Method for synthesizing chloralkane by high-selectivity chlorination of carbon-hydrogen bonds in saturated alkane under electrochemical condition

Abstract

The invention discloses a method for synthesizing chloralkane by high-selectivity chlorination of carbon-hydrogen bonds in saturated alkane under electrochemical conditions, and relates to the technical field of medicine synthesis. The synthesis method comprises the following steps: in an electrochemical reaction tank, dissolving alkane, a catalyst, electrolyte and hydrochloric acid in a solvent, connecting an electrode, and electrifying at room temperature for reaction, so that carbon-hydrogen bonds in saturated alkane can be selectively chlorinated into corresponding chloralkane. The method can be widely applied to large-scale synthesis of various drugs and industrial synthesis of chloralkane.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing chloroalkanes by high-selective chlorination of carbon-hydrogen bonds in saturated alkanes under electrochemical conditions. Background Art

[0002] Alkanes are one of the most abundant natural resources on earth. 3 )-H bonds and efficiently converting them into high-value chemicals will help people make full use of natural resources and promote sustainable development. In addition, saturated CH bonds are also widely present in organic molecules, including drug molecules. 3 )-H bonds are of great significance for the green and efficient synthesis of drugs, the structural modification of inert sites in drug molecules, and the discovery of innovative drugs. On the other hand, a large number of Chinese herbal medicine components and active natural drug molecules contain chlorine atoms, such as vancomycin, chlorothioesters, losartan, diazepam, etc. There is a famous "chlorine atom magic effect" in drug research, which means that the introduction of chlorine atoms into drug molecules usually has unexpected effects. Furthermore, chlorinated compounds are one of the most useful intermediates in synthetic chemistry and can undergo a wealth of functional group transformations. Therefore, by highly selectively activating saturated carbon-hydrogen bonds in alkanes and directly introducing chlorine atoms, not only can abundant natural resources be effectively utilized, but also drug molecules can be synthesized simply and efficiently, and novel structural modifications and optimizations of drug molecules can be performed for the development of innovative drugs. However, due to the 3 )-H bond energy is large, and the activation process often requires higher energy. In addition, C(sp 3 )-H bonds have small differences, so C(sp 3 )-H bonds still face great challenges. According to literature reports, the currently reported selective halogenation of saturated C(sp 3 There are several ways to create the )-H key:

[0003] (1) Classical saturated CH bond free radical substitution chlorination

[0004]

[0005] To achieve saturation C(sp 3 The classic strategy for halogenation of )-H bonds is to use ultraviolet light to homolytically split chlorine or bromine to produce chlorine or bromine free radicals, thereby achieving saturated C(sp 3 Disadvantages: This method requires the use of highly toxic chlorine or bromine as a halogen source, which has low safety, high requirements for operation and equipment, and serious environmental pollution. In addition, the reaction site selectivity is poor, and a mixture of monohalogenated and polyhalogenated compounds is often obtained.

[0006] (2) Halogenation of saturated CH bonds promoted by light and high-valent iodine reagents Chem. Sci. 2016, 7, 2679-2683.

[0007]

[0008] This method uses visible light irradiation strategy, uses LiCl as a chlorine source, and can achieve selective chlorination of saturated CH bonds under mild conditions with the participation of a high-valent iodine reagent, Zhdankin'sazidoiodinane (BIN3). Disadvantages: This method only examines six types of substrates, and the substrate applicability and functional group tolerance are poor; hexafluoroisopropanol is used as a reaction solvent, which does not meet the requirements of green chemistry development; an excessive amount of high-valent iodine (BIN3) reagent is required, and BIN3 is expensive, dangerous, and prone to explosion. Therefore, this method is difficult to achieve industrial production.

[0009] (3) Heating free radicals to induce chlorination of saturated CH bonds. Chem. Sci. 2018, 9, 5360-5365.

[0010]

[0011] This method uses N-chloroamide as a chlorine source and, under the promotion of benzoyl peroxide (BPO), can achieve saturated C (sp 3 Disadvantages: The reaction temperature of this method is relatively high (65°C); the use of N-chloroamide as a chlorine source is easy to prepare but cumbersome to operate; although this method was highly selectively applied to the chlorination of clarylide in the total synthesis of (+)-Chlorolissoclimide, the method has poor selectivity in the chlorination of other small molecules, often resulting in a mixture of primary and secondary carbon chlorination products.

[0012] (4) Silver-catalyzed free radical-induced chlorination of saturated CH bonds. Org. Lett. 2017, 19, 1430-1433.

[0013]

[0014] The method uses t-butyl hypochlorite (t-BuOCl) as a chlorine source and can achieve saturated C (sp 3 Disadvantages: This method is only applicable to a small amount of active secondary carbon, tertiary carbon and benzylic C (sp 3The chlorination of small molecular compounds with )-H bonds has poor substrate applicability and functional group tolerance; tert-butoxy will be produced in the reaction system, which will affect the selectivity of the reaction; for some complex natural products such as menthol, menthone, citronellol, etc., a mixture is often obtained; the reaction requires the use of a silver catalyst, which is not economical and environmentally friendly.

[0015] (5) Copper-catalyzed free radical-induced chlorination of saturated CH bonds Angew. Chem. Int. Ed. 2021, 60, 8276-8283.

[0016]

[0017] The method uses (phen)CuCl2 complex as chlorine source, and in the presence of high-valent iodine Zhdankin's azidoiodinane (BIN3) reagent, can achieve selective saturation of benzylic and tertiary carbon at 50 degrees C (sp 3 )-H bond chlorination. The substrate applicability and functional group tolerance of this method are good, the yield is good, and this method can also achieve the selective chlorination of some complex natural products and active drug molecules. Disadvantages: This method still requires the use of an excess of high-valent iodine (BIN3) reagent, which is expensive, dangerous and explosive; in addition, this method also requires an excess of (phen)CuCl2 complex as a chlorine source, which is costly; therefore, this method is also not suitable for industrial production.

[0018] (6) Electrochemically promoted three-stage saturated CH chlorination Green Chem.2024,26,507-512; Patent No.: ZL202210112988.5

[0019]

[0020] This method uses a graphite felt electrode, 5 equivalents of hydrochloric acid as a chlorine source, and acetonitrile as a solvent to achieve selective chlorination of tertiary saturated CH in a series of alkane molecules at room temperature. However, the use of a large amount of hydrochloric acid and acetonitrile solvents means that this method still has room for improvement. In addition, this method cannot achieve CH chlorination at other sites.

[0021] In summary, the existing methods for selective halogenation of saturated CH bonds have obvious shortcomings, for example, they cannot achieve activation of alkane ends and secondary sites with high selectivity, and most methods cannot be scaled up for industrial production, so they are in urgent need of improvement. Summary of the invention

[0022] The present invention aims to create a new, green, safe, low-cost and easy to industrially produce alkane terminal and secondary site selective C (sp 3 A new method for chlorination of )-H bonds.

[0023] In order to solve the shortcomings of the existing methods, the present invention has designed a method for highly selectively chlorinating saturated alkanes at the terminal and secondary sites C (sp 3 )-H bond, a new method for synthesizing chloroalkanes. In an electrochemical reaction cell, alkane, catalyst, electrolyte and hydrochloric acid are dissolved in a solvent, electrodes are connected, and electricity is turned on at room temperature to react, so that the saturated carbon-hydrogen bonds at specific sites in the alkane can be selectively chlorinated to the corresponding chloroalkanes. Catalysts with different cavity sizes can selectively achieve chlorination of the terminal or secondary CH sites of the alkane. The specific synthesis method is shown in the following formula:

[0024]

[0025] The invention has the following beneficial effects: compared with the existing synthesis process, the invention has a simple method and does not require the participation of a metal catalyst; uses cheap and readily available hydrochloric acid as a chlorine source; does not require the use of any chemical oxidant (such as high-valent iodine, peroxide, etc.); N-hydroxybutene dicarboximide and its derivatives are used as organic catalysts, which are easy to recycle; have high energy utilization rate; have good site selectivity and functional group tolerance; and can achieve CH chlorination at different sites by using only different catalysts; has mild reaction conditions; can be smoothly scaled up to kilogram-level preparation; is green, safe, energy-saving and efficient, and therefore is suitable for industrialized drug production. DETAILED DESCRIPTION

[0026] The method of the present invention will be further described below by way of examples, but the present invention is not limited to these examples.

[0027] Embodiment 1:

[0028]

[0029] Take n-propyl benzoate (164.0 mg, 1.0 mmol, 1.0 eq), Et4NBF4 (434.0 mg, 2.0 mmol, 2.0 eq) and catalyst Cat-1 (38.6 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL) and stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 13 h at a constant current of 10 mA. After the reaction is completed, distill and recover the solvent, extract with 2M NaOH aqueous solution and dichloromethane (3×5 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, distill and recover the solvent, and separate by column chromatography to obtain the product (yield is 48%), with a regioselectivity of >95:5.

[0030] Embodiment 2:

[0031]

[0032] Take n-octyl benzoate (234.0 mg, 1.0 mmol, 1.0 eq), Et4NBF4 (434.0 mg, 2.0 mmol, 2.0 eq) and catalyst Cat-1 (38.6 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL) and stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 12 h at a constant current of 10 mA. After the reaction is completed, distill and recover the solvent, extract with 2M NaOH aqueous solution and dichloromethane (3×5 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, distill and recover the solvent, and separate by column chromatography to obtain the product (yield is 56%), with a regioselectivity of >95:5.

[0033] Embodiment 3:

[0034]

[0035] Take valeronitrile (83.0 mg, 1.0 mmol, 1.0 eq), Et4NBF4 (434.0 mg, 2.0 mmol, 2.0 eq) and catalyst Cat-2 (57.2 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL), stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 12 h at a constant current of 10 mA. After the reaction is completed, distill and recover the solvent, extract with 2M NaOH aqueous solution and dichloromethane (3×5 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, distill and recover the solvent, and separate by column chromatography to obtain the product (yield is 62%), with a regioselectivity of >95:5.

[0036] Embodiment 4:

[0037]

[0038] Take 2,2-dimethylvalerate isobutyl ester (186.0 mg, 0.5 mmol, 1.0 eq), Et4NBF4 (217.0 mg, 1.0 mmol, 2.0 eq) and catalyst Cat-1 (38.6 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL) and stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 12 h at a constant current of 10 mA. After the reaction is completed, distill and recover the solvent, extract with 2M NaOH aqueous solution and dichloromethane (3×5 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, distill and recover the solvent, and separate by column chromatography to obtain the product (yield is 52%), with a regioselectivity of >95:5.

[0039] Embodiment 5:

[0040]

[0041] Take estrone caproate (368.0 mg, 0.5 mmol, 1.0 eq), Et4NBF4 (217.0 mg, 1.0 mmol, 2.0 eq) and catalyst Cat-1 (38.6 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL), stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 15 h at a constant current of 10 mA. After the reaction is completed, the solvent is distilled and recovered, extracted with 2M NaOH aqueous solution and dichloromethane (3×5 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is distilled and recovered. The product (yield is 49%) is separated by column chromatography, and the regioselectivity is >95:5.

[0042] Embodiment 6:

[0043] Take n-hexane (1.0kg, 11.6mol, 1.0eq), Et4NBF4 (1.26kg, 5.8mol, 0.5eq) and catalyst Cat-1 (8.95g, 11.6mmol, 0.1mol%) in a 5.0L beaker; add CH3CN (25.0mL) and stir to dissolve; add hydrochloric acid (aq.37%, 58.0mol, 5.0eq); stack two circular graphite felt electrodes (anode is graphite felt, cathode is graphite felt) at the bottom of the beaker, separate the two graphite felts with a polytetrafluoroethylene insulating film, apply power and react at room temperature for 24h at a constant current of 5.0A. After the reaction was completed, it was extracted with 2M NaOH aqueous solution and dichloromethane (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled at normal pressure to collect fractions to obtain dichloromethane (boiling point 40 degrees), n-hexane (boiling point 69 degrees) and acetonitrile (boiling point 81-82 degrees), followed by reduced pressure distillation to obtain 793.4 grams of the product 1-chlorohexane (identified by gas chromatography-mass spectrometry, yield 57%), with a regioselectivity of >95:5 (identified by gas chromatography-mass spectrometry).

[0044] Embodiment 7:

[0045]

[0046] Take n-pentyl benzoate (192.0 mg, 1.0 mmol, 1.0 eq), Et4NBF4 (434.0 mg, 2.0 mmol, 2.0 eq) and catalyst Cat-3 (41.0 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL), stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 12 h at a constant current of 10 mA. After the reaction is completed, distill and recover the solvent, extract with 2M NaOH aqueous solution and dichloromethane (3×5 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, distill and recover the solvent, and separate by column chromatography to obtain the product (yield is 72%), with a regioselectivity of >95:5.

[0047] Embodiment 8:

[0048]

[0049] Take valeronitrile (83.0 mg, 1.0 mmol, 1.0 eq), Et4NBF4 (434.0 mg, 2.0 mmol, 2.0 eq) and catalyst Cat-3 (41.0 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL), stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 13 h at a constant current of 10 mA. After the reaction is completed, the solvent is distilled and recovered, extracted with 2M NaOH aqueous solution and dichloromethane (3×5 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is distilled and recovered. The product is separated by column chromatography (yield is 53%), and the regioselectivity is >95:5.

[0050] Embodiment 9:

[0051]

[0052] Take estrone caproate (368.0 mg, 0.5 mmol, 1.0 eq), Et4NBF4 (217.0 mg, 1.0 mmol, 2.0 eq) and catalyst Cat-3 (41.0 mg, 0.05 mmol, 5.0 mol%) in a 10.0 mL three-necked flask; add CH3CN (2.0 mL), stir to dissolve; add hydrochloric acid (aq. 37%, 5.0 mmol, 5.0 eq); insert electrodes (anode is graphite felt, cathode is graphite felt) on the left and right sides of the three-necked flask, power on and react at room temperature for 15 h at a constant current of 10 mA. After the reaction is completed, the solvent is distilled and recovered, extracted with 2M NaOH aqueous solution and dichloromethane (3×5 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is distilled and recovered. The product (yield is 54%) is separated by column chromatography, and the regioselectivity is >95:5.

[0053] Embodiment 10:

[0054]

[0055] Take n-hexane (1.0kg, 11.6mol, 1.0eq), Et4NBF4 (1.26kg, 5.8mol, 0.5eq) and catalyst Cat-3 (9.51g, 11.6mmol, 0.1mol%) in a 5.0L beaker; add CH3CN (25.0mL) and stir to dissolve; add hydrochloric acid (aq.37%, 58.0mol, 5.0eq); stack two circular graphite felt electrodes (anode is graphite felt, cathode is graphite felt) at the bottom of the beaker, separate the two graphite felts with a polytetrafluoroethylene insulating film, apply power and react at room temperature for 24h at a constant current of 5.0A. After the reaction was completed, it was extracted with 2M NaOH aqueous solution and dichloromethane (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled at normal pressure to collect fractions to obtain dichloromethane (boiling point 40 degrees), n-hexane (boiling point 69 degrees) and acetonitrile (boiling point 81-82 degrees), followed by reduced pressure distillation to obtain 556.8 grams of the product 2-chlorohexane (identified by gas chromatography-mass spectrometry, yield 40%), with a regioselectivity of >95:5 (identified by gas chromatography-mass spectrometry).

[0056] Appendix-1 Yield overview of the reaction under different conditions (taking n-pentyl benzoate as an example) (the present invention is not limited to the reaction conditions listed in the table)

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Table notes: The amount of alkane in the table is 0.5 mmol; hydrochloric acid is 37%; the dimensions of the rod electrode are: diameter 0.8 cm, length 10 cm; the length, width and height of the graphite felt are: 2 cm×1 cm×0.5 cm; the length, width and height of the platinum sheet electrode are: 1 cm×1 cm×0.2 mm; DMF is N,N-dimethylformamide.

[0063] Appendix-2 Selected products and their yields corresponding to alkanes investigated by the present invention (not limited to these substrates)

[0064]

[0065]

[0066] Table Note: The yields in this table are all isolated yields obtained according to the reaction conditions in Example 1.

[0067]

[0068] Table Notes: The yields in this table are all isolated yields obtained under the reaction conditions in Example 7. The regioselectivity ratio data was determined by GC-MS, and the ratio of chlorination at C2: chlorination at other sites was >95:5.

Claims

1. A method for synthesizing chloroalkanes by highly selectively chlorinating carbon-hydrogen bonds in saturated alkanes under electrochemical conditions, characterized in that: In an electrochemical reaction cell, alkanes, catalysts, electrolytes and hydrochloric acid are dissolved in a solvent, electrodes are connected, and electricity is applied at room temperature to react, so as to selectively chlorinate saturated carbon-hydrogen bonds in alkanes into corresponding chloroalkanes. The electrodes include graphite felt, carbon, glassy carbon and platinum for the anode and graphite felt, carbon, glassy carbon and platinum for the cathode. The electrolyte is a salt composed of cations and anions; The catalyst is: N-hydroxybutene dicarboximide derivative; The hydrochloric acid is: hydrochloric acid (aq. 5% to 37%).

2. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes under electrochemical conditions with high selectivity according to claim 1, characterized in that: The electrochemical reaction cell is a partitioned cell or a non-partitioned cell.

3. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes under electrochemical conditions with high selectivity according to claim 1, characterized in that: The solvent is one or a mixture of two or more of acetonitrile, dichloromethane (DCM), dichloroethane (DCE), N,N-dimethylformamide (DMF), 1,4-dioxane, acetone, methanol, ethanol, isopropanol, butanol, hexafluoroisopropanol, trifluoroethanol, chloroform, and dimethyl sulfoxide.

4. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes under electrochemical conditions with high selectivity according to claim 1, characterized in that: The alkane is a compound shown in the following formula (1), and the chloroalkane product is a compound shown in the following formula (2): Wherein, FG and R are hydrogen or alkyl or halogen, ether, ester, amide, nitrile, ketone, sulfonate.

5. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes with high selectivity under electrochemical conditions according to any one of claims 1 to 4, characterized in that: The electrolyte is a salt composed of one or two or more cations and one or two or more anions; the cations described here are lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, zinc ions, divalent or trivalent iron ions, monovalent or divalent copper ions, cobalt ions, trivalent or tetravalent titanium ions, divalent or tetravalent manganese ions, divalent nickel ions, ammonium ions (NH4 ＋ ), tetraalkylammonium radical (R4N + ); the alkyl group is at least one of methyl, ethyl, propyl, isopropyl, butyl and n-hexadecyl; the anion is at least one of fluoride anion, chloride anion, bromide anion, iodine anion, perchlorate anion, tetrafluoroborate anion, hexafluorophosphate anion, p-toluenesulfonate anion, benzenesulfonate anion, methanesulfonate anion, acetate anion, benzoate anion, carbonate, bicarbonate, nitrate, nitrite, phosphate, hydrogen phosphate, dihydrogen phosphate, sulfate and hydrogen sulfate.

6. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes with high selectivity under electrochemical conditions according to any one of claims 1 to 5, characterized in that: The structural characteristics of the catalyst are shown in the following formula (3):

7. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes with high selectivity under electrochemical conditions according to any one of claims 1 to 5, characterized in that: The electrochemical reaction is powered in a constant current or constant voltage mode; the current intensity is 1 mA to 20 A; and the reaction temperature is 0 to 100°C.

8. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes with high selectivity under electrochemical conditions according to any one of claims 1 to 5, characterized in that: The molar concentration of the electrolyte is 0.01-100 mol / L.

9. The method for synthesizing chloroalkanes from carbon-hydrogen bonds in saturated alkanes with high selectivity under electrochemical conditions according to any one of claims 1 to 5, characterized in that: The molar concentration of the saturated alkane is 0.01-100 mol / L.

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