Cyclohexadiene derivative and preparation method thereof
By starting from D-ribose and using a multi-step chemical reaction, cyclohexadiene derivatives were successfully prepared, which solved the problem of lack of chemical synthesis in the prior art, and achieved efficient and low-cost intermediate synthesis, which was suitable for industrial production.
Patent Information
- Application Number
- CN202411699841.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-25
- Publication Date
- 2025-02-25
AI Technical Summary
In the prior art, there is no laboratory or industrial chemical synthesis method for tuterotoxin intermediate single chiral cyclohexadiene derivatives. There is only a recombinant E. coli fermentation process. The technology is difficult and costly, low unit reaction concentration, and the product is easy to aromatize, and it is difficult to separate the product from the fermentation system. It is very low compared to chemical synthesis efficiency, which is not conducive to industrial amplification.
D-ribose is used as raw material and cyclohexadiene derivatives are prepared by hydroxyl protection, alkylation, oxidation, addition, cyclosynthesis, elimination, and deprotection. The process route is novel, the cost is low, and suitable for industrial production.
It has achieved efficient chemical synthesis of single-chiral cyclohexadiene derivatives of trogatotoxin intermediates, reduced R&D costs, circumvented complex separation and purification operations, and has the prospect of industrial amplification.
Smart Images
Figure QLYQS_1 
Figure QLYQS_2 
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of medical immune in vitro diagnosis, and specifically relates to a cyclohexadiene derivative and a preparation method thereof. Background Art
[0002] Tetrodotoxin (TTX) is a neurotoxic natural product with a structure containing nine consecutive stereocenters in a molecule of only 11 carbon atoms and a molecular weight of just over 300. Tetrodotoxin occurs naturally in several species of pufferfish and some other aquatic animals, but is produced by symbiotic bacteria. The toxin is a potent inhibitor of voltage-gated sodium channels (Nav), and in very low doses it can be used to treat cancer pain or relieve withdrawal symptoms in opium addicts.
[0003] The molecular structure of tetrodotoxin is shown below:
[0004]
[0005] In 2018, "Chemoenzymatic Synthesis of Advanced Intermediates for Formal Total Syntheses of Tetrodotoxin" reported that the process of Daler Baidilov's team's total synthesis of tetrodotoxin from diene diol is as follows:
[0006]
[0007] Among them, the monochiral cyclohexadiene derivative intermediate 10 is the key starting intermediate for preparing tetrodotoxin. However, there is no laboratory and industrial chemical synthesis method for the monochiral cyclohexadiene derivative, and only reports on the preparation of the recombinant Escherichia coli fermentation process. However, this type of process technology is difficult and costly, and the unit reaction concentration is less than 20g / L. In addition, since the product is easily aromatized, it is difficult to separate the product from the fermentation system, and the efficiency is very low relative to chemical synthesis, which is not conducive to industrial scale-up. Therefore, it is of great significance to find a chemical synthesis route for the intermediate 10 with novel design, high yield, low cost, and suitable for industrial production. Summary of the invention
[0008] The object of the present invention is to provide a cyclohexadiene derivative and a preparation method thereof. The preparation method has a novel process route, low cost and is suitable for industrial production.
[0009] In order to achieve the above-mentioned invention object, the present invention adopts the following technical solutions:
[0010] The present invention provides a method for preparing a cyclohexadiene derivative, comprising the following steps:
[0011] (1) D-ribose is subjected to dihydroxy protection in an acidic catalyst to obtain compound 3;
[0012] (2) protecting the compound 3 by hydroxyl group to obtain compound 4;
[0013] (3) subjecting the compound 4 to a Witting reaction to obtain a compound 5;
[0014] (4) subjecting the compound 5 to a Swern oxidation reaction to obtain compound 6;
[0015] (5) subjecting the compound 6 to a Grignard reaction to obtain a compound 7;
[0016] (6) cyclizing the compound 7 with a cyclization catalyst to obtain compound 8;
[0017] (7) dehydrating the compound 8 to obtain compound 10;
[0018] (8) desilylation-protecting the compound 10 to obtain a cyclohexadiene derivative;
[0019] The chemical structural formulas of Compound 3-Compound 8 and Compound 10 are as follows:
[0020]
[0021] Wherein, R is selected from hydrogen or tributylsilane.
[0022] Furthermore, in the step (1), the dihydroxy protection reaction is carried out in acetone; the acid catalyst is one of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid; and the reaction temperature of the dihydroxy protection is 10°C to 70°C.
[0023] Preferably, the reaction temperature of the dihydroxy protection is 15°C to 45°C.
[0024] Furthermore, in the step (2), the reagent used for hydroxyl protection is one of trimethylsilyl bromide, trimethylsilyl chloride, triethylsilyl bromide, triethylsilyl chloride, dimethylisopropylsilyl chloride, dimethylisopropylsilyl bromide, dimethyltert-butylsilyl chloride, dimethyltert-butylsilyl bromide, diphenyltert-butylsilyl chloride, diphenyltert-butylsilyl bromide, triisopropylsilyl bromide, triisopropylsilyl chloride, p-methoxybenzyl bromide, and p-methoxybenzyl chloride; the solvent used is one of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, and xylene; and the reaction temperature for the hydroxyl protection is 10°C to 70°C.
[0025] Preferably, the reaction temperature of the hydroxyl protection is 15°C to 45°C.
[0026] Furthermore, in the step (3), the solvent used in the Witting reaction is one of tetrahydrofuran, ether, dimethyl ether, methyl tert-butyl ether, and toluene; the phosphorus-containing reagent used is one of triphenylphosphine, methyltriphenylphosphine bromide, and benzyltriphenylphosphine chloride; the alkaline solution used is one of n-butyl lithium, sodium hydride, sodium hydroxide, sodium bis(trimethylsilyl)amide, potassium hydroxide, and potassium tert-butoxide; and the Witting reaction temperature is 0°C to 50°C.
[0027] Preferably, the Witting reaction temperature is 0°C to 30°C.
[0028] Furthermore, in the step (4), the Swern oxidation reaction is carried out in the presence of dimethyl sulfoxide, the solvent used is toluene or dichloromethane, and the alkaline solution used is one of triethylamine, diisopropylethylamine, pyridine, and 4-methylpyridine; and the Swern oxidation reaction temperature is -10°C to 50°C.
[0029] Preferably, the Swern oxidation reaction temperature is -10°C to 25°C.
[0030] Furthermore, in step (5), the reagent used for the Grignard reaction is allylmagnesium bromide or allylmagnesium chloride; the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and toluene; and the reaction temperature is -55°C to 20°C.
[0031] Furthermore, in step (6), the cyclization catalyst is a Grubbs catalyst or a Jansler catalyst; the solvent used in the cyclization reaction is dichloromethane or toluene; and the reaction temperature is 25°C to 110°C.
[0032] Furthermore, in the step (7), the acid binding agent used in the dehydration reaction is one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine, and 4-methylpyridine; the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and dichloromethane; the reagent used is thionyl chloride or methanesulfonyl chloride; and the reaction temperature is -10°C to 25°C.
[0033] Furthermore, in the step (8), the reagent used for the desilylation reaction is tetrabutylammonium fluoride or potassium tert-butoxide, and the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; and the reaction temperature is 15°C to 25°C.
[0034] Furthermore, the compound 8 is dehydrated to obtain compound 9; and the compound 9 is protected by desilylation to obtain compound 10.
[0035] The present invention also provides a cyclohexadiene derivative prepared by the preparation method, and its specific chemical structural formula is:
[0036]
[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:
[0038] The present invention fills the gap in the chemical synthesis of tetrodotoxin intermediate 10, and uses cheap and readily available D-ribose as a raw material to obtain compound 1 through steps such as hydroxyl protection, alkylation, oxidation, addition, cyclization, elimination, and deprotection. This route has high atomic utilization, and each step has strong reaction specificity. Compared with enzyme catalysis, it reduces research and development costs, avoids complex separation and purification operations, and has the prospect of industrial scale-up. DETAILED DESCRIPTION
[0039] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.
[0040] In the following examples, unless otherwise specified, the experimental methods used are all conventional methods, and the materials and reagents used can be purchased from biological or chemical reagent companies.
[0041] Example 1
[0042]
[0043] D-ribose (15.0 g, 0.10 mol) and acetone (150 mL) were added to a three-necked flask at room temperature, and stirring was started. Concentrated sulfuric acid (0.45 mL, 8.5 mmol) was added dropwise. After the addition was completed, the mixture was kept warm and stirred for 6 to 8 hours. After the reaction was completed, sodium bicarbonate (2.5 g) was added, stirred for 0.5 hour, filtered, 15 g of anhydrous sodium sulfate was added to the filtrate, and allowed to stand for 2 hours, filtered, and the filtrate was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 2 / 1), and concentrated until there were no droplets to obtain a colorless viscous liquid compound 3 (15.9 g, 83.6%).
[0044] 1 HNMR-(MeOH-d4)δ, 5.28 (s, 1H), 4.78 (dd, 1H), 4.54 (d, 1H), 4.20 (m, 1H), 3.63 (dd, 1H), 3.60 (dd, 1H), 1.46 (s, 3H), 1.33 (s, 3H).
[0045]
[0046] Compound 3 (14.7 g, 0.079 mol) and dichloromethane (100 mL) were added to a three-necked flask at room temperature, imidazole (13.4 g, 0.2 mol) was added, dimethyl tert-butyl chlorosilane (14.3 g, 0.095 mol) was added, and the mixture was stirred at 15-30°C for 3-8 hours. After the reaction, a saturated sodium bicarbonate aqueous solution was added dropwise to the system, extracted with ethyl acetate, separated, the organic phase was washed with saturated brine, the organic phase was concentrated until there was no droplet, and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 15 / 1) to obtain compound 4 (16.3 g, 69.1%).
[0047] 1 HNMR-(300MHz, CDCl3)δ: 5.27(d,1H), 4.78(d,1H), 4.69(d,1H), 4.50(d,1H), 4.35(br s,1H), 3.75(d,2H,), 1.48(s,3H),1.32(s,3H),0.93(s,9H),0.14(s,6H).
[0048] Example 3
[0049]
[0050] At room temperature, under nitrogen atmosphere, tetrahydrofuran (200 mL) and methyl triphenylphosphine bromide (38.1 g, 106.8 mmol) were added to a three-necked flask, stirred, cooled to -5-0°C, potassium tert-butoxide (11.9 g, 106.8 mmol) was added, the temperature was raised to room temperature and stirred for 1 hour, cooled to -5-0°C, a mixture of compound 4 (16.25 g, 53.4 mmol) and tetrahydrofuran (100 mL) was added, and the reaction was carried out at room temperature for 4-8 hours. After the reaction was completed, saturated brine (100 mL) was added to the system, the liquid was separated, the organic phase was concentrated and purified by column chromatography (eluent ethyl acetate / petroleum ether=20 / 1), and compound 5 (13.7 g, 84.9%) was obtained after concentration.
[0051] 1 HNMR (300MHz, CDCl3) δ: 6.05 (ddd, 1H), 5.40 (d, 1H), 5.26 (d, 1H), 4.67 (dd, 1H), 4.05 (dd, 1H) , 3.81 (m, 1H), 3.65 (m, 2H), 2.51 (d, 1H), 1.41 (s, 3H), 1.36 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H).
[0052] Example 4
[0053]
[0054] Compound 5 (13.7 g, 45.3 mmol) and toluene (100 mL), dimethyl sulfoxide (8.96 g, 113 mmol), pyridine (3.6 g, 45.3 mmol), N'N-dicyclohexylcarbodiimide (19.6 g, 95.1 mmol) were added to a three-necked flask at room temperature, and trifluoroacetic acid (5.2 g, 45.3 mmol) was added dropwise to cool to 0°C. The reaction was allowed to react at room temperature for 4 to 6 hours until the reaction was completed. The mixture was cooled to room temperature, filtered through a silica gel pad, 100 mL of a saturated sodium bicarbonate solution was added to the filtrate, and the organic phase was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 30 / 1). A white solid was obtained after concentration, which was compound 6 (9.97 g, 73.3%).
[0055] 1 HNMR (300MHz, CDCl3) δ: 5.71-5.66(m,1H), 5.39(d,1H), 5.25(d,1H), 4.89-4.88(m, 2H), 4.48(d,1H), 4.24(d,1H), 1.61(s,3H), 1.39(s,3H), 0.92(s,9H), 0.08(s,6H).
[0056] Example 5
[0057]
[0058] Compound 6 (6.2 g, 20.6 mmol) and tetrahydrofuran (60 mL) were added to a three-necked flask at room temperature, and the atmosphere was replaced with nitrogen three times. The temperature was lowered to -45 °C, and allylmagnesium bromide (62 mL, 62 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 5 hours until the reaction was completed. The temperature was lowered to -15 °C, and an aqueous solution of ammonium chloride was added to quench the reaction. The mixture was separated, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a light yellow liquid, which was compound 7 (5.8 g, 82.2%).
[0059] 1 HNMR (300MHz, CDCl3) δ: 6.20-6.16 (ddd, 1H), 5.81-5.89 (m, 1H), 5.23 (dd, 1H), 5.10 (dd, 1H), 5.07 (dd, 1H), 4.54 (dd , 1H), 4.24(d, 1H), 3.52(s, 2H), 2.54-2.42(m, 2H), 2.27(s, 1H), 1.51(s, 3H), 1.35(s, 3H), 0.89(s, 9H), 0.05(s, 6H).
[0060] Example 6
[0061]
[0062] Compound 7 (2.03 g, 6.0 mmol), toluene (60 mL) and Grubbs first generation catalyst (0.244 g, 0.03 mmol) were added to a three-necked flask at room temperature, and the nitrogen was replaced by vacuum for 3 times. The temperature was raised to 90°C with stirring, and the reaction was completed after filtering. The filtrate was washed with saturated brine, and the liquids were separated. The organic phase was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 30 / 1) to give a light yellow liquid, which was compound 8 (1.35 g, 73.2%).
[0063] 1 HNMR (300MHz, CDCl3) δ: 5.77-5.75 (m, 2H), 4.54 (dd, 1H), 4.27 (d, 1H), 3.53 (d, 1H), 3.41 (d, 1H), 2.65 (s, 1H), 2.27-2.11 (m, 2H), 1.46 (s, 6H), 0.89 (s, 9H), 0.09 (s, 6H).
[0064] Example 7
[0065]
[0066] Compound 8 (0.276 g, 0.88 mmol), dichloromethane (5 mL) and triethylamine (0.36 g, 3.52 mmol) were added to a three-necked flask at room temperature. The temperature was lowered to 0°C, and methanesulfonyl chloride (0.20 g, 1.76 mmol) was added dropwise. The temperature was raised to room temperature and stirred until the reaction was complete. The temperature was lowered to 10°C, and a saturated aqueous solution of sodium bicarbonate was added dropwise. The liquids were separated, and the organic phase was washed with saturated brine. The liquids were separated, and the organic phase was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 10 / 1) to give a light yellow liquid, which was compound 9 (108 mg, 31.35%).
[0067] 1 HNMR (300MHz, CDCl3) δ: 5.71 (m, 2H), 4.56 (dd, 1H), 4.54 (dd, 1H), 4.03-3.95 (m, 2 H), 2.82(d, 1H), 2.53(d, 1H), 1.44(s, 3H), 1.40(s, 3H), 0.89(s, 9H), 0.08(s, 6H).
[0068] Example 8
[0069]
[0070] Compound 9 (108 mg, 0.28 mmol), tetrahydrofuran (2.0 mL) and potassium tert-butoxide (40 mg, 0.36 mmol) were added to a three-necked flask at room temperature and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added, the liquids were separated, the organic phase was washed with saturated brine, the liquids were separated, and the organic phase was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 30 / 1) to give a light yellow liquid, which was compound 10 (39 mg, 47.8%).
[0071] 1 HNMR (300MHz, CDCl3) δ: 6.02-5.97 (m, 2H), 5.85-5.82 (m, 1H), 4.71-4.68 (m, 1H), 4.59 (dd, 1H), 4.32 (d, 2H), 1.41 (s, 6H), 0.92 (s, 9H), 0.09 (s, 6H).
[0072] Example 9
[0073]
[0074] Compound 8 (108 mg, 0.28 mmol), dichloromethane (2.0 mL) and pyridine (88 mg, 1.12 mmol) were added to a three-necked flask at room temperature. The temperature was lowered to 0°C, thionyl chloride (67 mg, 0.56 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. A sodium bicarbonate aqueous solution was added to adjust the pH to 7-8, and the liquids were separated. The organic phase was washed with saturated brine, and the liquids were separated. The organic phase was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 30 / 1) to give a light yellow liquid, which was compound 10 (60 mg, 73.5%).
[0075] Example 10
[0076]
[0077] Compound 10 (39.0 mg, 0.13 mmol), tetrahydrofuran (5.0 mL) and tetrabutylammonium fluoride trihydrate (40 mg, 0.13 mmol) were added to a three-necked flask at room temperature and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added, the liquids were separated, and the organic phase was washed with saturated brine. The organic phase was concentrated and purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 4 / 1) to give a light yellow liquid, which was compound 1 (18 mg, 75%).
[0078] 1HNMR (300MHz, CDCl3) δ: 6.03 (dd, 1H), 5.98 (dd, 1H), 5.89 (dd, 1H), 4.72 (s, 2H), 4.32 (dd, 2H), 2.04 (s, 1H), 1.41 (s, 6H).
[0079] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for a person skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to replace some of the technical features therein by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions claimed to be protected by the present invention.
Claims
1. A method for preparing a cyclohexadiene derivative, characterized in that: The following steps are involved: (1) D-ribose is subjected to dihydroxy protection in an acidic catalyst to obtain compound 3; (2) protecting the compound 3 by hydroxyl group to obtain compound 4; (3) subjecting the compound 4 to a Witting reaction to obtain a compound 5; (4) subjecting the compound 5 to a Swern oxidation reaction to obtain compound 6; (5) subjecting the compound 6 to a Grignard reaction to obtain a compound 7; (6) cyclizing the compound 7 with a cyclization catalyst to obtain compound 8; (7) dehydrating the compound 8 to obtain compound 10; (8) desilylation-protecting the compound 10 to obtain a cyclohexadiene derivative; The chemical structural formulas of Compound 3-Compound 8 and Compound 10 are as follows: Wherein, R is selected from hydrogen or tributylsilane.
2. The preparation method according to claim 1, characterized in that: In the step (1), the dihydroxy protection reaction is carried out in acetone; the acid catalyst is one of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid; and the reaction temperature of the dihydroxy protection is 10° C. to 70° C.
3. The preparation method according to claim 1, characterized in that: In the step (2), the reagent used for hydroxyl protection is one of trimethylsilyl bromide, trimethylsilyl chloride, triethylsilyl bromide, triethylsilyl chloride, dimethylisopropylsilyl chloride, dimethylisopropylsilyl bromide, dimethyltert-butylsilyl chloride, dimethyltert-butylsilyl bromide, diphenyltert-butylsilyl chloride, diphenyltert-butylsilyl bromide, triisopropylsilyl bromide, triisopropylsilyl chloride, p-methoxybenzyl bromide, and p-methoxybenzyl chloride; the solvent used is one of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, and xylene; and the reaction temperature for the hydroxyl protection is 10° C. to 70° C.
4. The preparation method according to claim 1, characterized in that: In the step (3), the solvent used for the Witting reaction is one of tetrahydrofuran, ether, dimethyl ether, methyl tert-butyl ether, and toluene; the phosphorus-containing reagent used is one of triphenylphosphine, methyltriphenylphosphine bromide, and benzyltriphenylphosphine chloride; the alkaline solution used is one of n-butyl lithium, sodium hydride, sodium hydroxide, sodium bis(trimethylsilyl)amide, potassium hydroxide, and potassium tert-butoxide; and the reaction temperature is 0°C to 50°C.
5. The preparation method according to claim 1, characterized in that: In the step (4), the Swern oxidation reaction is carried out in the presence of dimethyl sulfoxide, the solvent used is toluene or dichloromethane, and the alkaline solution used is one of triethylamine, diisopropylethylamine, pyridine, and 4-methylpyridine; the reaction temperature is -10°C to 50°C.
6. The preparation method according to claim 1, characterized in that: In the step (5), the reagent used for the Grignard reaction is allylmagnesium bromide or allylmagnesium chloride; the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and toluene; and the reaction temperature is -55°C to 20°C.
7. The preparation method according to claim 1, characterized in that: In the step (6), the cyclization catalyst is a Grubbs catalyst or a Jansler catalyst; the solvent used in the cyclization reaction is dichloromethane or toluene; and the reaction temperature is 25°C to 110°C.
8. The preparation method according to claim 1, characterized in that: In the step (7), the acid binding agent used in the dehydration reaction is one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, N,N-diisopropylethylamine, pyridine, and 4-methylpyridine; the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and dichloromethane; the reagent used is thionyl chloride or methanesulfonyl chloride; and the reaction temperature is -10°C to 25°C.
9. The preparation method according to claim 1, characterized in that: In the step (8), the reagent used for the desilylation reaction is tetrabutylammonium fluoride or potassium tert-butoxide, and the solvent used is one of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; and the reaction temperature is 15° C. to 25° C.
10. The cyclohexadiene derivative prepared by the preparation method according to any one of claims 1 to 9, characterized in that: The specific chemical structural formula of the cyclohexadiene derivative is: