Method for synthesizing beta-sulfur trifluoromethyl alkylamine through olefin bifunctionalization reaction

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing beta-sulfur trifluoromethyl alkylamine through olefin bifunctionalization reaction. The method comprises the following steps: providing an olefin compound, an amination reagent, a Cu < + > catalyst, a sulfur trifluoromethyl compound and a bipyridine compound, mixing under an acidic condition, carrying out a heating reaction, and then carrying out post-treatment to obtain the beta-sulfur trifluoromethyl alkylamine compound. A Cu < + > catalyst is introduced to catalyze an ammoniation bifunctionalization reaction of olefin, so that sulfur trifluoromethyl groups are introduced into tertiary alkylamine molecules; the synthesis method is simple in reaction condition, convenient to treat, high in product recovery rate, economical, cheap and beneficial to wide application.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins. Background Art

[0002] The difunctionalization reaction of olefins by amination can simultaneously construct CN bonds and CX bonds. It is an efficient way to construct functionalized tertiary alkylamines, with the characteristics of cheap and readily available raw materials, step economy and atom economy.

[0003] The difunctionalization reaction of olefins by amination can be divided into two main pathways: one is the ionic pathway, in which organic metal species migrate and insert into olefins to form carbon-metal bonds, and then the target product is obtained through electrophilic amination. However, this pathway can only achieve ammonia boron and ammonia carbonization reactions; the other is the addition pathway of electrophilic amino radical cations to olefins. The key to the success of this type of reaction lies in how to effectively capture the newly generated carbon radical intermediates.

[0004] In order to solve this inherent challenge, several reaction models have been developed. The first is a trivalent copper intermediate stabilized by a directing group. This strategy can be used to introduce halogen, azide and amino functional groups into alkylamine molecules. The need for pre-installation and subsequent removal of the directing group in this method will reduce the overall efficiency of the reaction. The second is the nucleophilic ring opening of aziridine intermediates. This method can be used to achieve the aminofluorination reaction of olefins, but the regioselectivity of this process is often difficult to control. In addition, the generation of amino radical cations requires acidic conditions, but the acid will greatly reduce the nucleophilicity of sulfur, making it difficult to undergo further ring-opening reactions. The third is a bimolecular homolytic substitution reaction, which has excellent regioselectivity. So far, this strategy has only achieved the synthesis of tertiary alkylamines with chlorine atoms attached to the β-position; no synthetic method for attaching other groups to tertiary alkylamine molecules has been provided for the time being. Summary of the invention

[0005] The purpose of the present application is to provide a method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins, aiming to solve the problem that there is no synthetic method for connecting groups other than chlorine atoms to tertiary alkylamine molecules in the prior art.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0007] In a first aspect, the present application provides a method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins, comprising the following steps: providing an olefin compound, an amination reagent, Cu +The catalyst, the sulfur trifluoromethyl compound and the bipyridine compound are mixed under acidic conditions, heated for reaction, and then post-treated to obtain a β-sulfur trifluoromethyl alkylamine compound.

[0008] In some embodiments, the olefin compound is selected from any one of aryl olefins, alkyl olefins, or olefin derivatives.

[0009] In some embodiments, the aromatic olefin is selected from any one of styrene, substituted styrene, naphthylene vinyl, and substituted naphthylene vinyl; wherein the substituent is selected from at least one of C1-C3 alkyl, phenyl, methoxy, methylthio, halogen, azide, and alkyne.

[0010] In some embodiments, the alkyl olefin is selected from any one of C1-C15 alkyl olefins and C1-C15 alkyl olefins containing substituted functional groups; wherein the substituted functional group is selected from any one of phenyl, halogen, azide, ester, amino, and ether.

[0011] In some embodiments, the olefin derivative is selected from any one of diketone galactose, estrone, and lithocholic acid.

[0012] In some embodiments, the amination agent is selected from any one of morpholinobenzoate, piperidinylbenzoate, piperazinebenzoate, C1-C5 dialkylaminebenzoate, tert-butylaminebenzoate, adamantaneaminebenzoate, maprotilinebenzoate, and fluoxetinebenzoate.

[0013] In some embodiments, Cu + The catalyst is selected from any one of CuSCN, CuI and CuCN.

[0014] In some embodiments, the bipyridine compound is selected from any one of 6,6'-dimethyl-2,2'-bipyridine and 2,9-dimethyl-1,10-phenanthroline.

[0015] In some embodiments, the step of mixing under acidic conditions further includes: adding an additive, a proton source and a solvent and mixing them together; wherein the additive is selected from any one of potassium bromide, cesium bromide, and cesium iodide; the proton source is selected from trifluoroacetic acid; and the solvent is selected from any one of 1,2-dichloroethane and chloroform.

[0016] In some embodiments, the molar ratio of the olefin compound, the amination reagent, the Cu+ catalyst, the sulfur trifluoromethyl compound and the bipyridine compound is 1-1.2: 2-2.2: 0.1-0.2: 2-2.2: 0.15-0.18.

[0017] In some embodiments, the heating reaction is performed at a temperature of 80 to 90° C. for 2 to 3 hours.

[0018] In some embodiments, the post-treatment step further includes: providing an alkaline solution to quench the reaction, extracting with an organic solvent to obtain an organic phase; and then washing, drying, concentrating, separating and purifying in sequence to obtain β-thiotrifluoromethylalkylamine compounds.

[0019] The first aspect of the present application provides a method for synthesizing β-thiotrifluoromethylalkylamine by a difunctionalization reaction of olefins. In the reaction, an aminating agent is protonated under acidic conditions and undergoes a single electron transfer with an in-situ generated LCu(I)SCF3 catalyst to form an amino radical cation and LCu(II)SCF3; then, the amino radical cation undergoes an addition reaction with an olefin compound to form a carbon radical intermediate; further, the carbon radical intermediate undergoes a bimolecular homolytic substitution reaction (S H 2) to obtain the final target product and release Cu + Returning to the catalytic cycle again; in this reaction, by introducing Cu + The catalyst is used to catalyze the difunctionalization reaction of olefin amination to introduce the sulfur trifluoromethyl group into the tertiary alkylamine molecule; the synthesis method has simple reaction conditions, convenient treatment, high product recovery rate, and is economical and cheap, which is conducive to wide use. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0021] Figure 1 The β-thiotrifluoromethylalkylamine prepared in Example 1 of the present invention 1 H NMR spectra;

[0022] Figure 2 The β-thiotrifluoromethylalkylamine prepared in Example 1 of the present invention 13 C NMR spectra;

[0023] Figure 3 The β-thiotrifluoromethylalkylamine prepared in Example 1 of the present invention 19 F NMR spectra;

[0024] Figure 4 The β-thiotrifluoromethylalkylamine prepared in Example 2 of the present invention 1 H NMR spectra;

[0025] Figure 5 The β-thiotrifluoromethylalkylamine prepared in Example 2 of the present invention 13 C NMR spectra;

[0026] Figure 6 The β-thiotrifluoromethylalkylamine prepared in Example 2 of the present invention 19 F NMR spectra;

[0027] Figure 7 The β-thiotrifluoromethylalkylamine prepared in Example 3 of the present invention 1 H NMR spectra;

[0028] Figure 8 The β-thiotrifluoromethylalkylamine prepared in Example 3 of the present invention 13 C NMR spectra;

[0029] Fig. 9 The β-thiotrifluoromethylalkylamine prepared in Example 3 of the present invention 19 F NMR spectra;

[0030] Fig.10 The β-thiotrifluoromethylalkylamine prepared in Example 4 of the present invention 1 H NMR spectra;

[0031] Fig.11 The β-thiotrifluoromethylalkylamine prepared in Example 4 of the present invention 13 C NMR spectra;

[0032] Fig.12 The β-thiotrifluoromethylalkylamine prepared in Example 4 of the present invention 19 F NMR spectra;

[0033] Fig.13 The β-thiotrifluoromethylalkylamine prepared in Example 5 of the present invention 1 H NMR spectra;

[0034] Fig.14 The β-thiotrifluoromethylalkylamine prepared in Example 5 of the present invention 13 C NMR spectra;

[0035] Fig.15 The β-thiotrifluoromethylalkylamine prepared in Example 5 of the present invention 19 F NMR spectra;

[0036] Fig.16 The β-thiotrifluoromethylalkylamine prepared in Example 6 of the present invention 1 H NMR spectra;

[0037] Fig.17 The β-thiotrifluoromethylalkylamine prepared in Example 6 of the present invention 13 C NMR spectra;

[0038] Fig.18 The β-thiotrifluoromethylalkylamine prepared in Example 6 of the present invention 19 F NMR spectra;

[0039] Fig.19 The β-thiotrifluoromethylalkylamine prepared in Example 7 of the present invention 1 H NMR spectra;

[0040] Fig. 20 The β-thiotrifluoromethylalkylamine prepared in Example 7 of the present invention 13 C NMR spectra;

[0041] Fig.21 The β-thiotrifluoromethylalkylamine prepared in Example 7 of the present invention 19 F NMR spectra;

[0042] Fig. 22 The β-thiotrifluoromethylalkylamine prepared in Example 8 of the present invention 1 H NMR spectra;

[0043] Fig.23 The β-thiotrifluoromethylalkylamine prepared in Example 8 of the present invention 13 C NMR spectra;

[0044] Fig.24 The β-thiotrifluoromethylalkylamine prepared in Example 8 of the present invention 19 F NMR spectra;

[0045] Fig.25 The β-thiotrifluoromethylalkylamine prepared in Example 9 of the present invention 1 H NMR spectra;

[0046] Fig.26 The β-thiotrifluoromethylalkylamine prepared in Example 9 of the present invention 13 C NMR spectra;

[0047] Fig. 27 The β-thiotrifluoromethylalkylamine prepared in Example 9 of the present invention 19 F NMR spectra;

[0048] Fig.28 The β-thiotrifluoromethylalkylamine prepared in Example 10 of the present invention 1 H NMR spectra;

[0049] Fig.29 The β-thiotrifluoromethylalkylamine prepared in Example 10 of the present invention 13 C NMR spectra;

[0050] Fig.30 The β-thiotrifluoromethylalkylamine prepared in Example 10 of the present invention 19 F NMR spectra;

[0051] Fig.31 The β-thiotrifluoromethylalkylamine prepared in Example 11 of the present invention 1 H NMR spectra;

[0052] Fig.32 The β-thiotrifluoromethylalkylamine prepared in Example 11 of the present invention 13 C NMR spectra;

[0053] Fig.33 The β-thiotrifluoromethylalkylamine prepared in Example 11 of the present invention 19 F NMR spectra;

[0054] Fig.34 The β-sulfur trifluoromethyl alkylamine 3k-1 prepared by the present invention 1 H NMR spectra;

[0055] Fig.35 The β-sulfur trifluoromethyl alkylamine 3k-1 prepared by the present invention 13 C NMR spectra;

[0056] Fig.36 The β-sulfur trifluoromethyl alkylamine 3k-1 prepared by the present invention 19 F NMR spectra;

[0057] Fig.37 The β-sulfur trifluoromethyl alkylamine 3k-2 prepared by the present invention 1 H NMR spectra;

[0058] Fig.38 The β-sulfur trifluoromethyl alkylamine 3k-2 prepared by the present invention 13 C NMR spectra;

[0059] Fig.39 The β-sulfur trifluoromethyl alkylamine 3k-2 prepared by the present invention 19 F NMR spectra;

[0060] Fig.40 The β-sulfur trifluoromethyl alkylamine 3k-3 prepared by the present invention 1 H NMR spectra;

[0061] Fig.41 The β-sulfur trifluoromethyl alkylamine 3k-3 prepared by the present invention 13 C NMR spectra;

[0062] Fig.42 The β-sulfur trifluoromethyl alkylamine 3k-3 prepared by the present invention 19 F NMR spectrum. DETAILED DESCRIPTION

[0063] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0064] The first aspect of the embodiment of the present application provides a method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins, comprising the following steps:

[0065] Provide olefin compounds, amination reagents, Cu + The catalyst, the sulfur trifluoromethyl compound and the bipyridine compound are mixed under acidic conditions, heated for reaction, and then post-treated to obtain a β-sulfur trifluoromethyl alkylamine compound.

[0066] The first aspect of the present invention provides a method for synthesizing β-thiotrifluoromethylalkylamine by a difunctionalization reaction of olefins. In the reaction, an amination reagent is protonated under acidic conditions and reacts with Cu + The catalyst undergoes a single electron transfer to form an amino radical cation and Cu 2+ ; Then, the amino radical cation reacts with the olefin compound to form a carbon radical intermediate, Cu 2+ The carbon radical intermediate undergoes a ligand exchange reaction with a sulfur trifluoromethyl compound to generate an intermediate CuSCF3; further, the carbon radical intermediate undergoes a bimolecular homolytic substitution reaction with CuSCF3 (S H 2) to obtain the final target product and release Cu + Returning to the catalytic cycle again; in this reaction, by introducing Cu + The catalyst is used to catalyze the difunctionalization reaction of olefin amination to introduce the sulfur trifluoromethyl group into the tertiary alkylamine molecule; the synthesis method has simple reaction conditions, convenient treatment, high product recovery rate, and is economical and cheap, which is conducive to wide use.

[0067] As an important fluoroalkyl group, the sulfur trifluoromethyl group plays an important role in organic synthesis and medicinal chemistry. This group has special physical and chemical properties, with hydrophobicity parameter: π = 1.44, Hammett constant: σm is 0.40 and σp is 0.50. The main purpose of this synthetic method is to introduce the sulfur trifluoromethyl group into the tertiary alkylamine molecule to adjust the alkalinity of the molecule, improve metabolic stability and cell membrane permeability, etc., and affect the application performance of the molecule in the field of medicinal chemistry and biology.

[0068] In some embodiments, the sulfur trifluoromethyl compound is selected from AgSCF3.

[0069] In some embodiments, the olefin compound is selected from any one of aryl olefins, alkyl olefins, or olefin derivatives.

[0070] In some embodiments, the aromatic olefin is selected from any one of styrene, substituted styrene, naphthylene vinyl, and substituted naphthylene vinyl; wherein the substituent is selected from at least one of C1-C3 alkyl, phenyl, methoxy, methylthio, halogen, azide, and alkyne.

[0071] In some embodiments, the alkyl olefin is selected from any one of C1-C15 alkyl olefins and C1-C15 alkyl olefins containing substituted functional groups; wherein the substituted functional group is selected from any one of phenyl, halogen, azide, ester, amino, and ether.

[0072] In some embodiments, the olefin derivative is selected from any one of diketone galactose, estrone, and lithocholic acid.

[0073] In some embodiments, the amination agent is selected from any one of morpholinobenzoate, piperidinylbenzoate, piperazinebenzoate, C1-C5 dialkylaminebenzoate, tert-butylaminebenzoate, adamantaneaminebenzoate, maprotilinebenzoate, and fluoxetinebenzoate.

[0074] In some embodiments, Cu + The catalyst is selected from any one of CuSCN, CuI and CuCN.

[0075] In some embodiments, the bipyridine compound is selected from any one of 6,6'-dimethyl-2,2'-bipyridine and 2,9-dimethyl-1,10-phenanthroline.

[0076] In some embodiments, the step of mixing under acidic conditions further includes: adding an additive, a proton source and a solvent and mixing them together; wherein the additive is selected from any one of potassium bromide, cesium bromide, and cesium iodide; the proton source is selected from trifluoroacetic acid; and the solvent is selected from any one of 1,2-dichloroethane and chloroform.

[0077] In some embodiments, olefin compounds, amination reagents, Cu + The molar ratio of the catalyst, the sulfur trifluoromethyl compound and the bipyridine compound is 1-1.2: 2-2.2: 0.1-0.2: 2-2.2: 0.15-0.18. In some specific embodiments, the olefin compound, the amination reagent, the Cu + The molar ratio of the catalyst, the sulfur trifluoromethyl compound and the bipyridine compound is 1:2:0.1:2:0.15.

[0078] In some embodiments, the temperature of the heating reaction is 80-90° C., and the time is 2-3 hours. In some specific embodiments, the temperature of the heating reaction is 80° C., and the time is 3 hours.

[0079] In some embodiments, the post-treatment step further includes: providing an alkaline solution to quench the reaction, extracting with an organic solvent to obtain an organic phase; and then washing, drying, concentrating, separating and purifying in sequence to obtain β-thiotrifluoromethylalkylamine compounds.

[0080] The following describes the invention in conjunction with specific embodiments.

[0081] Example 1

[0082]

[0083] Morpholinobenzoate 2a (82.8 mg, 0.40 mmol, 2.0 equiv), AgSCF3 (83.6 mg, 0.40 mmol, 2.0 equiv), CuSCN (2.5 mg, 0.02 mmol, 0.10 equiv), L1 (5.5 mg, 0.03 mmol, 0.15 equiv), cesium bromide (CsBr, 106 mg, 0.50 mmol, 2.5 equiv), and anhydrous 1,2-dichloroethane (DCE, 2.0 mL) were added to a 10 mL vial with a magnetic rod. The mixture was purged with nitrogen three times. Subsequently, 4-tert-butylstyrene 1a (32.1 mg, 0.20 mmol, 1.0 equiv) and trifluoroacetic acid (TFA, 23 μL, 0.30 mmol, 1.5 equiv) were added to the reaction solution and stirred at 80°C for 3 hours. The reaction was quenched with 1M sodium hydroxide aqueous solution (3.0mL), and then extracted with dichloromethane (8mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA=10:1) to obtain the target product 3a (48.6mg, 0.14mmol, 70%) as a yellow oil. 1H NMR (600MHz, CDCl3) δ7.27(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),4.45(dd,J=9.0,6.6Hz,1H),3.64–3.56(m,4H ),2.76(dd,J=13.2,9.0Hz,1H),2.69(dd,J=13.2,6.0Hz,1H),2.50–2.44(m,2H),2.38–2.31(m,2H),1.24(s,9H). 13 C NMR (150MHz, CDCl3) δ151.1, 136.1, 130.8 (q, J = 306.0Hz), 127.4, 125.6, 66.8, 63.7, 53.5, 47.6, 34.6, 31.3. 19 F NMR(565MHz,CDCl3)δ-39.27(s).IRν max (film):2962,2857,2810,1620,1510,1455,1363,1303,1114,1007,807cm -1 .HRMS(ESI)m / z calcd for C 17 H 25 F3NOS[M+H] + :348.1603; found:348.1614. (e.g. Figure 1-3 ).

[0084] Example 2

[0085]

[0086] The experimental conditions were the same as those in Example 1, except that 4-tert-butylstyrene in Example 1 was replaced with 4-bromostyrene. White solid 3b (42.1 mg, 0.11 mmol, 57%) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3) δ7.47(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),4.49(t,J=7.2Hz,1H),3.69–3.63(m ,4H),2.79(dd,J=13.2,9.0Hz,1H),2.74(dd,J=13.2,6.6Hz,1H),2.54–2.49(m,2H),2.44–2.39(m,2H). 13C NMR (150MHz, CDCl3) δ138.5, 131.8, 130.8 (q, J = 306.0Hz), 129.5, 122.0, 66.8, 63.4, 53.5, 47.4. 19 F NMR(565MHz,CDCl3)δ-39.28(s).IRν max (film):2959,2855,2812,1632,1488,1455,1406,1303,1271,1112,1010,869,755cm -1 .HRMS(ESI)m / z calcd forC 13 H 16 BrF3NOS[M+H] + :370.0083; found:370.0077. (e.g. Figure 4-6 ).

[0087] Example 3

[0088]

[0089] The experimental conditions were the same as those in Example 1, except that 4-tert-butylstyrene in Example 1 was replaced with 1,2-dihydronaphthalene. Yellow oily liquid 3c (41.2 mg, 0.13 mmol, 65%, dr>20:1) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3) δ7.35–7.33(m,1H),7.13–7.09(m,2H),7.00(d,J=6.6Hz,1H),4.57(d,J=3.0Hz,1H),3.64–3.56(m,4H), 2.84–2.82(m,1H),2.80–2.75(m,1H),2.62(dt,J=16.2,5.4Hz,1H),2.55–2.47(m,4H),2.14–2.08(m,1H),1.90–1.84(m,1H). 13 C NMR (150MHz, CDCl3) δ138.0, 132.7, 131.1, 130.8 (q, J = 306.0Hz), 128.8, 127.6, 126.4, 67.0, 65.3, 50.6, 45.8, 25.6, 21.3. 19 F NMR(565MHz,CDCl3)δ-39.81(s).IRν max (film):2957,2855,2811,1601,1489,1453,1271,1112,1008,877,754cm -1.HRMS(ESI)m / z calcd forC 15 H 19 F3NOS[M+H] + :318.1134; found:318.1142. (e.g. Figure 7-9 ).

[0090] Example 4

[0091]

[0092] The experimental conditions were the same as those in Example 1, except that 4-tert-butylstyrene in Example 1 was replaced with α-methylstyrene. Yellow oily liquid 3d (38.4 mg, 0.13 mmol, 63%) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3) δ7.60–7.58(m,2H),7.34–7.31(m,2H),7.25–7.23(m,1H),3.57–3.50(m,4H), 2.86(d,J=13.8Hz,1H),2.82(d,J=13.8Hz,1H),2.35–2.32(m,2H),2.31–2.25(m,2H),1.99(s,3H). 13 C NMR (150MHz, CDCl3) δ 142.4, 130.7 (q, J = 307.5Hz), 128.1, 127.4, 127.1, 70.2, 67.1, 58.4, 55.3, 25.5. 19 F NMR(565MHz,CDCl3)δ-35.27(s).IRν max (film):2964,2858,2818,1613,1497,1447,1356,1319,1119,1014,864,771,699cm -1 .HRMS(ESI)m / z calcd forC 14 H 19 F3NOS[M+H] + :306.1134; found:306.1128. (e.g. Figure 10-12 ).

[0093] Example 5

[0094]

[0095] The experimental conditions were the same as those in Example 1, except that the morpholinobenzoate in Example 1 was replaced with piperidone glycol acetal benzoate. White solid 3e (53.2 mg, 0.13 mmol, 66%) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3) δ7.26(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),4.44(t,J=6.6Hz,1H),3.86–3.84(m,4H),2.79(dd,J =13.2,9.0Hz,1H),2.72(dd,J=13.2,6.6Hz,1H),2.60–2.52(m,2H),2.48–2.39(m,2H),1.68–1.60(m,4H),1.23(s,9H). 13 C NMR (150MHz, CDCl3) δ151.0, 136.3, 130.9 (q, J = 306.0Hz), 127.5, 125.5, 107.1, 64.2, 62.9, 51.3, 48.4, 34.6, 34.5, 31.3. 19 F NMR(565MHz,CDCl3)δ-39.25(s).IRν max (film):3062,3027,2963,2867,2796,1605,1509,1454,1364,1268,1114,1053,831,746cm -1 .HRMS(ESI)m / z calcd forC 20 H 29 F3NO2S[M+H] + :404.1866; found:404.1867. (e.g. Figure 13-15 ).

[0096] Example 6

[0097]

[0098] The experimental conditions were the same as those in Example 1, except that the morpholinobenzoate in Example 1 was replaced with adamantane benzoate. Yellow oily liquid 3f (31.3 mg, 0.08 mmol, 38%) was obtained by column chromatography. 1H NMR (600MHz, CDCl3) δ7.36 (d, J = 8.4Hz, 2H), 7.26 (d, J = 7.8Hz, 2H), 4.41 (t, J = 7.2Hz, 1H), 3.15 (dd, J = 12.0, 7. 2Hz,1H),3.10(dd,J=12.0,6.6Hz,1H),2.08–2.00(m,3H),1.67–1.62(m,3H),1.61–1.54(m,9H),1.32(s,9H). 13 C NMR (150MHz, CDCl3) δ151.1, 136.0, 130.8 (q, J = 305.4Hz), 127.3, 125.8, 50.5, 50.3, 46.0, 42.8, 36.7, 34.6, 31.3, 29.6. 19 F NMR(565MHz,CDCl3)δ-39.59(s).IRν max (film):2961,2906,2849,1681,1507,1467,1363,1310,1268,1146,1116,1016,833,754cm -1 .HRMS(ESI)m / z calcd for C 23 H 32 F3NNaS[M+Na] + :434.2100; found:434.2104. (e.g. Figure 16-18 ).

[0099] Example 7

[0100]

[0101] The experimental conditions were the same as those in Example 1, except that the morpholinobenzoate in Example 1 was replaced with maprotilinebenzoate. 3 g (61.2 mg, 0.11 mmol, 57%) of white solid was obtained by column chromatography. 1H NMR (600MHz, CDCl3) δ7.43–7.38(m,4H),7.34–7.30(m,4H),7.20–7.15(m,4 H),4.70–4.67(m,1H),4.35–4.33(m,1H),3.10–3.03(m,1H),3.02–2.95(m, 1H),2.82–2.77(m,1H),2.76–2.69(m,1H),2.57–2.49(m,1H),2.48–2.44(m ,4H),2.01–1.93(m,2H),1.92–1.85(m,2H),1.66–1.58(m,2H),1.33(s,9H). 13 C NMR (150MHz, CDCl3) δ151.1,145.6,145.5,145.1,136.3,131.0(q,J=306.0Hz),127.6,125.7,125.3 ,125.2,123.5,121.5,121.4,63.1,58.9,48.7,44.9,44.6,42.4,34.6,31.3,29.7,28.8,27.8,22.6. 19 F NMR(565MHz,CDCl3)δ-39.13(s).IRν max (film):3068,3019,2954,2867,2796,1610,1509,1456,1415,1364,1267,1114,1051,831,756cm -1 .HRMS(ESI)m / z calcd for C 33 H 39 F3NS[M+H] + :538.2750;found:538.2756.

[0102] (like Figure 19-21 ).

[0103] Example 8

[0104]

[0105] The experimental conditions were the same as those in Example 1, except that the solvent 1,1-dichloroethane in Example 1 was replaced with dichloroethane / hexafluoroisopropanol (2.0 mL / 1.0 mL), trifluoroacetic acid was replaced with trifluoroacetic anhydride (84 μL, 0.60 mmol, 3.0 equiv), and 4-tert-butylstyrene was replaced with 7-azidoheptene. Yellow oily liquid 3j (39.1 mg, 0.12 mmol, 60%) was obtained by column chromatography. 1HNMR(600MHz, CDCl3)δ3.66–3.60(m,4H),3.21(t,J=6.6,2H),3.17–3.19(m,1H),2.52(dd,J= 12.6,6.0Hz,1H),2.46–2.39(m,5H),1.85–1.81(m,1H),1.59–1.43(m,4H),1.41–1.30(m,3H). 13 CNMR (150MHz, CDCl3) δ131.2 (q, J=304.5Hz), 66.9, 63.2, 53.9, 51.3, 43.7, 32.6, 28.7, 26.4, 25.8. 19 FNMR(565MHz,CDCl3)δ-38.99(s).IRν max (film):2935,2857,2811,2096,1646,1456,1273,1115,1005,866,755cm -1 .HRMS(ESI)m / zcalcd for C 12 H 22 F3N4OS[M+H] + :327.1461; found:327.1465. (e.g. Figure 22-24 ).

[0106] Example 9

[0107]

[0108] The experimental conditions were the same as those in Example 1, except that the solvent 1,1-dichloroethane in Example 1 was replaced with dichloroethane / hexafluoroisopropanol (2.0 mL / 1.0 mL), trifluoroacetic acid was replaced with trifluoroacetic anhydride (84 μL, 0.60 mmol, 3.0 equiv), and 4-tert-butylstyrene was replaced with 10-hydroxynonene. Yellow oily liquid 3k (39.3 mg, 0.11 mmol, 55%) was obtained by column chromatography. 1 HNMR (600MHz, CDCl3) δ3.62(t,J=4.8Hz,4H),3.55(t,J=6.6Hz,2H),3.22–3.17(m,1H),2.51(dd,J=12.6,6.0Hz,1H),2.45(dd,J=12 .6,7.8Hz,1H),2.43–2.37(m,4H),1.82–1.76(m,1H),1.75–1.65(m,1H),1.53–1.47(m,3H),1.43–1.38(m,1H),1.33–1.23(m,11H). 13C NMR (150MHz, CDCl3) δ131.3 (q, J=304.5Hz), 66.9, 63.1, 62.9, 53.9, 43.8, 32.8, 32.7, 29.5, 29.4, 29.3, 29.2, 26.2, 25.7. 19 F NMR(565MHz,CDCl3)δ-38.99(s).IRν max (film):2927,2855,2811,1646,1456,1305,1274,1113,1005,866,755cm - 1 .HRMS(ESI)m / z calcd for C 16 H 31 F3NO2S[M+H] + :358.2022; found:358.2025. (e.g. Figure 25-27 ).

[0109] Example 10

[0110]

[0111] The experimental conditions were the same as those in Example 1, except that the solvent 1,1-dichloroethane in Example 1 was replaced with dichloroethane / hexafluoroisopropanol (2.0 mL / 1.0 mL), trifluoroacetic acid was replaced with trifluoroacetic anhydride (84 μL, 0.60 mmol, 3.0 equiv), 4-tert-butylstyrene was replaced with 4-phenyl-1-butene, and morpholinobenzoate was replaced with diethylaminobenzoate. Yellow oily liquid 31 was obtained by column chromatography. 1 H NMR (500MHz, CDCl3) δ7.21(d,J=7.5Hz,2H),7.14–7.10(m,3H),3.14–3.08(m,1H),2.82–2.78(m,1H),2.67–2.64(m,1H),2.61(dd,J=14.0,6 .0Hz,1H),2.51(dd,J=13.5,9.0Hz,1H),2.48–2.41(m,2H),2.41–2.34(m,2H),2.29–2.20(m,1H),1.77–1.68(m,1H),0.89(t,J=7.0Hz,6H). 13 C NMR (125MHz, CDCl3) δ 141.2, 131.3 (q, J = 303.8Hz), 128.5, 128.4, 126.0, 58.5, 47.5, 44.7, 33.9, 32.5, 11.8. 19FNMR(471MHz,CDCl3)δ-38.62(s).IRν max (film):3028,2968,2926,2854,1496,1455,1385,1203,1147,1112,746,698cm -1 .HRMS(ESI)m / z calcd for C 15 H 23 F3NS[M+H] + :306.1498; found:306.1490.IRν max (film):3028,2968,2926,2854,1496,1455,1385,1203,1147,1112,746,698cm -1 .HRMS(ESI)m / z calcd for C 15 H 23 F3NS[M+H] + :306.1498; found:306.1490. (e.g. Figure 28-30 ).

[0112] Embodiment 11

[0113]

[0114] The experimental conditions were the same as those in Example 5, except that 4-tert-butylstyrene in Example 5 was replaced by styrene. Yellow oily liquid 3k (43.7 mg, 0.13 mmol, 63%) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3) δ7.35–7.34(m,2H),7.32(d,J=7.8Hz,2H),7.29–7.27(m,1H),4.53(t,J=7.2,1H),3.93(s,4H), 2.86(dd,J=13.2,9.0Hz,1H),2.80(dd,J=13.2,6.6Hz,1H),2.63–2.61(m,2H),2.51–2.50(m,2H),1.74–1.67(m,4H). 13 CNMR(150MHz, CDCl3)δ139.6,130.8(q,J=304.5),128.6,128.0,127.9,107.0,64.21,62.8,51.3,48.8,34.7. 19 F NMR (565MHz, CDCl3) δ-39.30 (s). Figure 31-33 ).

[0115] Synthesis of SCF3-modified fentanyl:

[0116]

[0117] 3k (174 mg, 0.5 mmol, 1.0 equiv) and p-toluenesulfonic acid hydrate (TsOH·H2O, 4.8 mg, 0.025 mmol, 5 mol%) were dissolved in 2 mL of acetone. The reaction mixture was reacted at 80°C for 3 hours. After the reaction, the solvent was dried by spin drying, and the residue was separated by column chromatography to obtain a yellow oily liquid 3k-1 (118 mg, 0.39 mmol, 78%). 1 H NMR (600MHz, CDCl3) δ7.37–7.36(m,2H),7.35(t,J=7.8,2H),7.32–7.29(m,1H),4.62–4.50(t,J=7.2,1H),3.00 (dd,J=13.2,8.4Hz,1H),2.94(dd,J=13.2,7.2Hz,1H),2.87–2.81(m,2H),2.78–2.72(m,2H),2.46–2.38(m,4H). 13 C NMR (150MHz, CDCl3) δ208.5, 139.1, 130.7 (q, J = 304.5), 128.8, 128.2, 127.8, 62.1, 53.0, 48.8, 41.1. 19 FNMR (565MHz,CDCl3)δ-39.31(s). Figure 34-36 ).

[0118]

[0119] 3k-1 (106 mg, 0.35 mmol, 1.0 equiv) and aniline (64 μL, 0.70 mmol, 2.0 equiv) were dissolved in 3.5 mL of anhydrous methanol. After stirring at room temperature overnight, NaBH4 (26.5 mg, 0.70 mmol, 2.0 equiv) was added and stirring was continued for two hours. Water (2 mL) was added to quench the reaction, and it was extracted with DCM (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain a crude product, which was further separated by column chromatography to obtain a yellow oily liquid 3k-2 (97.2 mg, 0.26 mmol, 73%). 1HNMR(600MHz, CDCl3)δ7.37–7.31(m,4H),7.31–7.26(m,1H),7.19–7.12(m,2H),6.67(t ,J=7.2Hz,1H),6.57(d,J=8.4Hz,2H),4.62–4.47(m,1H),3.48(br,1H),3.29–3.23(m,1H ),2.91(d,J=11.4Hz,1H),2.86(dd,J=12.6,9.6Hz,1H),2.78(dd,J=12.6,6.0Hz,2H),2. 27(t,J=10.8Hz,1H),2.16(t,J=10.8Hz,1H),2.00(d,J=12.0Hz,2H),1.47–1.38(m,2H). 13 CNMR (150MHz, CDCl3) δ 139.6, 130.8 (q, J = 306.0), 129.4, 128.7, 128.1, 127.9, 117.3, 113.3, 63.3, 53.1, 51.8, 49.8, 48.7, 32.4, 32.3. 19 F NMR (565MHz,CDCl3)δ-39.12–-39.25(m). Figure 37-39 ).

[0120]

[0121] At 0°C, triethylamine (83 μL, 0.60 mmol, 3.0 equiv) was added to a DCM solution of 3k-2 (76.1 mg, 0.20 mmol, 1.0 equiv), followed by slow addition of propionyl chloride (35 μL, 0.40 mmol, 2.0 equiv), and stirring was continued for 2 hours. The reaction was quenched with saturated ammonium chloride solution (3 mL), extracted with DCM (8 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, and dried under reduced pressure. The residue was separated by column chromatography to obtain thiotrifluoromethyl-modified fentanyl as a yellow oily liquid 3k-3 (80.3 mg, 0.18 mmol, 92%). 1H NMR (600MHz, CDCl3) δ7.45–7.37(m,3H),7.33–7.28(m,4H),7.28–7.26(m,1H),7.07(d,J= 6.0Hz,2H),4.60(tt,J=12.0,3.6Hz,1H),4.47(dd,J=9.0,6.0Hz,1H),2.97–2.95(m,1H),2 .78(dd,J=13.2,9.6Hz,2H),2.70(dd,J=13.2,6.0Hz,1H),2.28–2.21(m,1H),2.14–2.10( m,1H),1.90(q,J=7.2Hz,2H),1.77–1.69(m,2H),1.38–1.32(m,2H),1.00(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ173.6,139.5,138.9,130.7(q,J=306.0),130.3,129.4,1 28.6,128.4,128.0,127.8,63.1,54.2,52.2,52.0,48.5,30.5,30.3,28.5,9.6. 19 F NMR (565MHz, CDCl3) δ-39.31 (s). Figure 40-42 ).

[0122] The copper-catalyzed difunctionalization reaction of olefins was used as the key step to synthesize thiotrifluoromethyl-modified fentanyl. ) showed obvious advantages in inducing apoptosis of HL60 cells, and its half inhibitory concentration (IC50) was significantly lower than that of ordinary fentanyl, which indicated that the thiotrifluoromethyl modification enhanced the inhibitory effect of the compound on HL60 cells.

[0123] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization of olefins, characterized in that: The steps include: providing an olefin compound, an amination reagent, and Cu + The catalyst, the sulfur trifluoromethyl compound and the bipyridine compound are mixed under acidic conditions, heated for reaction, and then post-treated to obtain a β-sulfur trifluoromethyl alkylamine compound.

2. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The olefin compound is selected from any one of aryl olefins, alkyl olefins or olefin derivatives.

3. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 2, characterized in that: The aromatic olefin is selected from any one of styrene, styrene containing a substituent, naphthylene vinyl, and naphthylene vinyl containing a substituent; wherein the substituent is selected from at least one of C1-C3 alkyl, phenyl, methoxy, methylthio, halogen, azido, and alkyne; The alkyl olefin is selected from any one of C1-C15 alkyl olefin and C1-C15 alkyl olefin containing a substituted functional group; wherein the substituted functional group is selected from any one of a phenyl group, a halogen group, an azide group, an ester group, an amino group, and an ether group; The olefin derivative is selected from any one of diketone galactose, estrone and lithocholic acid.

4. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The amination reagent is selected from any one of morpholinobenzoate, piperidinebenzoate, piperazinebenzoate, C1-C5 dialkylaminebenzoate, tert-butylaminebenzoate, adamantaneaminebenzoate, maprotilinebenzoate, and fluoxetinebenzoate.

5. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The Cu + The catalyst is selected from any one of CuSCN, CuI and CuCN.

6. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The bipyridine compound is selected from any one of 6,6'-dimethyl-2,2'-bipyridine and 2,9-dimethyl-1,10-phenanthroline.

7. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The step of mixing under acidic conditions also includes: adding an additive, a proton source and a solvent and mixing them together; wherein the additive is selected from any one of potassium bromide, cesium bromide and cesium iodide; the proton source is selected from trifluoroacetic acid; and the solvent is selected from any one of 1,2-dichloroethane and chloroform.

8. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The olefin compound, the amination reagent, the Cu + The molar ratio of the catalyst, the sulfur trifluoromethyl compound and the bipyridine compound is 1-1.2: 2-2.2: 0.1-0.2: 2-2.2: 0.15-0.

18.

9. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The temperature of the heating reaction is 80-90° C. and the time is 2-3 hours.

10. The method for synthesizing β-thiotrifluoromethylalkylamine by difunctionalization reaction of olefins according to claim 1, characterized in that: The post-treatment step also includes: providing an alkaline solution to quench the reaction, extracting with an organic solvent to obtain an organic phase; and then washing, drying, concentrating, separating and purifying in sequence to obtain the β-thiotrifluoromethylalkylamine compound.

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