A method for preparing 5-oxotricyclic [2,2,1,0] 2,6 Method for heptane-3-carboxylic acid

Abstract

The application discloses a 5-oxotricyclo[2,2,1,0] 2,6 The application discloses a preparation method of heptane-3-carboxylic acid, and belongs to the technical field of synthesis of medical intermediates. A diformyl glycol ester II is hydrolyzed under alkaline conditions to generate a diol III, and then the diol III is oxidized into 5-oxotricyclo[2,2,1,0] 2,6 Heptane-3-carboxylic acid 1. The application adopts a catalytic oxidation method, has mild conditions, is easy to operate, has high conversion rate and yield, does not use chromium oxide and concentrated sulfuric acid, thereby avoiding generation of a large amount of toxic solid waste and a large amount of waste acid, and has small three-waste burden; a multi-metal catalytic system Fe(NO3)3-Co(OAc)2 is adopted, compared with a traditional Fe(NO3)3 catalyst system, the reaction speed is faster, the production efficiency is higher, and the method is suitable for industrialized production.

Description

Technical Field

[0001] This invention relates to a method for preparing fused-ring carboxylic acid analogs, specifically to 5-oxotricyclic [2,2,1,0] 2,6 A novel method for preparing heptane-3-carboxylic acid belongs to the field of pharmaceutical intermediate synthesis technology. Background Technology

[0002] Prostaglandins are an important class of endogenous physiologically active natural products. They can induce smooth muscle contraction, as well as defensive responses such as inflammation and pain, and act as important mediators of various physiological processes. They can control physiological phenomena such as pregnancy, hypertension, ulcers, asthma, and pain.

[0003] Since 1969, when EJ Corey et al. synthesized the key intermediate bicyclo[2,2,1]heptane derivative from cyclopentadiene, the synthesis has been a key process. A synthetic method with good stereoselectivity and high yield was developed from this intermediate, and after a series of improvements, it has become an effective route for the total synthesis of prostaglandins. A typical synthetic method for this fused-ring carboxylic acid derivative is as follows:

[0004] The traditional preparation method (Collection Czechoslovak Chern. Commun. 1983, 3565-3566) uses norbornadiene as a raw material, and through a two-step reaction of Prins reaction and Jones reagent oxidation, yields the racemic 5-oxotricyclic [2,2,1,0]heptane-3-carboxylic acid. The reaction equation is as follows:

[0005]

[0006] This method uses a system of chromium trioxide (CrO3), sulfuric acid, water, and acetone for the oxidation reaction. However, the chromium reagent (Jones' reagent) is highly toxic, and the treatment of waste is difficult, posing a significant environmental challenge. There is a need to find an alternative oxidation method that is safer, more economical, and more environmentally friendly, while also being suitable for industrial scale-up.

[0007] The literature, Org. Process Res. Dev. 2019, 23, 825-835, J. Am. Chem. Soc. 2016, 138, 8344-8347, describes the catalytic oxidation of most alcohols to aldehydes or ketones using the Fe(NO3)3-TEMPO system. However, no studies on substrates with fused-ring structures have been found in this literature. Fused-ring compounds exhibit strong steric hindrance and reaction inertness, resulting in reaction times of 36-48 hours for intermediate III, severely impacting production efficiency and making them uneconomical. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a 5-oxotricyclic [2,2,1,0] ring. 2,6 A novel method for the preparation of heptane-3-carboxylic acid. The synthetic strategy involves hydrolyzing the Prins reaction intermediate to diol intermediate III, followed by catalytic oxidation to directly obtain the target product. The synthetic route is represented by the following reaction equation:

[0009]

[0010] The final oxidation step involves using oxygen or air as an oxidant and a multi-element catalyst to efficiently synthesize the corresponding carboxylic acid or ketone compounds from primary or secondary alcohols.

[0011] The present invention describes a 5-oxotricyclic [2,2,1,0] ring. 2,6 A novel method for preparing heptane-3-carboxylic acid includes the following steps: hydrolyzing diformyl diol ester II under alkaline conditions to generate diol III, followed by catalytic oxidation of diol III to 5-oxotricyclic [2,2,1,0] in the presence of an oxidant and a catalyst. 2,6 The reaction equation for heptane-3-carboxylic acid 1 is as follows:

[0012]

[0013] Furthermore, in the above technical solution, in the first step, the alkaline conditions are achieved by reacting sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate in an alcohol solvent.

[0014] Furthermore, in the above technical solution, the oxidant in the second step is selected from oxygen or air; it is added to the reaction system in the form of a balloon or by bubbling.

[0015] Furthermore, in the above technical solution, in the second step, the catalytic system is ferric nitrate / cobalt acetate / 2,2,6,6-tetramethylpiperidine oxide. The molar ratio of ferric nitrate to cobalt acetate is 0.5-2:1. During the catalytic reaction, the catalyst exhibits good synergistic effect, resulting in a faster reaction rate and higher yield compared to the pure ferric nitrate (Fe) catalytic system. However, this synergy is not obvious; if Fe-Mn is used as a cohesive catalyst, the reaction rate may actually decrease.

[0016] Furthermore, in the above technical solution, the reaction temperature in the second step is 0-30℃, and the reaction time is 12-24 hours.

[0017] Furthermore, in the above technical solution, the molar ratio of the catalyst to the diol in the second step is 0.02-0.1:1.

[0018] Beneficial effects of the invention

[0019] 1. The catalytic oxidation method is mild, easy to operate, and has high conversion and yield. It does not use chromium oxide or concentrated sulfuric acid, thus avoiding the generation of large amounts of highly toxic solid waste and waste acid, resulting in a small burden of waste.

[0020] 2. The catalyst of this invention adopts a multi-metal catalytic system Fe(NO3)3-Co(OAc)2, which has a faster reaction rate and higher production efficiency than the traditional Fe(NO3)3 catalyst system, making it suitable for industrial production.

[0021] 3. The reaction is clean and environmentally friendly, using air or oxygen as an oxidant, with atom economy, and will not produce secondary pollution. Detailed Implementation

[0022] Example 1

[0023]

[0024] In a 500 mL three-necked flask, 20 g of norbornene, 200 mL of formic acid, and 6.8 g of paraformaldehyde were added sequentially. The mixture was stirred at room temperature to form a suspension. The system was cooled to 0 °C, and 2.25 mL of concentrated sulfuric acid was added dropwise. After the addition was complete, the system was warmed back to room temperature and stirred overnight until the system became clear. GC analysis confirmed the reaction was complete. The mixture was then quenched in 200 g of ice water, extracted twice with 100 mL of dichloromethane, and the organic phases were combined. The mixture was washed with 50 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 45.3 g of oily intermediate II, which was set aside for later use.

[0025] Example 2

[0026]

[0027] In a 500 mL three-necked flask, 20.0 g of intermediate II, 200 mL of methanol, and 0.7 g of potassium carbonate were added sequentially, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed by TLC, the mixture was concentrated to an oily state, dissolved in 200 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solution containing intermediate III was reserved for use (intermediate III was purified by chromatographic purification to obtain 13.28 g, yield 93.0%).

[0028] Example 3

[0029]

[0030] Compound III (5.0 g, 35.67 mmol) was added to a 250 mL three-necked flask and dissolved in 60 mL of dichloromethane. Then, ferric nitrate nonahydrate (1.44 g, 3.56 mmol), cobalt acetate tetrahydrate (0.89 g, 3.56 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.55 g, 3.56 mmol), and potassium chloride (0.13 g, 1.78 mmol, dissolved in 1 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at room temperature (25 °C) for 16 hours under an oxygen atmosphere. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tertiary ether was added to form a slurry, which was then crystallized. The mixture was filtered to obtain 4.94 g of fused-ring carboxylic acid 1, with a yield of 91%. 1 HNMR(300MHz, CDCl3)d 1.50(t,J=5.9Hz,1H),d 1.92(d,J=10.8Hz,1H),d 1.98(d,J=10.8Hz,1H),d 2.15(s,1H),d 2.16(t,J=5.9Hz,1H),d 2.40(t,J=5.9Hz,1H),d3.04(s,1H).

[0031] Example 4

[0032] Compound III (2.0 g, 14.27 mmol) was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. Then, ferric nitrate nonahydrate (0.58 g, 1.43 mmol), cobalt acetate tetrahydrate (0.18 g, 0.72 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.22 g, 1.43 mmol), and potassium chloride aqueous solution (0.05 g, 0.72 mmol, dissolved in 0.5 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at room temperature (25 °C) for 16 hours under an oxygen atmosphere. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tert-methyl ether was added to form a slurry, which was then crystallized. The mixture was filtered to give 1.87 g of fused-ring carboxylic acid 1, with a yield of 86%.

[0033] Example 5

[0034] Compound III (2.0 g, 14.27 mmol) was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. Then, ferric nitrate nonahydrate (0.29 g, 0.72 mmol), cobalt acetate tetrahydrate (0.18 g, 0.72 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.22 g, 1.43 mmol), and potassium chloride aqueous solution (0.05 g, 0.72 mmol, dissolved in 0.5 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at room temperature (25 °C) for 14 hours under an oxygen atmosphere. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tert-methyl ether was added to form a slurry, which was then crystallized. The mixture was filtered to give 1.95 g of fused-ring carboxylic acid 1, with a yield of 90%.

[0035] Example 6

[0036] Compound III (2.0 g, 14.27 mmol) was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloroethane. Then, ferric nitrate nonahydrate (0.29 g, 0.72 mmol), cobalt acetate tetrahydrate (0.36 g, 1.43 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.22 g, 1.43 mmol), and potassium chloride aqueous solution (0.05 g, 0.72 mmol, dissolved in 0.5 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at 30 °C for 12 hours under an oxygen atmosphere. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tertiary ether was added to form a slurry, which was then crystallized. The mixture was filtered to give 1.92 g of fused-ring carboxylic acid 1, with a yield of 88%.

[0037] Example 7

[0038] Compound III (2.0 g, 14.27 mmol) was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. Then, ferric nitrate nonahydrate (0.58 g, 1.43 mmol), cobalt acetate tetrahydrate (0.71 g, 2.86 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.22 g, 1.43 mmol), and potassium chloride aqueous solution (0.05 g, 0.72 mmol, dissolved in 0.5 mL of water) were added sequentially. The mixture was purged with air three times, and then stirred at room temperature (25 °C) under air atmosphere for 15 hours. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tert-methyl ether was added to form a slurry, which was then crystallized. The mixture was filtered to give 1.90 g of fused-ring carboxylic acid 1, with a yield of 88%.

[0039] Example 8

[0040] Compound III (14.02 g, 0.10 mol) was added to a 500 mL three-necked flask and dissolved in 150 mL of dichloromethane. Then, ferric nitrate nonahydrate (0.81 g, 0.002 mol), cobalt acetate tetrahydrate (2.49 g, 0.01 mol), 2,2,6,6-tetramethylpiperidine oxide (1.56 g, 0.01 mol), and sodium chloride aqueous solution (0.59 g, 0.01 mmol, dissolved in 3 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at room temperature (25 °C) for 16 hours under an oxygen atmosphere. The reaction was monitored by TLC until complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tert-methyl ether was added and the mixture was stirred to crystallize. The crystals were filtered to obtain 13.06 g of fused-ring carboxylic acid 1, with a yield of 86%.

[0041] Comparative Example 1

[0042] Compound III (5.0 g, 35.67 mmol) was added to a 250 mL three-necked flask and dissolved in 60 mL of dichloromethane. Then, ferric nitrate nonahydrate (1.44 g, 3.56 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.55 g, 3.56 mmol), and potassium chloride aqueous solution (0.26 mg, 3.56 mmol, dissolved in 1 mL of water) were added sequentially. The mixture was replaced with pure oxygen three times and stirred at room temperature (25 °C) under an oxygen atmosphere for 48 hours. The reaction was monitored by TLC until it was complete. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to an oily state. Methyl tertiary ether was added to form a slurry and crystallized. The mixture was filtered to give 3.96 g of fused-ring carboxylic acid 1, with a yield of 73%.

[0043] Comparative Example 2

[0044] Compound III (5.0 g, 35.67 mmol) was added to a 250 mL three-necked flask and dissolved in 60 mL of dichloromethane. Then, ferric nitrate nonahydrate (1.44 g, 3.56 mmol), manganese acetate tetrahydrate (0.47 g, 3.56 mmol), 2,2,6,6-tetramethylpiperidine oxide (0.55 g, 3.56 mmol), and potassium chloride aqueous solution (0.13 mg, 1.78 mmol, dissolved in 1 mL of water) were added sequentially. The mixture was purged three times with pure oxygen and stirred at room temperature (25 °C) for 48 hours under an oxygen atmosphere. TLC monitoring showed that a number of intermediate states were present. The mixture was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to an oily state, and purified by column chromatography to give 3.15 g of fused-ring carboxylic acid 1, with a yield of 58%.

[0045] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid, characterized in that, Includes the following steps: ； Diformyl glycol ester II is hydrolyzed under alkaline conditions to generate glycol III, which is then catalytically oxidized to 5-oxotricyclo[2,2,1,0]2,6-heptane-3-carboxylic acid 1 in the presence of an oxidant and a catalyst; the catalyst is a mixture of ferric nitrate / cobalt acetate / 2,2,6,6-tetramethylpiperidine oxide; the oxidant is selected from oxygen or air.

2. The method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid according to claim 1, characterized in that: The first step involves using sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate in an alcohol solvent to form alkaline conditions.

3. The method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid according to claim 1, characterized in that: The second step is to add the substance to the reaction system using either a balloon or a bubble-like method.

4. The method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid according to claim 1, characterized in that: The second step involves using a ferric nitrate / cobalt acetate molar ratio of 0.5-2:

1.

5. The method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid according to claim 1, characterized in that: The second step involves a reaction temperature of 0-30℃ and a reaction time of 12-24 hours.

6. The method for preparing 5-oxotricyclic [2,2,1,0]2,6-heptane-3-carboxylic acid according to claim 1, characterized in that: The second step involves a catalyst to diol molar ratio of 0.02-0.1:1.

Images