A method for synthesizing allyl trifluoroethyl ether compounds

Abstract

The application discloses a synthesis method of allyl trifluoroethyl ether compounds. Allyl methyl ether is used as raw material, trifluoroethanol is used as solvent, Lewis acid is used as catalyst, additives and alkali are added, and selective nucleophilic substitution of methyl ether on different types of C in the allyl position is realized by controlling the reaction temperature, so that the allyl trifluoroethyl ether compounds are obtained with high selectivity. The application has the advantages of high efficiency, mild reaction condition, convenient operation, short reaction time, few by-products and the like, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of allyl trifluoroethyl ether compounds, which realizes synthesis of allyl trifluoroethyl ether compounds through selective nucleophilic substitution of methyl ethers on different types of C in allyl positions, and belongs to the field of organic synthesis. BACKGROUND

[0002] Bioactive molecules containing ether bonds are widely used in the fields of medicine, pesticides and the like. Direct synthesis transformation of the ether bonds in the drug molecules has important pharmacological significance for realizing post-modification of the structures [1] . Fluoroalkyl ethers are valuable structural units in the field of drug and pesticide chemical discovery [2,3] . Compared with non-fluorinated analogues, the introduction of polyfluoroalkoxy groups leads to improvement in lipophilicity [4,5] and metabolic stability [6,7] . For example, the lipophilicity (logD=3.34) of riluzole used for treating amyotrophic lateral sclerosis is higher than that (logD=1.94) of a non-fluorinated analogue thereof; a hexafluoroisopropoxy analogue is even more lipophilic (logD=3.85) [8] . Therefore, it is of great significance to selectively transform the ether bonds in drug molecules into fluoroalkyl ethers through reasonable means.

[0003]

[0004] In a traditional organic synthesis path, fluoroalkylation of methyl ethers usually needs multiple synthesis steps: firstly, the ether bond is transformed into an alcohol through a deprotection reaction, and then the alcohol hydroxyl group is transformed into other active functional groups such as -Br, -Cl and the like, and then a nucleophilic polyfluoroalkyl substitution reaction is performed on the basis of an allyl bromide or the like. This reaction process not only needs to consume time and resources, but also easily leads to low yield of products and occurrence of side reactions. Therefore, people pay more attention to direct nucleophilic substitution reactions of ethers. The direct nucleophilic substitution reaction of ethers has the following advantages: 1) shortening of a synthesis process and saving of reaction time; 2) improvement of product yield; and 3) avoidance of side reactions and improvement of reaction purity. In summary, it is of great application value to develop a direct polyfluoroalkyl nucleophilic substitution reaction of methyl ethers.

[0005] A direct method for synthesis of trifluoroethoxy ethers is nucleophilic substitution of allyl bromide or chlorine [9,10]However, this method can only perform nucleophilic substitution on primary and secondary carbon bromine and chlorine on allyl, and the range is limited. How to use a good method to perform trifluoroethoxy on different types of C on the allyl position is still a problem. In order to solve this problem, we realized the selective direct trifluoroethoxylation of hydrogen bond-mediated methyl ether on different types of C on the allyl position by controlling the reaction temperature under the catalysis of Lewis acid. This reaction has the characteristics of wide substrate range, easy to obtain raw materials, less by-products, short reaction steps, etc. It provides a new idea for the synthesis of trifluoroethoxy ether.

[0006] Reference:

[0007] [1]Schelhaas M.,Waldmann H.Protecting Group Strategies in Organic Synthesis[J].Angewandte Chemie International Edition in English,2003,35(18):2056-83.

[0008] [2]Johnson B.M.,Shu Y.Z.,Zhuo X.,et al.Metabolic and PharmaceuticalAspects ofFluorinated Compounds[J].Journal ofMedicinal Chemistry,2020,63(12):6315-86.

[0009] [3]Fre′de′ric L.,Peter J.,Manfred S..α-Fluorinated Ethers,Thioethers,and Amines:Anomerically Biased Species[J].Chemical Review.2005,105,827-856

[0010] [4]Corwin H.,Albert L.,Stefan H.U.,et al.“Aromatic”Substituent Constants for Structure-Activity Correlations[J].Journal ofMedicinal Chemistry.1973.16(11)

[0011] [5]Corwin H., Albert L.., and Tafta R.W..Survey of Hammett Substituent Constants and Resonance and Field Parameters[J]. Chemical Review. 1991, 91, 165-195.

[0012] [6]O'hagan D.. Understanding organofluorine chemistry. An introduction to the C–F bond[J]. Chemcal Society Reviews, 2008, 37(2): 308-19.

[0013] [7]Wang C., Chen Z., Wu W, et al. How the Generalized Anomeric Effect Influences the Conformational Preference[J]. Chemistry–A European Journal, 2012, 19(4): 1436-44.

[0014] [8]Su J., Chen K., Kang Q.K., et al. Catalytic SNAr Hexafluoroisopropoxylation of Aryl Chlorides and Bromides[J]. Angewandte Chemie International Edition, 2023, 62(24):

[0015] [9]Audouard C,. Garayt M.R., Kérourédan E., et al. A direct and rapid route to α,α-difluoroacylsilanes from trifluoroethanol[J]. Journal of Fluorine Chemistry, 2005, 126(4): 609-21.

[0016]

[10] Christophe A., John F., Hongli Y., et al.A Potentially Divergent and Rapid Route to Analogues ofDeoxycyclitols,Pentopyranoses,6-Deoxyhexoses,andHexoses[J].Organic Letters, 2004, 6(23):4269-4272. Summary of the Invention

[0017] This invention addresses the drawbacks of ether exchange reactions, such as long reaction cycles, low yields, and numerous side reactions, as well as the limitation of substrates in the trifluoroethoxylation of allyl bromides. It provides a method for synthesizing allyl trifluoroethyl ethers. This method, through temperature control, enables selective nucleophilic substitution of trifluoroethoxy groups of different types of methyl ethers at the C-position of the allyl group. This method offers advantages such as readily available starting materials, simple process, mild conditions, high yield, broad substrate range, and few byproducts.

[0018] The present invention discloses a method for synthesizing allyl trifluoroethyl ether compounds, which uses allyl methyl ether as a raw material and trifluoroethanol as a solvent, and reacts in the presence of Lewis acid catalyst, additives and base, and then obtains allyl trifluoroethyl ether compounds after separation and purification.

[0019] Specifically, allyl methyl ether is dissolved in a solvent and reacted in a Shelenk reaction tube in the presence of a Lewis acid catalyst, additives, and a base. After the reaction is completed, the product is separated and purified to obtain the target product.

[0020] The structural formula of the allyl methyl ether is:

[0021]

[0022] Wherein: R1 is a phenyl or a phenyl containing different substituents, R2 is a CH3 or H group, and R3 is a CH3 or H functional group.

[0023] The Lewis acid catalyst is selected from any one of zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, aluminum trifluoromethanesulfonate, trifluoromethanesulfonic acid, hafnium tetrachloride, and bis(trifluoromethanesulfonyl)imide, and the amount of catalyst added is 5 mol%-50 mol%, calculated as allyl methyl ether.

[0024] The alkali is at least one of potassium fluoride, sodium formate, and sodium fluoride, and the amount added is 1-7 times the equivalent, calculated as allyl methyl ether.

[0025] The additive is at least one of sodium hexafluoroantimonate, sodium tetrafluoroborate, and sodium hexafluorophosphate, and the amount of additive added is 1-7 times the equivalent, calculated as allyl methyl ether.

[0026] The solvent is trifluoroethanol.

[0027] The reaction temperature of the synthesis method of this invention is from -10℃ to 100℃, wherein the nucleophilic substitution of the methoxy group on the primary carbon is preferably carried out at 90℃, the nucleophilic substitution of the methoxy group on the secondary carbon is preferably carried out at 70℃, and the nucleophilic substitution of the methoxy group on the tertiary carbon is preferably carried out at 0℃. The reaction time is 4-48 h, preferably 12 h.

[0028] The separation and purification process involves adding water to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and finally purifying by column chromatography. The eluent for column chromatography purification is petroleum ether:ethyl acetate = 50:1, v / v.

[0029] The reaction route of this invention is shown below:

[0030]

[0031] The beneficial effects of this invention are reflected in:

[0032] 1. The synthesis method of the present invention is a Lewis acid-catalyzed trifluoroethoxy nucleophilic substitution reaction of allyl methyl ether, which has the advantages of simple and readily available raw materials, simple process and mild conditions.

[0033] 2. The synthesis method of the present invention has wide substrate applicability, high yield, few by-products, and is compatible with a variety of functional groups. It is suitable for allyl methyl ethers containing multiple substituents on the aromatic ring. Attached Figure Description

[0034] Figure 1 Gas chromatography-mass spectrometry (GC-MS) chromatogram of the reaction products after 2 hours.

[0035] Figure 2 Gas chromatography-mass spectrometry (GC-MS) chromatogram of the reaction mixture after 1 hour.

[0036] Figure 3 This is a gas chromatography-mass spectrometry (GC-MS) chromatogram of reaction product 2i.

[0037] Figure 4 This is a gas chromatography-mass spectrometry (GC-MS) chromatogram of reactant 1i. Detailed Implementation

[0038] Single-factor experiments confirmed that the presence of base, Lewis acid, and trifluoroethanol is essential in the reaction process.

[0039] The absence of additives will reduce the reaction yield.

[0040] Changes in temperature (compared to optimal reaction conditions) will reduce the reaction yield.

[0041] Shortening the reaction time will result in an incomplete reaction, while extending the reaction time will not further improve the reaction yield.

[0042] Changing the reaction solvent will prevent the reaction from taking place.

[0043] The conditional screening process was carried out using (E)-(3-methoxybut-1-en-1-yl)benzene (1a) as a model substrate, and the specific implementation is as follows:

[0044] Table 1

[0045]

[0046] Table 1 shows the reaction yield measured by gas chromatography (GC) using benzophenone as an internal standard.

[0047] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below with reference to specific embodiments. However, the following embodiments are only for further illustration of the present invention and are not intended to limit the present invention.

[0048] Example 1:

[0049]

[0050] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, add the following ingredients: (E)-(3-methoxybut-1-en-1-yl)benzene (1a) (0.2 mmol), zinc trifluoromethanesulfonate catalyst (0.04 mmol, 20 mol%), sodium hexafluoroantimonate (0.4 mmol, 2 eq), KF (0.4 mmol, 2 eq), and 2.0 mL of trifluoroethanol. Fix the reaction tube in an oil bath at 70 °C and react for 12 h. Extract with water and ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate under vacuum. Purify the product by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1, V / V) to give a pale yellow liquid (2a) (33 mg, 72%). The NMR data for this compound are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.40(d,J=7.0Hz,2H),7.34(t,2H),7.28(d,1H),6.57(d,J =15.9Hz,1H),6.07(dd,J=15.9,7.9Hz,1H),4.17(p,1H),3.90–3.72(m,2H),1.40(d,3H). 13C NMR (101MHz, Chloroform-d) δ 136.12, 133.02, 129.71, 128.81, 128.27, 126.73, 124.34 (q, J = 280Hz) 78.58, 65.46 (q, J = 34Hz), 21.62. 19 F NMR(564MHz,Chloroform-d)δ-74.13.

[0051] Example 2:

[0052]

[0053] (E)-1-(3-methoxybut-1-en-1-yl)-4-methylbenzene (1b) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a colorless oily liquid (2b) (33 mg, 68%). The NMR data of this compound are as follows: 1 HNMR(600MHz,Chloroform-d)δ7.31(s,2H),7.16(s,2H),6.55(d,J=15.9,1H),6.02 (dd,J=15.9,8.1Hz,1H),4.16(m,1H),3.86-3.77(m,2H),2.36(s,3H),1.41(d,3H). 13 C NMR (151MHz, Chloroform-d) δ138.21, 133.35, 133.00, 129.50, 128.67, 126.65, 124.36 (q, J = 280Hz), 78.68, 65.40 (q, J = 34Hz), 21.66, 21.35. 19 F NMR(376MHz,Chloroform-d)δ-74.06.

[0054] Example 3:

[0055]

[0056] (E)-(3-methoxybut-1-en-1-yl)benzene (1c) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a pale yellow liquid (2c) (34 mg, 69%). The NMR data of this compound are as follows: 1HNMR(600MHz,Chloroform-d)δ7.40–7.34(m,2H),7.03(m,2H),6.54(d,J=15.9Hz,1 H),6.00(dd,J=15.9,7.8Hz,1H),4.22–4.11(m,1H),3.92–3.70(m,2H),1.40(d,3H). 13 C NMR (151MHz, Chloroform-d) δ 162.74 (m), 132.37 (m), 131.70, 129.44 (m), 128.32 (m), 124.35 (q, J = 280Hz), 115.73 (m), 78.48, 65.54 (q, J = 34Hz), 21.53. 19 FNMR(564MHz,Chloroform-d)δ-74.14(s,3F),-113.67(s,1F).

[0057] Example 4:

[0058]

[0059] (E)-1-chloro-4-(3-methoxybut-1-en-1-yl)benzene (1d) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a colorless oily liquid (2d) (39 mg, 73%). The NMR data of this compound are as follows: 1 HNMR(600MHz,Chloroform-d)δ7.36–7.28(m,4H),6.52(d,J=15.9Hz,1H),6.06(dd,J=16.0,7.8Hz,1H),4.17(m,1H),3.90–3.72(m,2H),1.40(d,3H).13C NMR (151MHz, Chloroform-d) δ134.67, 133.88, 131.56, 130.45, 128.96, 127.94, 124.28 (q, J = 280Hz), 78.39, 65.58 (q, J = 34Hz), 21.49. 19 F NMR(564MHz,Chloroform-d)δ-74.12.

[0060] Example 5:

[0061]

[0062] (E)-1-bromo-4-(3-methoxybut-1-en-1-yl)benzene (1e) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a colorless oily liquid (2e) (49 mg, 80%). The NMR data of this compound are as follows: 1 H NMR (600MHz, Chloroform-d) δ7.45(m,2H),7.26(m,2H),6.50(d,J=15.9Hz,1H),6.07(dd,J=16.0,7.8Hz,1H),4.16(m,1H),3.80(m,2H),1.39(d,3H). 13 C NMR (151MHz, Chloroform-d) δ 135.10, 131.89, 131.57, 130.58, 128.24, 124.27 (q, J = 280Hz), 122.02, 78.36, 65.58 (q, J = 34Hz), 21.45. 19 F NMR(564MHz,Chloroform-d)δ-74.10.

[0063] Example 6:

[0064]

[0065] (E)-(3-methoxybut-1-en-1-yl)benzene (1f) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a colorless oily liquid (2f) (27 mg, 52%). The NMR data of this compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.34(m,2H),6.88(m,2H),6.50(d,J=15.9Hz,1H),5.92(dd ,J=15.9Hz,8.1Hz,1H),4.19–4.09(m,1H),3.82(s,3H),3.90–3.70(m,2H),1.39(d,3H). 13 C NMR (101MHz, Chloroform-d) δ159.72, 132.65, 128.84, 127.97, 124.38 (q, J = 280Hz), 114.18, 78.76, 65.33 (q, J = 34Hz), 55.45, 21.73. 19FNMR(564MHz,Chloroform-d)δ-74.09.

[0066] Example 7:

[0067]

[0068] (E)-(3-methoxypent-1-en-1-yl)benzene (1g) was used instead of (E)-(3-methoxybut-1-en-1-yl)benzene (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1, v / v) to give a pale yellow liquid (2f) (35 mg, 72%). The NMR data of this compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.47–7.41(m,2H),7.41–7.34(m,2H),7.34–7.28(m,1H),6.59(d, J=16.0Hz,1H),6.06(dd,J=16.0,8.3Hz,1H),3.97–3.71(m,3H),1.88–1.61(m,2H),1.00(t,3H). 13 C NMR(151MHz,Chloroform-d)δ136.14,133.01,129.73,128.82,128.27,126.74,124.35(q,J=280Hz),78.57,65.49(q,J=34Hz),

[0069] 21.62. 19 F NMR(564MHz,Chloroform-d)δ-74.10.

[0070] Example 8:

[0071]

[0072] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, add the following ingredients: (E)-(3-methoxypropyl-1-en-1-yl)benzene (1 h) (0.2 mmol), zinc trifluoromethanesulfonate catalyst (0.04 mmol, 20 mol%), sodium hexafluoroantimonate (0.4 mmol, 2 eq), KF (0.4 mmol, 2 eq), and 2.0 mL of trifluoroethanol. The reaction tube was fixed in an oil bath at 90 °C, and the reaction was allowed to proceed for 12 h. After simple processing, the reaction solution was sent to GC-MS. The formation of the reaction product was observed after 2 h.

[0073] The reaction products 2h MW=216

[0074] Reaction raw materials 1h MW=148

[0075] Example 9:

[0076]

[0077] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, the following were added: (E)-(3-methoxy-3-methylbut-1-en-1-yl)benzene (1i) (0.2 mmol), zinc trifluoromethanesulfonate catalyst (0.04 mmol, 20 mol%), sodium hexafluoroantimonate (0.4 mmol, 2 eq), KF (0.4 mmol, 2 eq), and 2.0 mL of trifluoroethanol. The reaction tube was fixed on a cryogenic reactor at 0 °C, and after reacting for 12 h, the reaction solution was simply processed and sent to GC-MS. The formation of product 2i was detected.

[0078] reaction product 2i MW=244

[0079] Reaction material 1i MW=176

Claims

1. A method for synthesizing an allyl trifluoroethyl ether compound, characterized in that: Allyl methyl ether was dissolved in a solvent and reacted in the presence of Lewis acid catalyst, additives and base. After separation and purification, allyl trifluoroethyl ether compounds were obtained. The allyl methyl ether is selected from compounds with the following structures: ； The Lewis acid catalyst is selected from any one of zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, aluminum trifluoromethanesulfonate, trifluoromethanesulfonic acid, hafnium tetrachloride, and bis(trifluoromethanesulfonyl)imide. The alkali is at least one of potassium fluoride, sodium formate, and sodium fluoride; The additive is at least one of sodium hexafluoroantimonate, sodium tetrafluoroborate, and sodium hexafluorophosphate. The solvent is trifluoroethanol.

2. The synthesis method according to claim 1, characterized in that: The amount of Lewis acid catalyst added is 5 mol%-50 mol%, calculated as allyl methyl ether.

3. The synthesis method according to claim 1, characterized in that: The amount of alkali added is 1-7 times the equivalent, calculated as allyl methyl ether.

4. The synthesis method according to claim 1, characterized in that: The amount of the additive added is 1-7 times the equivalent, calculated as allyl methyl ether.

5. The synthesis method according to claim 1, characterized in that: The reaction temperature ranges from -10℃ to 100℃, and the reaction time is 4-48 h.

6. The synthesis method according to claim 1, characterized in that: The separation and purification process involves adding water to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and finally purifying by column chromatography. The eluent for column chromatography purification is petroleum ether:ethyl acetate = 50:1, v / v.

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