500 mL), cooled to 0°C, and p-nitrobenzenesulfonyl chloride (20.0 g, 0.09 mol) was slowly added. The temperature was raised to 60°C for reaction for 48 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the intermediate INT-1 (25.5 g) with a yield of 91%.

[0057] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0058] The intermediate INT-1 (25.0 g, 38.7 mmol) was dissolved in N,N-dimethylformamide (500 mL), potassium iodide (17.0 g, 0.1 mol) and iodine (23.0 g, 0.09 mol) were added, the temperature was raised to 60 ° C for reaction for 4 h, the temperature was lowered to room temperature, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the finished product (13.5 g) with a yield of 90%.

[0059] Example 5

[0060] (1) Preparation of intermediate INT-1:

[0061] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (8 g, 29.0 mmol) and N,N-diisopropylethylamine (22.0 g, 0.17 mol) were dissolved in dichloromethane (500 mL), cooled to 5°C, and p-nitrobenzenesulfonyl chloride (17.0 g, 76.7 mmol) was slowly added. The temperature was raised to 55°C for reaction for 36 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The solution was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the intermediate INT-1 (17.0 g) with a yield of 91%.

[0062] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0063] The intermediate INT-1 (17.0 g, 26.3 mol) was dissolved in N,N-dimethylacetamide (500 mL), potassium iodide (9.0 g, 54.2 mmol) and iodine (20.0 g, 78.8 mmol) were added, the temperature was raised to 55 ° C for reaction for 7 h, the temperature was lowered to room temperature, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the finished product (9.5 g) with a yield of 93%.

[0064] Example 6

[0065] (1) Preparation of intermediate INT-1:

[0066] 7-Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one (15 g, 54.5 mmol) and pyridine (22.0 g, 0.28 mol) were dissolved in tetrahydrofuran (500 mL), cooled to 0°C, and p-nitrobenzenesulfonyl chloride (48.0 g, 0.22 mol) was slowly added. The temperature was raised to 80°C for reaction for 5 h, cooled to room temperature, and water was added dropwise to quench the reaction solution. The organic solvent was removed by concentration under reduced pressure, and dichloromethane was added for extraction. The solution was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized with methanol, and dried under vacuum to obtain the intermediate INT-1 (31.0 g) with a yield of 88%.

[0067] (2) Preparation of finished product, i.e. preparation of lipoic acid intermediate 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one:

[0068] The intermediate INT-1 (31.0 g, 48.0 mol) was dissolved in N,N-dimethylacetamide (500 mL), potassium iodide (23.0 g, 0.14 mol) and iodine (25.0, 98.5 mmol) were added, the temperature was raised to 75 ° C for reaction for 6 h, the temperature was lowered to room temperature, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, recrystallized from methanol, and dried under vacuum to obtain the finished product (17.0 g) with a yield of 92%.

[0069] The applicant declares that the present invention illustrates the preparation method of 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one of the present invention through the above-mentioned embodiment, but the present invention is not limited to the above-mentioned embodiment, that is, it does not mean that the present invention must rely on the above-mentioned embodiment to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one, characterized in that: The preparation method comprises the following steps: (1) 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one reacts with p-nitrobenzenesulfonyl chloride to obtain compound INT-1. The reaction formula is as follows: (2) Compound INT-1 is subjected to iodination reaction with potassium iodide and iodine to obtain 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one. The reaction formula is as follows: The reaction temperature in step (1) is 50-90° C. and the reaction time is 5-48 hours; The solvent for the iodination reaction in step (2) is N,N-dimethylformamide and / or N,N-dimethylacetamide; the temperature for the iodination reaction in step (2) is 50-80° C., and the reaction time is 3-8 hours.

2. The preparation method according to claim 1, characterized in that: The molar ratio of 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one to p-nitrobenzenesulfonyl chloride in step (1) is 1:2-4.

3. The preparation method according to claim 1, characterized in that: The reaction in step (1) is carried out in the presence of an alkaline substance.

4. The preparation method according to claim 3, characterized in that: The alkaline substance is any one of triethylamine, N,N-diisopropylethylamine or pyridine, or a combination of at least two thereof.

5. The preparation method according to claim 3, characterized in that: The molar ratio of the alkaline substance to 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one is 4-6:

1.

6. The preparation method according to claim 1, characterized in that: In step (1), the p-nitrobenzenesulfonyl chloride is added into the reaction system at 0-10°C.

7. The preparation method according to claim 1, characterized in that: The solvent for the reaction in step (1) is any one of dichloromethane, methyl tert-butyl ether or tetrahydrofuran, or a combination of at least two thereof.

8. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of the compound INT-1 to potassium iodide is 1:2-3.

9. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of the compound INT-1 to iodine is 1:2-3.

10. The preparation method according to claim 1, characterized in that: The solvent for the iodination reaction in step (2) is N,N-dimethylformamide and / or N,N-dimethylacetamide.

11. The preparation method according to claim 1, characterized in that: (1) In the presence of an alkaline substance, 7-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one and p-nitrobenzenesulfonyl chloride are reacted at a molar ratio of 1:2-4 at 50-90° C. for 5-48 hours to obtain compound INT-1; (2) Compound INT-1 is subjected to iodination reaction with potassium iodide and iodine at 50-80° C. for 3-8 hours, wherein the molar ratio of compound INT-1 to potassium iodide is 1:2-3, and the molar ratio of compound INT-1 to iodine is 1:2-3, to obtain 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methoxy}heptane-3-one.

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