CN110790689A - A kind of synthetic method of 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compounds - Google Patents

Abstract

The invention discloses a synthesis method of a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound, which is synthesized by the steps of reduction, oxidation, alcohol amination, formylation, dehydration reaction and the like of a 2, 2-difluoro-2- (phenylthio) ethyl acetate compound. The method avoids using a reducing agent lithium aluminum hydride with high risk and poor selectivity to reduce the difluoromethyl amide intermediate with low reaction activity, and uses a mild reducing agent sodium borohydride to reduce the 2, 2-difluoro-2- (phenylthio) ethyl acetate compound with high activity, so that the reduction yield and selectivity are greatly improved, and the method is simple to operate, stable in product property and beneficial to large-scale production.

Description

A kind of synthetic method of 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compounds

technical field

The invention relates to a method for synthesizing 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compounds, in particular to a method for synthesizing 2,2-difluoro-2-(phenylthio) ethyl acetate A method for efficiently synthesizing difluoroisonitrile aryl sulfone compounds through reduction, oxidation, alcohol amination, formylation and dehydration reaction as raw materials of such compounds belongs to the technical field of synthesis of pharmaceutical intermediate isonitrile compounds.

Background technique

As a class of important synthetic intermediates with high activity, isonitrile compounds have played an irreplaceable role in the field of organic synthesis. Represented by Ugi reaction, isonitrile compounds are often used to synthesize some amides and polypeptide compounds (Ugi.Angew.Chem.Int.Ed.2000,39,3168.). In 1985, Lieke discovered the first isonitrile for the first time. Isonitrile compounds are widely used in the synthesis of heterocyclic derivatives and are important intermediates in the synthesis of amine derivatives and nitrogen-containing compounds. Nitrogen-containing compounds are an important class of compounds that are widely found in natural products and medicines and have a wide range of biological activities. Among the numerous methods that have been developed, the direct [3+2] cycloaddition of isocyanates has emerged as one of the most efficient and promising routes for pyrroles, oxazoles and imidazoles (Meijere, A.D.; Angew.Chem.Int.Ed. 2010, 49, 9094-9124; Zhu, J.P.; Chem. Soc. Rev., 2017, 46, 1295-1357.). Some heterocyclic derivatives are shown below:

The introduction of fluorine atoms can greatly change the chemical, physical and related biological properties of molecules, and fluorination has become a commonly used modification method in modern medicinal chemistry (Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320-330.). At present, about 20%-25% of drug molecular structures contain fluorine, and common fluorine-containing functional groups include fluorine atom F, trifluoromethyl CF ₃ , trifluoromethylthio SCF ₃ , trifluoromethoxy OCF ₃ , etc. structure. In general, the introduction of fluorine atoms changes the lipophilicity, hydrogen bonding, metabolic stability, bioavailability, etc. of the compound. In recent years, the frequency of the difluoromethyl CF ₂ H structure in active compounds has increased significantly, which is not only a hydrogen-bond donor functional group but also can modulate the lipophilicity of the molecule. The following are active compounds containing difluoro(methylene) groups:

In 2012, Cao Song et al. reported for the first time a novel synthesis method of difluoromethyl isocyanide building blocks, using Ugi reaction to synthesize pseudopeptide compounds with difluoromethyl groups (Cao, S.; Org. Biomol. Chem., 2010, 8, 2386–2391.). The method takes thiophenol as a raw material, and sequentially passes through the steps of nucleophilic substitution, aminolysis, reduction, amidation and dehydration to obtain the target product. The synthetic route is as follows:

When the difluoromethylene amide is reduced by lithium aluminum hydride in this route, since the fluorine atom is also easily reduced, the by-product diphenylthioethylamine is easily generated, and the target product 2,2-difluoro-phenylthio-ethylamine produces The reduction rate is only 45%, and excessive flammable and high-risk lithium aluminum hydride is used as the reducing agent, which has poor reduction selectivity and cumbersome post-processing, which restricts the large-scale production of difluoromethyl isocyanide.

SUMMARY OF THE INVENTION

In view of the defects in the method for synthesizing difluoromethyl isocyanide reported in the prior art, such as low reduction efficiency of difluoromethyl amide, high risk of lithium aluminum hydride, poor selectivity and cumbersome post-processing. The purpose of the technical solution of the present invention is to provide a 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound as a raw material, which is sequentially reduced, oxidized, alcohol amination, formylation, dehydration, etc. Steps to synthesize 1,1-difluoro-2-isonitrile-ethylphenylsulfone compounds. This method avoids the use of highly hazardous, low-selectivity lithium aluminum hydride for the reduction of low-activity difluoromethylamides and uses the mild reducing agent sodium borohydride for the reduction of high-activity 2,2-difluoro-2-(benzene). thio) ethyl acetate compounds, the reduction yield and selectivity are greatly improved, the operation is simple, the reaction yield is good, and the product properties are stable, which is conducive to realizing large-scale production.

In order to achieve the above technical purpose, the present invention provides a method for synthesizing 1,1-difluoro-2-isonitrile-ethylphenylsulfone compounds, which comprises the following steps:

1) 2,2-difluoro-2-(phenylthio) ethyl acetate compounds of formula ₁ are subjected to reduction reaction with NaBH to obtain an intermediate of formula 2;

2) carrying out oxidation reaction with intermediate of formula 2 and hydrogen peroxide to obtain intermediate of formula 3;

3) react the intermediate of formula 3 with trifluoromethanesulfonic anhydride and pyridine and triethylamine to obtain intermediate of formula 4;

4) the intermediate of formula 4 is subjected to formylation reaction with the formylation reagent to obtain the intermediate of formula 5;

5) The intermediate of formula 5 is subjected to dehydration reaction under the action of phosphorus oxychloride to obtain the 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound of formula 6;

Wherein, R ₁ is hydrogen, alkyl, halogen substituent, nitro, amino or hydroxyl.

In the 2,2-difluoro-2-(phenylthio) ethyl acetate compounds and various intermediate compounds of the present invention, the effect of the substituent on the benzene ring on the reaction is not obvious, and the substituent can be hydrogen, or Common substituents such as alkyl, halogen substituent, nitro, amino or hydroxyl. The alkyl group is generally a short-chain alkyl group, such as a C ₁ -C ₅ alkyl group, and the alkyl group can be a straight-chain alkyl group or a branched-chain alkyl group. Halogen substituents are fluoro, chloro or bromo.

In a preferred scheme, 2,2-difluoro-2-(arylthio) ethyl acetate compounds and sodium borohydride are stirred and reacted in an ethanol solvent at room temperature for 2-4 hours.

In a more preferred solution, the molar ratio of 2,2-difluoro-2-(arylthio) ethyl acetate compounds to sodium borohydride is: 1:4 to 1:1; more preferably, 1:3 to 1:2 .

In a preferred scheme, the intermediate of formula 2 and hydrogen peroxide are stirred and reacted in an acetic acid-water mixed solvent at a temperature of 100-120° C. for 3-5 hours.

In a more preferred solution, the mass percentage concentration of the hydrogen peroxide is 20-40%; the molar ratio of the intermediate of formula 2 to the hydrogen peroxide is 1:2.5-1:1; more preferably 1:2.5-1:1.5.

In a preferred scheme, the intermediate of formula 3, pyridine and trifluoromethanesulfonic anhydride are stirred and reacted at room temperature for 1 to 3 h in acetonitrile solvent, and then the triethylamine aqueous solution is added, and the reaction is continued to be stirred for 24 to 48 h; wherein, the intermediate of formula 3 The molar ratio of the compound, pyridine and trifluoromethanesulfonic anhydride is 1:(1~2):(1~2); more preferably, it is 1:(1~1.5):(1~2). The addition amount of triethylamine is excessive, which is more than 1 times the required theoretical molar amount.

In a more preferred scheme, the intermediate of formula 4 and the formylation reagent are stirred and reacted in an organic solvent at a temperature of 80-100° C. for 1-4 h. More preferably, the reaction is stirred at a temperature of 80 to 100° C. for 1 to 2 hours.

In a more preferred solution, the organic solvent is at least one of methanol, ethanol, propylene glycol, glycerol, tert-butanol, ethylene glycol and hexylene glycol. Most preferred is tert-butanol.

In a more preferred solution, the formylation reagent is at least one of sodium formate, sodium acetate, formic acid, and ethyl formate. Most preferred is sodium formate.

In a more preferred solution, the molar ratio of the intermediate of formula 4 to the formylation reagent is 1:4 to 1:1; more preferably, it is 1:3 to 1:4.

In a preferred scheme, the intermediate of formula 5 reacts with phosphorus oxychloride and triethylamine in a dichloromethane solvent at -20 to 20° C. under stirring for 1 to 4 hours. In a more preferred scheme, the intermediate of formula 5 reacts with phosphorus oxychloride and triethylamine in a dichloromethane solvent at -10 to 10° C. under stirring for 1 to 2 hours.

The molar ratio of the intermediate of formula 5, phosphorus oxychloride and triethylamine is 1:(1-2):(2-5); more preferably, it is 1:(1-1.5):(2-4).

The 2,2-difluoro-2-(phenylthio) ethyl acetate compounds of the present invention can be routinely synthesized according to known literature reports in the prior art, such as: thiophenol or thiophenol derivatives and sodium hydride After stirring for 1 h, it was dissolved in dimethyl sulfoxide with ethyl difluorobromoacetate, and the reaction was stirred at 40 °C for 15 h.

The method for synthesizing 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compounds of the present invention cleverly adopts "reduction-oxidation-alcohol amination-formylation and dehydration reaction" to replace the existing "nucleophilic" The "substitution-aminolysis-reduction-amidation and dehydration" synthetic route avoids the difluoromethylamide reduction step and avoids the use of a highly dangerous and poorly selective lithium aluminum hydride reducing reagent. However, the present invention utilizes sodium borohydride to reduce ethyl 2,2-difluoro-2-(phenylthio)acetate, which has high reactivity and high selectivity, greatly improves the reduction yield, and is simple to operate, thereby facilitating the Achieving large-scale production of 1,1-difluoro-2-isonitrile-ethylphenylsulfone compounds.

In the process of synthesizing 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compounds of the present invention, thiophenol or thiophenol derivatives are used as raw materials, such as thiophenol, p-toluene Thiophenol, p-methoxythiophenol, p-nitrothiophenol, p-aminothiophenol, p-bromothiophenol, o-bromothiophenol, 2-hydroxythiophenol, etc. The present invention uses thiophenol , P-methyl thiophenol is described in detail.

The specific synthesis process of the 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound of the present invention is as follows: according to the literature, the raw material 2,2 is obtained by nucleophilic substitution reaction of thiophenol and ethyl difluorobromoacetate - Difluoro-2-(phenylthio) ethyl acetate compound raw material. 2,2-Difluoro-2-(phenylthio) ethyl acetate compounds were selectively reduced to alcohols with sodium borohydride, then sulfhydryls were oxidized to sulfones with hydrogen peroxide, and then treated with trifluoromethanesulfonic anhydride, pyridine And amination under the action of triethylamine, then formylation with sodium formate, and finally dehydration reaction under the action of phosphorus oxychloride and triethylamine to obtain the target product, and the main reaction steps are as follows:

Relative to the prior art, the technical solution of the present invention brings the following technical advantages:

(1) The technical scheme of the present invention uses 2,2-difluoro-2-(phenylthio) ethyl acetate compounds as raw materials, and cleverly designs "reduction-oxidation-alcohol amination-formylation and dehydration reaction" to synthesize Route, directly reducing sodium borohydride with 2,2-difluoro-2-(phenylthio) ethyl acetate, avoiding the reduction step of difluoromethyl amide and avoiding the highly dangerous and poor selective reduction of lithium aluminum hydride The use of reagents improves the reduction yield and selectivity, and the yield of the reduction step can reach 90%, which is beneficial to the realization of large-scale preparation of 1,1-difluoro-2-isonitrile-ethylphenylsulfone.

(2) Technical scheme of the present invention 2,2-difluoro-2-(phenylthio) ethyl acetate compound synthesis has mild reaction conditions, simple operation and handling, and high yield (each step yield reaches 85%) %), the product separation is simple, the target product can be obtained in high yield, the product property is stable, and a large amount of difluoroisonitrile intermediates are provided for the synthesis of medicines.

Description of drawings

Figure 1 shows ¹ H NMR (400 MHz, CDCl ₃ ) of ethyl 2,2-difluoro-2-(phenylthio)acetate;

Figure 2 shows ¹⁹ F NMR (376 MHz, CDCl ₃ ) of ethyl 2,2-difluoro-2-(phenylthio)acetate;

Figure 3 is the ¹ H NMR (400 MHz, CDCl ₃ ) of the intermediate product prepared in Example 2;

Figure 4 is the ¹⁹ F NMR (376MHz, CDCl ₃ ) of the intermediate product prepared in Example 2;

Figure 5 is the ¹³ C NMR (100 MHz, CDCl ₃ ) of the intermediate product prepared in Example 2;

Figure 6 is the ¹ H NMR (400 MHz, CDCl ₃ ) of the intermediate product prepared in Example 3;

Figure 7 is the ¹⁹ F NMR (376MHz, CDCl ₃ ) of the intermediate product prepared in Example 3;

Figure 8 is the ¹ H NMR (400 MHz, D ₂ O) of the intermediate product prepared in Example 4;

Figure 9 is the ¹⁹ F NMR (376 MHz, D ₂ O) of the intermediate product prepared in Example 4;

Figure 10 is the ¹ H NMR (400 MHz, CDCl ₃ ) of the intermediate product prepared in Example 5;

Figure 11 is the ¹ H NMR (400MHz, MeOD) of the product prepared in Example 6;

Figure 12 is the ¹⁹ F{ ¹ H} NMR (376 MHz, MeOD) of the product prepared in Example 6;

Figure 13 is the ¹⁹ F NMR (376MHz, MeOD) of the product prepared in Example 6;

Figure 14 is the ¹³ C NMR (100MHz, MeOD) of the product prepared in Example 6;

Figure 15 is the HRMS of the product prepared in Example 6.

Detailed ways

The following examples are intended to further illustrate the content of the present invention, rather than limit the protection scope of the claims of the present invention.

Example 1

Thiophenol (5.5 mL, 1.0 equiv) was dissolved in dimethyl sulfoxide (50 mL), sodium hydride (2.4 g, 1.1 equiv) was slowly added in an ice bath, and the reaction was stirred at 40° C. for 1 h. Ethyl difluorobromoacetate (12.0 g, 1.1 equiv) was added to the reaction solution, and the reaction was stirred for 15 h. TLC showed that the raw materials were completely reacted. It was quenched with aqueous ammonium chloride solution and extracted with ether. The organic layer was washed successively with water and brine, dried over anhydrous MgSO ₄ , and concentrated under reduced pressure to obtain the crude product. The product isolated by column chromatography was 10.7 g with a yield of 86%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57-7.51 (m, 2H), 7.41-7.35 (m, 1H), 7.31 (dd, J=8.2, 6.5 Hz, 3H), 4.16 (q, J= 7.2 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-82.21.

Example 2

Ethyl 2,2-difluoro-2-(phenylthio)acetate (20 g, 1.0 equiv) was dissolved in dry ethanol (200 mL), sodium borohydride (6.5 g, 2.0 equiv) was added under ice bath conditions, and the room temperature The reaction was stirred at low temperature for 3h, and TLC showed that the starting material was completely reacted. Quenched with ammonium chloride aqueous solution and extracted with dichloromethane, washed the organic phase with saturated brine, and distilled under reduced pressure to obtain a crude product, which was separated by column chromatography (PE:EA=30:1) to obtain 14.7 g of the product with a yield of 90 %. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66-7.61 (m, 2H), 7.48-7.36 (m, 3H), 3.87 (t, J=11.8 Hz, 2H); ¹⁹ F NMR (376 MHz, CDCl _{3 )} ): δ-84.27; ¹³ CNMR (100 MHz, CDCl ₃ ) δ 136.5, 130.2, 129.4, 128.3 (t, J=280.0 Hz), 126.0 (t, J=2.8 Hz), 65.0 (t, J=29.9 Hz).

Example 3

2,2-Difluoro-2-(phenylthio)ethan-1-ol (10 g, 1.0 eqiv) was dissolved in a mixed solution of HOAc:H ₂ O (10:19 mL), followed by 30% H ₂ O ₂ (3.9 g, 2.2 equiv) was added to the reaction system, the reaction system was stirred at 120 °C for about 4 h under the protection of N ₂ , the reaction mixture was cooled to room temperature and extracted with EA, and the organic phase was washed with saturated brine and saturated Washed with NaHCO ₃ solution, the organic phase was dried with anhydrous sodium sulfate, and the crude product was obtained by distillation under reduced pressure. The product was separated by column chromatography (PE:EA=9:1) to obtain 9.9 g of the product with a yield of 85%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, 2H, J=7.8 Hz), 7.80 (t, 1H, J=7.5 Hz), 7.65 (t, J=7.9 Hz, 2H), 4.31 (t , J=12.8Hz, 2H), 2.74 (s, 1H). ¹⁹ F NMR (376MHz, CDCl ₃ )δ-111.20 (t, J=12.9Hz).

Example 4

Pyridine (2.0 g, 1.4 equiv) was added to a solution of 2,2-difluoro-2-(benzenesulfonyl)ethan-1-ol (4.0 g, 1.0 equiv) in acetonitrile (33 mL), and the reaction solution was mixed with Cool to 0°C and add trifluoromethanesulfonic anhydride (5.23 g, 1.03 equiv), stir the reaction at this temperature for 30 min, then raise the temperature to room temperature and stir the reaction for 2 h. Subsequently, 28% triethylamine (14 mL) was added and the reaction was stirred at room temperature for 48 h, extracted three times with DCM, the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain a reddish-brown liquid. It was dissolved in 10 ml of DCM, 2N hydrochloric acid ether solution was added, the reaction was stirred at room temperature for 10 min, filtered, and washed with hot ether solution to obtain 4.4 g of a reddish-brown product with a yield of 95%. ¹ H NMR (400 MHz, D ₂ O): δ 7.97-7.93 (m, 2H), 7.86-7.81 (m, 1H), 7.65 (t, J=8.0 Hz, 2H), 3.93 (t, J=15.3 Hz, 2H). ¹⁹ F NMR (376 MHz, D ₂ O) δ-107.96 (t, J=15.3 Hz).

Example 5

2,2-Difluoro-2-(benzenesulfonyl)ethyl-1-ammonium chloride (10g, 1.0equiv), sodium formate (7.92g, 3.0equiv) were added to the reaction flask, and tert-butanol (150mL) was added, The reaction mixture was stirred at 80° C. for 1.5 h, concentrated under reduced pressure, and extracted three times with dichloromethane. The organic phases were combined, the organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a crude product. Column chromatography (PE:EA= 4:1) Separation and purification to obtain 8.2 g of pure product with a yield of 85%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 8.02-7.95 (m, 2H), 7.84-7.75 (m, 1H), 7.64 (t, J=7.9 Hz, 2H), 6.41 (s, 1H), 4.25 (td, J=13.4, 6.5Hz, 2H).

Comparative Example 1

2,2-Difluoro-2-(benzenesulfonyl)ethan-1-amine (5.0 g, 1.0 equiv) and sodium formate (3.95 g, 3.0 equiv) were added to the reaction flask and replaced with nitrogen three times under nitrogen conditions Methanol was added and the reaction system was stirred at 65°C for 1.5h. TLC showed that a large amount of raw materials remained and the target product was formed. The product was separated by column chromatography with PE:EA=4:1 to obtain 2.10g of the product with a yield of 44%. Under the condition of not using tert-butanol solvent and lower temperature, the yield of the obtained target product is low.

Comparative Example 2

2,2-Difluoro-2-(benzenesulfonyl)ethyl-1-ammonium chloride (10g, 1.0equiv), sodium formate (5.28g, 2.0equiv) were added to the reaction flask, and tert-butanol (150mL) was added, The reaction mixture was stirred at 80° C. for 1.5 h, concentrated under reduced pressure, and extracted three times with dichloromethane. The organic phases were combined, the organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a crude product. Column chromatography (PE:EA= 4:1) Separation and purification to obtain 6.75 g of pure product with a yield of 70%. Properly increasing the molar dosage of sodium formate can improve the yield of the target product.

Comparative Example 3

2,2-Difluoro-2-(benzenesulfonyl)ethyl-1-ammonium chloride (10g, 1.0equiv), sodium formate (7.92g, 3.0equiv) were added to the reaction flask, and tert-butanol (100mL) was added, The reaction mixture was stirred at 60° C. for 3.0 h, concentrated under reduced pressure, and extracted three times with dichloromethane. The organic phases were combined, the organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a crude product. Column chromatography (PE:EA= 4:1) Separation and purification to obtain 6.75 g of pure product with a yield of 70%. If the reaction temperature is low, the yield of the target product obtained is low.

Comparative Example 4

2,2-Difluoro-2-(benzenesulfonyl)ethane-1-amine (0.52g, 1.0equiv) and ethyl formate (0.47g, 2.5equiv) were added to the reaction flask and heated to reflux for 12h, TLC showed A large amount of raw material remained, and 73 mg of product was obtained by column chromatography with PE:EA=4:1, and the yield was 15%. Although ethyl formate can also be used as a formylation reagent, its formylation effect is far lower than that of sodium formate.

Comparative Example 5

2,2-Difluoro-2-(benzenesulfonyl)ethan-1-amine (0.43g, 1.0equiv), formamide (0.09g, 1.0equiv) were dissolved in water, potassium persulfate (0.81g, 1.5equiv) was dissolved in water. ) was added to the reaction system and refluxed for 8h, TLC showed that the reaction system was complicated and no target product was formed. The combination of formamide and potassium persulfate is a common formylation reagent in the prior art, but it is difficult to obtain the target product of the present invention through formamide in the technical solution of the present invention.

Comparative Example 6

2,2-Difluoro-2-(benzenesulfonyl)ethane-1-amine (2.2g, 1.0equiv), formic acid (20mL) and acetic anhydride (5ml, 5.3equiv) were added to the reaction system, and the reaction was stirred at room temperature , TLC showed no change in starting material.

Example 6

A 0.2N solution of 2,2-difluoro-2-(benzenesulfonyl)ethane-1-carboxamide (10g, 1.0equiv) in dichloromethane (20ml) was cooled to -10°C, NEt ₃ (13.8g) was added , 3.4 equiv) and POCl ₃ (6.7 g, 1.1 equiv) was slowly added dropwise. The reaction mixture was stirred at -10 °C for 2 h. After the reaction was completed, saturated aqueous sodium carbonate solution was added to quench the reaction. After stirring at room temperature for 1 hour, the organic layer was separated, the aqueous phase was extracted three more times with DCM, the organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was separated by column chromatography (PE:EA=30:1) to give 7.8 g of pure product in 85% yield. ¹ H NMR (400MHz, MeOD): δ8.13-7.97 (m, 2H), 7.98-7.88 (m, 1H), 7.76 (t, J=7.9Hz, 2H), 4.64 (t, J=14.0Hz, 2H); ¹⁹ F{ ¹ H} NMR (376 MHz, MeOD): δ-109.72 (t, J=14.2 Hz). ¹⁹ F NMR (376 MHz, MeOD): δ-109.72; ¹³ C NMR (100 MHz, MeOD): δ164.9,137.7,132.9,132.0,131.1,112.0(t,J=289.9Hz),42.2(t,J=24.5Hz).HRMS calcd for C ₉ H ₈ F ₂ NO ₂ S ⁺ (M+H) ⁺ 232.02383 ,found 232.02390.

Example 7

2,2-Difluoro-2-(p-methylphenylthio)ethan-1-ol (10.7g, 1.0eqiv) was dissolved in a mixed solution of HOAc: _H2O (11:20mL), followed by 30 % H ₂ O ₂ (4.2 g, 2.2 equiv) was added to the reaction system, the reaction system was stirred at 120 °C for about 4 h under the protection of N ₂ , the reaction mixture was cooled to room temperature and extracted with EA, and the organic phase was saturated with common salt Washed with water and saturated NaHCO ₃ solution, the organic phase was dried with anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product, which was separated by column chromatography (PE:EA=9:1) to obtain 11.7 g of the product with a yield of 95%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (d, J=8.1 Hz, 2H), 7.54 (t, J=8.2 Hz, 2H), 4.31 (td, J=12.8, 7.8 Hz, 2H), 2.77 (t, J=7.8 Hz, 1H), 2.60 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-111.40 (t, J=12.4 Hz).

Example 8

Pyridine (4.0 g, 1.4 equiv) was added to a solution of 2,2-difluoro-2-(p-methylbenzenesulfonyl)ethan-1-ol (8.5 g, 1.0 equiv) in acetonitrile (60 mL), The reaction solution was cooled to 0° C. and trifluoromethanesulfonic anhydride (10.5 g, 1.03 equiv) was added, and the reaction was stirred at this temperature for 30 min, then the temperature was raised to room temperature and the reaction was stirred for 2 h. Subsequently, 28% triethylamine (30 mL) was added and the reaction was stirred at room temperature for 48 h, extracted three times with DCM, the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain a reddish-brown liquid. It was dissolved in 25 mL of DCM, 2N hydrochloric acid ether solution was added, the reaction was stirred at room temperature for 10 min, filtered, and washed with hot ether solution to obtain 9.30 g of a white solid with a yield of 96%. ¹ H NMR (400 MHz, D ₂ O): δ 7.64 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 4.20 (td, J=12.8, 8.0 Hz, 2H) , 2.66 (t, J=8.0 Hz, 1H), 2.50 (s, 3H); ¹⁹ F NMR (376 MHz, D ₂ O) δ-111.85 (t, J=12.5 Hz).

Example 9

2,2-Difluoro-2-(p-methylbenzenesulfonyl)ethyl-1-ammonium chloride (5.27g, 1.0equiv), sodium formate (3.96g, 3.0equiv) were added to the reaction flask, and tert-butanol was added (70 mL), the reaction mixture was stirred at 80° C. for 2.0 h, concentrated under reduced pressure, and extracted three times with dichloromethane. The organic phase was integrated, and the organic phase was washed with saturated brine. The organic phase was concentrated under reduced pressure to obtain a crude product. Column chromatography ( PE:EA=5:1) was separated and purified to obtain 4.48 g of pure product, the yield was 88%, which was directly put into one-step reaction.

A 0.2N solution of 2,2-difluoro-2-(p-methylbenzenesulfonyl)ethane-1-carboxamide (10.6g, 1.0equiv) in dichloromethane (20mL) was cooled to -10°C, and NEt was added. ₃ (14.2 g, 3.5 equiv) was then slowly added dropwise POCl ₃ (6.7 g, 1.1 equiv). The reaction mixture was stirred at -10 °C for 2 h. After the reaction was completed, saturated aqueous sodium carbonate solution was added to quench the reaction. After stirring at room temperature for 1 hour, the organic layer was separated, the aqueous phase was extracted three more times with DCM, the organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was separated by column chromatography (PE:EA=30:1) to give 8.76 g of pure product in 90% yield. ¹ H NMR (400MHz, MeOD): δ 7.85 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 4.62 (t, J=13.8 Hz, 2H), 2.58 (s , 3H); ¹⁹ F NMR (376 MHz, D ₂ O) δ-113.74 (t, J=12.5 Hz).

Claims (10)

1. a synthetic method of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound, is characterized in that: comprise the following steps: 1) carrying out a reduction reaction with the structure 2,2-difluoro-2-(phenylthio) ethyl acetate of formula 1 and sodium borohydride to obtain an intermediate of formula 2; 2) carrying out oxidation reaction with intermediate of formula 2 and hydrogen peroxide to obtain intermediate of formula 3; 3) react the intermediate of formula 3 with trifluoromethanesulfonic anhydride and pyridine and triethylamine to obtain intermediate of formula 4; 4) the intermediate of formula 4 is subjected to formylation reaction with the formylation reagent to obtain the intermediate of formula 5; 5) The intermediate of formula 5 is subjected to dehydration reaction under the action of phosphorus oxychloride to obtain the 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound of formula 6;

Wherein, R ₁ is hydrogen, alkyl, halogen substituent, nitro, amino or hydroxyl. 2. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound according to claim 1, is characterized in that: 2,2-difluoro-2-(aryl sulfur (base) ethyl acetate compound and sodium borohydride in ethanol solvent at room temperature for stirring reaction for 2-4h. 3. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound according to claim 2, is characterized in that: 2,2-difluoro-2-(aryl sulfur The molar ratio of ethyl acetate compound and sodium borohydride is: 1:4～1:1. 4. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 1, is characterized in that: formula 2 intermediate and hydrogen peroxide are in acetic acid-water mixed solvent , at a temperature of 100-120 °C, stirring and reacting for 3-5 h. 5 . The method for synthesizing a 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound according to claim 4 , wherein the mass percentage concentration of the hydrogen peroxide is 20-40%. 6 . ; The molar ratio of the intermediate of formula 2 and hydrogen peroxide is 1:2.5～1:1. 6. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 1, is characterized in that: formula 3 intermediate is combined with pyridine, trifluoromethanesulfonic acid The acid anhydride is in acetonitrile solvent, stirred and reacted at room temperature for 1 to 3 hours, and after adding the triethylamine aqueous solution, the stirring reaction was continued for 24 to 48 hours; wherein, the molar ratio of the intermediate of formula 3, pyridine and trifluoromethanesulfonic anhydride was 1:(1 ~2):(1~2). 7. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 1, is characterized in that: intermediate of formula 4 and formylation reagent are in organic solvent The reaction is stirred at a temperature of 80 to 100 ° C for 1 to 4 hours; the organic solvent is at least one of methanol, ethanol, propylene glycol, glycerol, tert-butanol, ethylene glycol, and hexylene glycol; the formyl The chemical reagent is at least one of sodium formate, sodium acetate, formic acid and ethyl formate. 8. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 7, is characterized in that: the mol ratio of formula 4 intermediate and formylation reagent 1:4～1:1. 9. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 1, is characterized in that: formula 5 intermediate and phosphorus oxychloride and triethyl The amine is stirred and reacted in dichloromethane solvent at -20～20℃ for 1～4h. 10. the synthetic method of a kind of 1,1-difluoro-2-isonitrile-ethyl phenyl sulfone compound according to claim 9, is characterized in that: formula 5 intermediate, phosphorus oxychloride and triethyl The amine molar ratio is 1:(1~2):(2~5).

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