CN112430202B - Alpha-chloro-alpha-fluoroalkyl thioether derivative and its synthesis method and use - Google Patents

Alpha-chloro-alpha-fluoroalkyl thioether derivative and its synthesis method and use Download PDF

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CN112430202B
CN112430202B CN202011322615.8A CN202011322615A CN112430202B CN 112430202 B CN112430202 B CN 112430202B CN 202011322615 A CN202011322615 A CN 202011322615A CN 112430202 B CN112430202 B CN 112430202B
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李玖零
郑新华
李彬
夏西超
王福安
陈秋
李钦
贾欣宇
陈娟
王敏
郭佳康
杨玉洁
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Pingdingshan University
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Abstract

The invention relates to an alpha-chloro-alpha-fluoroalkyl thioether derivative and a synthesis method and application thereof. An α -chloro- α -fluoroalkyl thioether derivative having the structural formula:
Figure 676312DEST_PATH_IMAGE002
(ii) a Wherein R is 1 Is phenyl, C 1 ‑C 10 Alkyl-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, naphthyl, furyl, thienyl, benzyl or C 1 ‑C 10 An alkyl group; x is sulfur or selenium; r 2 Is polyfluoro-substituted alkyl, phosphate group, C 1 ‑C 10 Alkyl-substituted phosphate group, ester group, C 1 ‑C 10 An alkyl-substituted ester group, a benzyl ester group, or a phenylcarbonyl group.The synthesis method of the alpha-chloro-alpha-fluoroalkyl thioether derivative takes a diazo compound, a diether compound and dichloroiodobenzene as raw materials and takes an organic solvent as a solvent, and the alpha-chloro-alpha-fluoroalkyl thioether derivative is obtained through one-step reaction. The method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, no need of metal catalysts, good substrate universality and the like. The obtained fluorine-containing organic compound has wide application in the fields of pesticide and medicinal chemistry.

Description

Alpha-chloro-alpha-fluoroalkyl thioether derivative and its synthesis method and use
Technical Field
The invention belongs to the field of synthetic medicine and chemical industry, and mainly relates to an alpha-chloro-alpha-fluoroalkyl thioether derivative, a synthetic method and application thereof.
Background
Fluorine-containing organic compounds are widely used in the field of pesticide chemistry and pharmaceutical chemistry, and in addition, sulfur-containing organic compounds have good pharmaceutical activities such as antibiosis and anticancer in vivo and are widely used in drug design.
Alpha-fluoroalkyl substituted drug molecules have attracted much attention because of their excellent biological activity, for example, anti-AIDS drug DPC083 developed by Shi Guibao, USA, is an organic small molecule containing alpha-fluoroalkyl substitution, and further contains an alpha-fluoroalkyl substitution structure as well as anti-cancer active small molecule Triazolopyrimidine developed by Hui's corporation. Therefore, the alpha-chloro-alpha-fluoroalkyl thioether derivative has great application potential in medicine synthesis as an important synthesis intermediate.
And the compound with sulfur-containing and fluoroalkyl structures can be constructed to provide or develop more lead compounds with potential pharmaceutical activity. Because the sulfur fluorine products contain more functional groups and are difficult to synthesize, no report exists at present about a synthesis method of the compounds with both sulfur-containing and fluoroalkyl structures.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method for synthesizing a compound with sulfur and fluoroalkyl simultaneously in one step, and the method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, no need of metal catalysts, good substrate universality and the like. The invention fills the blank of the synthetic method of the compound.
The technical scheme adopted by the invention is as follows:
the invention provides an alpha-chloro-alpha-fluoroalkyl thioether derivative, the structure of which is shown as the following formula (1):
Figure SMS_1
wherein R is 1 Is phenyl, C 1 -C 10 Alkyl-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, naphthyl, furyl, thienyl, benzyl, C 1 -C 10 An alkyl group; x is sulfur or selenium; r is 2 Is polyfluoro-substituted alkyl, phosphate group, C 1 -C 10 Alkyl-substituted phosphate group, ester group, C 1 -C 10 Alkyl-substituted ester groups, benzyl ester groups, phenylcarbonyl groups.
Preferably, said R is 1 Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, p-hydroxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenylAny one group of methoxyphenyl, o-fluorophenyl, 2-naphthyl, 2-methyl-3-furyl, 2-thienyl, cyclohexyl, benzyl and methyl propionate;
R 2 is any one of p-toluenesulfonyldifluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, phenylcarbonyl, ethyl ester group, benzyl ester group and ethyl phosphate ester group.
The invention also provides a synthesis method of the alpha-chloro-alpha-fluoroalkyl thioether derivative shown in the formula (1), which is characterized in that a diazo compound, a diether compound and dichloroiodobenzene are used as raw materials, no catalyst is needed, an organic solvent is used as a solvent, and the alpha-chloro-alpha-fluoroalkyl thioether derivative is obtained through one-step reaction;
the synthesis reaction process is shown as a reaction formula (I):
Figure SMS_2
the method specifically comprises the following steps: dissolving a diether compound and dichloroiodobenzene in an organic solvent to form a first mixed solution, dissolving a diazo compound in the organic solvent to form a second mixed solution, mixing the first mixed solution and the second mixed solution, and reacting to obtain the alpha-chloro-alpha-fluoroalkyl thioether derivative.
The molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = (1.5-2.0): (0.8-1.0): (0.8-1.0); the organic solvent is chloralkane, acetonitrile and toluene, wherein the chloralkane is any one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane and the like. Preferably, the organic solvent is acetonitrile, dichloromethane.
The invention also provides application of the alpha-chloro-alpha-fluoroalkyl thioether derivative in organic synthesis.
The invention has the beneficial effects that:
1. the alpha-chloro-alpha-fluoroalkyl thioether derivative and the synthesis method thereof can synthesize compounds containing sulfur and fluoroalkyl simultaneously in one step. The method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, no need of metal catalysts, good substrate universality and the like. Filling the blank of the synthetic method of the compound.
2. The invention relates to an alpha-chloro-alpha-fluoroalkyl thioether derivative and a synthesis method thereof. The obtained alpha-chloro-alpha-fluoroalkyl thioether derivative has the advantages of high efficiency, atom economy and the like. The synthesis method has higher yield.
3. The invention relates to an alpha-chloro-alpha-fluoroalkyl thioether derivative and a synthesis method thereof, which firstly develops sulfur-chlorine double functionalization of fluoroalkyl diazo: the alpha-chloro-alpha-fluoroalkyl thioether compound is efficiently constructed under mild reaction conditions without adding any organic catalyst or metal catalyst. The reaction condition is mild, the operation is simple and safe, and the synthesized alpha-chloro-alpha-fluoroalkyl thioether derivative is an important organic synthesis and medical intermediate.
4. The invention relates to an alpha-chloro-alpha-fluoroalkyl thioether derivative and a synthesis method thereof, and a series of trifluoromethyl compounds containing chlorine and fluoroalkyl substitution are synthesized by a more efficient and green method. The method is different from the existing synthesis means and reaction mechanism requiring heavy metal or noble metal catalysis through simple and easily obtained raw materials. It is worth noting that in the synthesis reaction, the feeding of the diether compound and the dichloroiodobenzene only needs half of the material of the diazo compound, thereby greatly improving the atom economy of the reaction.
Drawings
FIGS. 1A-1C show NMR of α -chloro- α -fluoroalkyl thioether derivatives of example 8 of the invention 1 H NMR (FIG. 1A), 13 C NMR (FIG. 1B), 19 F NMR spectrum (fig. 1C);
FIGS. 2A-2C show NMR of α -chloro- α -fluoroalkyl thioether derivatives according to example 9 of the present invention 1 H NMR (FIG. 2A), 13 C NMR (FIG. 2B), 19 F NMR spectrum (fig. 2C);
FIGS. 3A-3C show NMR of α -chloro- α -fluoroalkyl sulfide derivatives according to example 10 of the present invention 1 H NMR (FIG. 3A), 13 C NMR (FIG. 3B), 19 F NMR spectrum (fig. 3C);
FIGS. 4A to 4C show the NMR of α -chloro- α -fluoroalkyl thioether derivatives according to example 11 of the present invention 1 H NMR (FIG. 4A), 13 C NMR (FIG. 4B), 19 F NMR spectrum (fig. 4C);
FIGS. 5A to 5C show NMR of α -chloro- α -fluoroalkyl sulfide derivatives according to example 12 of the present invention 1 H NMR (FIG. 5A), 13 C NMR (FIG. 5B), 19 F NMR spectrum (fig. 5C);
FIGS. 6A-6B show NMR of α -chloro- α -fluoroalkyl thioether derivatives according to example 13 of the present invention 1 H NMR (FIG. 6A), 13 C NMR spectrum (fig. 6B);
FIGS. 7A-7B show NMR of α -chloro- α -fluoroalkyl thioether derivatives according to example 14 of the present invention 1 H NMR (FIG. 7A), 13 C NMR spectrum (FIG. 7B).
Detailed Description
The technical solution of the present invention is further described in detail below by using specific embodiments and with reference to the accompanying drawings. The present invention is not limited to the following embodiments, and variations and advantages that can be conceived by one skilled in the art are included in the present invention without departing from the spirit and scope of the inventive concept.
Example 1
The structure of the alpha-chloro-alpha-fluoroalkyl thioether derivative is shown as the formula (1):
Figure SMS_3
wherein R is 1 Is phenyl, C 1 -C 10 Alkyl-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, naphthyl, furyl, thienyl, benzyl, C 1 -C 10 An alkyl group; x is sulfur or selenium; r 2 Is polyfluoro-substituted alkyl, phosphate group, C 1 -C 10 Alkyl-substituted phosphate group, ester group, C 1 -C 10 An alkyl-substituted ester group, a benzyl ester group, or a phenylcarbonyl group.
Preferably, R 1 Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, p-hydroxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-fluorophenyl, 2-naphthyl, 2-methyl-3-furyl, 2-thienyl, cyclohexyl, benzyl, methyl propionate; r is 2 Is p-toluenesulfonyldifluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, phenylcarbonyl, an ethyl ester group, a benzyl ester group or an ethyl phosphate ester group.
Example 2
The embodiment is a synthesis method of an alpha-chloro-alpha-fluoroalkyl thioether derivative, which comprises the steps of taking a diazo compound, a diether compound and dichloroiodobenzene as raw materials, taking an organic solvent as a solvent, and carrying out one-step reaction to obtain the alpha-chloro-alpha-fluoroalkyl thioether derivative shown in a formula (1); the reaction process is shown as a reaction formula (I):
Figure SMS_4
dissolving the diether compound and dichloroiodobenzene in the organic solvent to form a first mixed solution, dissolving the diazo compound in the organic solvent to form a second mixed solution, mixing the first mixed solution and the second mixed solution, and reacting to obtain the alpha-chloro-alpha-fluoroalkyl thioether derivative shown in the formula (4).
The molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = (1.5-2.0): (0.8-1.0): (0.8-1.0).
Example 3
The synthesis method of α -chloro- α -fluoroalkyl thioether derivative of the present example is different from example 2 in that the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = 1.5.
Example 4
The synthesis method of α -chloro- α -fluoroalkyl thioether derivative of the present example is different from example 2 in that the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = 1.5.
Example 5
The synthesis method of α -chloro- α -fluoroalkyl thioether derivative in this example is different from example 2 in that the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = 2.0.
Example 6
The synthesis method of α -chloro- α -fluoroalkyl thioether derivative in this example is different from example 2 in that the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = 1.6.
Example 7
The synthesis method of α -chloro- α -fluoroalkyl thioether derivative in this example is different from example 2 in that the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = 1.8.
The invention relates to a synthesis method of alpha-chloro-alpha-fluoroalkyl thioether derivatives, wherein an organic solvent comprises chloralkane, acetonitrile and toluene; wherein, the halogenated alkane is selected from any one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane. The reaction temperature is 0-40 ℃. Preferably, it is 25 ℃. The reaction time is 0.5h-3h; preferably, it is 1.0h.
The preparation method also comprises the steps of separation and purification after the alpha-chloro-alpha-fluoroalkyl thioether derivative is prepared. The separation and purification is to perform column chromatography by using a mixed solution of ethyl acetate and petroleum ether with the volume ratio of 1 (30-10).
Example 8
Figure SMS_5
Dichloroiodobenzene (0.11 mmol), diphenyldisulfide (0.11 mmol) were dissolved in acetonitrile (2.0 mL), and then difluoroalkyldiazo (0.2 mmol) diluted in acetonitrile (1 mL) was slowly added dropwise to the reaction system at room temperatureAt the temperature of 25 ℃, after the slow dropwise addition, stirring for 1.0h, and removing the solvent under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-1). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1 = 30 to 1) to obtain a pure product. The yield was 91%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 1A-1C, 1 H NMR(400MHz,CDCl 3 ):δ7.88(d,J＝8.3Hz, 2H),7.71-7.64(m,2H),7.46-7.37(m,5H),5.78(dd,J＝14.1,10.6Hz,1H),2.49(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ147.3,134.9,130.8,130.2,130.1,130.0,129.7,129.5,119.5(t,J CF ＝ 292.0Hz),64.9(t,J CF ＝23.0Hz),21.9ppm； 19 F NMR(376MHz,CDCl 3 ):δ-97.92(dd,J＝230.0, 10.6Hz),-102.80(dd,J＝230.0,14.1Hz)ppm.
example 9
Figure SMS_6
Dichloroiodobenzene (0.11 mmol) and bis (4-hydroxyphenyl) disulfide (0.11 mmol) are dissolved in acetonitrile (2.0 mL), then difluoroalkyldiazo (0.2 mmol) diluted in acetonitrile (1 mL) is slowly dripped into a reaction system, the reaction system is stirred for 1.0h at room temperature (25 ℃) after dripping is finished, and the solvent is removed under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-2). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1. The yield was 95%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 2A-2C, 1 H NMR(500MHz,CDCl 3 ):δ7.87(d,J＝7.9Hz, 2H),7.54(d,J＝8.1Hz,2H),7.42(d,J＝7.9Hz,2H),6.85(d,J＝8.1Hz,2H),5.89(s,1H),5.67-5.59(m,1H),2.48(s,3H)ppm； 13 C NMR(125MHz,CDCl 3 ):δ157.88,147.36,137.77, 130.76,130.15,130.11,119.6(t,J CF ＝235.0Hz),119.6 116.5,65.0(t,J CF ＝23.0Hz),21.9ppm； 19 F NMR(470MHz,CDCl 3 ):δ-97.91(d,J＝229.2Hz),-102.45(d,J＝229.2Hz)ppm.
example 10
Figure SMS_7
Dichloroiodobenzene (0.11 mmol) and dibenzyl disulfide (0.11 mmol) are dissolved in acetonitrile (2.0 mL), then difluoroalkyl diazo (0.2 mmol) diluted in acetonitrile (1 mL) is slowly dripped into a reaction system, the reaction system is stirred for 1.0h at room temperature (25 ℃) after the dripping is finished, and the solvent is removed under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-3). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1. The yield was 86%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 3A-3C, 1 H NMR(500MHz,CDCl3):δ7.84(d,J＝8.0Hz,2H), 7.42-7.30(m,7H),5.47(dd,J＝15.7,9.3Hz,1H),4.07(s,2H),2.48(s,3H)ppm； 13 C NMR(125 MHz,CDCl 3 ):δ147.3,134.8,130.8,130.2,130.1,129.4,128.9,128.0,119.7(t,J CF ＝234.0Hz), 61.0(t,J CF ＝20.0Hz),35.7,21.9ppm； 19 F NMR(470MHz,CDCl 3 ):δ-95.94(d,J＝230.4Hz), -103.88(d,J＝230.4Hz)ppm.
example 11
Figure SMS_8
Dichloroiodobenzene (0.11 mmol) and bis-2-thienyl disulfide (0.11 mmol) are dissolved in acetonitrile (2.0 mL), then difluoroalkyldiazo (0.2 mmol) diluted in acetonitrile (1 mL) is slowly dripped into a reaction system, the reaction system is at room temperature (25 ℃), after the dripping is finished, stirring is carried out for 1.0h, and the solvent is removed under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-4). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1 = 30 to 1) to obtain a pure product. The yield was 90%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 31 P NMR spectra are shown in FIGS. 4A to 4C, 1 H NMR(500MHz,CDCl 3 ):δ7.85(d,J＝7.9Hz, 2H),7.67(d,J＝1.3Hz,1H),7.40(d,J＝7.9Hz,2H),7.37-7.32(m,1H),7.25(s,1H),5.58(dd,J＝15.9,10.1Hz,1H),2.48(s,3H)ppm； 13 C NMR(125MHz,CDCl 3 ):δ147.23,133.94,133.81, 130.75,130.27,130.10,126.82,119.9(t,J CF ＝236.0Hz),118.70,52.0(t,J CF ＝24.0Hz),21.9ppm； 19 F NMR(470MHz,CDCl 3 ):δ-96.26(d,J＝229.3Hz),-101.81(d,J＝229.2Hz)ppm。
example 12
Figure SMS_9
Figure SMS_10
Dichloroiodobenzene (0.11 mmol) and diphenyl diselenide (0.11 mmol) are dissolved in acetonitrile (2.0 mL), then difluoroalkyl diazo (0.2 mmol) diluted in acetonitrile (1 mL) is slowly dripped into a reaction system, the reaction system is stirred for 1.0h at room temperature (25 ℃) after the dripping is finished, and the solvent is removed under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-5). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1 = 30 to 1) to obtain a pure product. The yield was 90%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 5A to 5C, 1 H NMR(500MHz,CDCl 3 ):δ7.86(d,J＝7.8Hz,2H),7.74 (d,J＝7.6Hz,2H),7.42(dd,J＝16.7,8.0Hz,3H),7.36(t,J＝7.3Hz,2H),5.71(dd,J＝15.8,10.4Hz,1H),2.48(s,3H)ppm； 13 C NMR(125MHz,CDCl 3 ):δ147.2,136.6,130.8,130.3,130.1, 129.9,129.5,126.1,120.0(t,J CF ＝236.0Hz),52.6(t,J CF ＝24.0Hz),21.9ppm； 19 F NMR(470 MHz,CDCl 3 ):δ-96.05(d,J＝229.1Hz),-101.45(d,J＝229.2Hz)ppm.
example 13
Figure SMS_11
Dichloroiodobenzene (0.11 mmol), bis 4-methoxyphenyldisulfide (0.11 mmol) were dissolved in acetonitrile (2.0 mL), and then phenylcarbonyldiazo (0.2 mmol) diluted in acetonitrile (1 mL) was slowly added dropwise to the reaction systemAnd after the dropwise addition of the reaction system at room temperature (25 ℃), stirring for 1.0h, and removing the solvent under reduced pressure to obtain a crude product, wherein the structure of the crude product is shown as a formula (4-6). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1. The yield was 90%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 6A-6B, 1 H NMR(500MHz,CDCl 3 ):δ8.02(d,J＝7.8 Hz,2H),7.62(t,J＝7.3Hz,1H),7.50(t,J＝7.5Hz,2H),7.46(d,J＝8.0Hz,2H),6.89(d,J＝8.0Hz,2H),6.33(s,1H),3.82(s,3H)；13C NMR(125MHz,CDCl 3 ):δ188.1,161.3,137.0,134.0, 133.3,129.3,128.9,120.4,114.9,69.3,55.4ppm.
example 14
Figure SMS_12
Dichloroiodobenzene (0.11 mmol) and bis 4-methoxyphenyl disulfide (0.11 mmol) are dissolved in acetonitrile (2.0 mL), then ethyl ester based diazo (0.2 mmol) diluted in acetonitrile (1 mL) is slowly dripped into a reaction system, the reaction system is at room temperature (25 ℃), after the dripping is finished, stirring is carried out for 1.0h, and the solvent is removed under reduced pressure, thus obtaining a crude product, wherein the structure of the crude product is shown as formula (4-7). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether =1. The yield was 82%. Nuclear magnetic resonance 1 H NMR、 13 C NMR、 19 F NMR spectra are shown in FIGS. 7A-7B, 1 H NMR(500MHz,CDCl 3 ):δ7.52(d,J＝7.7 Hz,2H),6.90(d,J＝7.7Hz,2H),5.41(s,1H),4.22(q,J＝7.1Hz,2H),3.81(s,3H),1.28(t,J＝7.1 Hz,3H)ppm； 13 C NMR(125MHz,CDCl 3 ):δ166.0,161.3,137.1,120.4,114.8,65.3,62.8,55.4, 14.0ppm.
example 15
Figure SMS_13
The experimental method of this example is basically the same as example 12, the selenide used in this example is di-2-naphthyl diselenide, and the obtained product is shown in structural formula (4-8). The yield was 85%.
Example 16
Figure SMS_14
This example, which was conducted in substantially the same manner as example 11, used a thioether that was bis-3-bromophenyl disulfide and yielded a product of the formula (4-9). The yield was 81%.
Example 17
Figure SMS_15
The experimental procedure of this example is essentially the same as example 11, the thioether employed in this example was di-p-tolyl disulfide, and the resulting product is represented by structural formula (4-10). The yield was 88%.
Example 18
Figure SMS_16
This example, which was conducted in substantially the same manner as example 11, uses a thioether which is di-p-chlorophenyl disulfide, and gives a product represented by the formula (4-11). The yield was 78%.
Example 19
Figure SMS_17
The experimental procedure of this example was substantially the same as in example 11, the thioether employed in this example was di-p-methoxyphenyl disulfide, and the resulting product was represented by the formula (4-12). The yield was 93%.
Example 20
Figure SMS_18
This example was conducted in substantially the same manner as in example 11 except that the sulfide used in this example was bis-2-fluorophenyl disulfide, and the obtained product was represented by the formula (4-13). The yield was 81%.
Example 21
Figure SMS_19
The experimental procedure of this example was essentially the same as in example 8, the thioether employed in this example was bis-2-naphthyl disulfide, and the resulting product was represented by the formula (4-14). The yield was 80%.
Example 22
Figure SMS_20
This example, which was conducted in substantially the same manner as example 11, uses bis 3, 5-dimethylphenyldisulfide as the sulfide, and gives a product represented by the formula (4-15). The yield was 88%.
Example 23
Figure SMS_21
The experimental procedure of this example was essentially the same as in example 8, the thioether employed in this example was bis-3, 5-dichlorophenyl disulfide, and the resulting product was represented by the formula (4-16). The yield was 75%.
Example 24
Figure SMS_22
The experimental procedure of this example was substantially the same as in example 9, except that the thioether employed in this example was bis-2-methoxyphenyl disulfide, and the resulting product was represented by the formula (4-17). The yield was 82%.
Example 25
Figure SMS_23
In this example, the same experimental procedure as in example 8 was followed, and the thioether used in this example was bis-2-methyl-3-furanyldisulfide, and the resulting product was represented by the formula (4-18). The yield was 88%.
Example 26
Figure SMS_24
The experimental procedure of this example is the same as example 10, the thioether used in this example was dicyclohexyldisulfide, and the product obtained is represented by the formula (4-19). The yield was 78%.
Example 27:
Figure SMS_25
the experimental procedure of this example was the same as in example 9, the thioether employed in this example was bis 3-methoxyphenyl disulfide, and the resulting product was represented by the formula (4-20). The yield was 86%.
Example 28
Figure SMS_26
The experimental procedure of this example was the same as example 8, the thioether employed in this example was dimethyl propionyldisulfide, and the resulting product was represented by structural formula (4-21). The yield was 80%.
Example 29
Figure SMS_27
The experimental method of this example is the same as example 12, the selenide used in this example is bis 4-bromophenyl diselenide, and the obtained product is represented by structural formula (4-22). The yield was 78%.
Example 30
Figure SMS_28
The experimental method of this example is the same as example 12, the selenide used in this example is di-2-thienyl diselenide, and the obtained product is shown in structural formula (4-23). The yield was 82%.
Example 31
Figure SMS_29
The experimental method of this example is the same as example 12, the selenide used in this example is bis 4-methylphenyl diselenide, and the obtained product is shown as structural formula (4-24). The yield was 81%.
Example 32
Figure SMS_30
The experimental method of this example is the same as example 12, the selenide used in this example is bis-4-pyridyl diselenide, and the obtained product is represented by structural formula (4-25). The yield was 60%.
Example 33
Figure SMS_31
The experimental procedure of this example was the same as example 13, the diazonium salt employed in this example was trifluoromethyl diazomethane, and the resulting product was represented by structural formula (4-26). The yield was 70%.
Example 34
Figure SMS_32
The experimental procedure of this example was the same as in example 13, and the diazonium salt employed in this example was pentafluoroethyl diazomethane, and the resulting product was represented by the structural formula (4-27). The yield was 72%.
Example 35
Figure SMS_33
The experimental procedure of this example was the same as example 13, the diazonium salt employed in this example was heptafluoropropyldiazomethane, and the product obtained was represented by the structural formula (4-28). The yield was 66%.
Example 36
Figure SMS_34
The experimental procedure of this example is the same as example 14, the diazonium species used in this example is a benzylesterdiazonium, and the product obtained is represented by the formula (4-29). The yield was 90%.
Example 37
Figure SMS_35
The experimental procedure of this example was the same as example 14, the diazonium used in this example was ethylphosphate based diazonium, and the resulting product was represented by structural formula (4-30). The yield was 78%.
The chemical synthesis method of the alpha-chloro-alpha-fluoroalkyl thioether derivative containing sulfur and fluorine, which is provided by the invention, takes a diazo compound, a diether compound and dichloroiodobenzene as raw materials, does not need any organic or metal catalyst, takes an organic solvent as a solvent, and obtains a product through one-step multi-component reaction. Different from the existing catalytic synthesis means and reaction mechanism which need heavy metal or noble metal, the invention synthesizes a series of trifluoromethyl compounds containing chlorine and fluoroalkyl substitution by a more efficient and green method.
The invention develops the sulfur-chlorine double functionalization of fluoroalkyl diazo for the first time: the alpha-chloro-alpha-fluoroalkyl thioether compound is efficiently constructed under mild reaction conditions by using simple and easily obtained raw materials without adding any catalyst or additive.
It is worth noting that in the synthesis reaction, the feeding of the diether compound and the dichloroiodobenzene only needs half of the material of the diazo compound, thereby greatly improving the atom economy of the reaction.
Alpha-fluoroalkyl substituted drug molecules have attracted much attention because of their excellent biological activity, such as the anticancer drug DPC083 and Triazolopyrimidine, which contain such a group. In addition, sulfur-containing compounds are widely present in nature or in pharmaceutically active molecules, and are also widely used in organic synthesis as important synthetic intermediates. Therefore, the alpha-chloro-alpha-fluoroalkyl thioether derivative has great application potential in medicine synthesis as an important medicine synthesis intermediate.

Claims (7)

1. A synthetic method of alpha-chloro-alpha-thioether derivatives is characterized by comprising the following steps: the method comprises the following steps of (1) carrying out one-step reaction by taking a diazo compound, a diether compound and dichloroiodobenzene as raw materials and an organic solvent as a solvent to obtain an alpha-chloro-alpha-thioether derivative shown in a formula (1);
Figure 907539DEST_PATH_IMAGE001
（1）
the reaction process is shown as the reaction formula (I):
Figure 156118DEST_PATH_IMAGE002
（I）；
in the formula, R 1 Is phenyl, C 1 -C 10 Alkyl-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, naphthyl, furyl, thienyl, benzyl or C 1 -C 10 An alkyl group; x is sulfur; r is 2 Is polyfluoro-substituted alkyl, C 1 -C 10 Alkyl-substituted phosphate group, C 1 -C 10 An alkyl-substituted ester group, a benzyl ester group, or a phenylcarbonyl group.
2. The method for synthesizing α -chloro- α -thioether derivative according to claim 1, wherein: dissolving the diether compound and dichloroiodobenzene in an organic solvent to form a first mixed solution, dissolving the diazo compound in the organic solvent to form a second mixed solution, mixing the first mixed solution and the second mixed solution, and reacting to obtain the alpha-chloro-alpha-thioether derivative shown in the formula (1).
3. The method for the synthesis of α -chloro- α -thioether derivatives according to claim 1 or 2, characterized in that: the organic solvent is chloralkane, acetonitrile and toluene; wherein the chloralkane is selected from any one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane.
4. The method for the synthesis of α -chloro- α -thioether derivatives according to claim 3, characterized in that: the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene = (1.5-2.0): (0.8-1.0): (0.8-1.0).
5. The method for the synthesis of α -chloro- α -thioether derivatives according to claim 3, characterized in that: the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene =1.5:0.8:0.8.
6. The method for the synthesis of α -chloro- α -thioether derivatives according to claim 3, wherein: the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene =1.5:1:1.
7. The method for the synthesis of α -chloro- α -thioether derivatives according to claim 3, wherein: the molar ratio of the raw materials is diazo compound: diether compounds: dichloroiodobenzene =2.0:0.8:0.8.
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