CN110790689B - Synthetic method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound - Google Patents
Synthetic method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound Download PDFInfo
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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
Technical Field
The invention relates to a synthesis method of a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound, in particular to a method for efficiently synthesizing a difluoro isonitrile aryl sulfone compound by adopting a 2, 2-difluoro-2- (phenylthio) ethyl acetate compound raw material through reduction, oxidation, alcohol amination, formylation and dehydration reaction in sequence, belonging to the technical field of synthesis of a drug intermediate isonitrile compound.
Background
The isonitrile compound is used as an important synthetic intermediate with high activity and plays an irreplaceable role in the field of organic synthesis. Isonitrile type compounds are commonly used to synthesize several amides and polypeptides, as typified by Ugi (Ugi) reaction (Ugi. angelw. chem. int. ed.2000,39,3168.). In 1985, Lieke firstly discovered the first isonitrile compound which is widely applied to the synthesis of heterocyclic derivatives and is an important intermediate for synthesizing amine derivatives and nitrogen-containing compounds. Nitrogen-containing compounds are important compounds, widely exist in natural products and medicines, and have wide biological activity. Among the numerous methods developed, the direct [3+2] cycloaddition of isocyanates has become one of the most efficient and promising routes for pyrroles, oxazoles and imidazoles (Meijere, A.D.; Angew. chem. int. Ed.2010,49, 9094-. Some of the heterocyclic derivatives are shown below:
the introduction of fluorine atoms can greatly change the chemical, physical and related biological properties of molecules, and the fluorination is a commonly used modification means in modern pharmaceutical chemistry (Gouverneur, V.chem.Soc.Rev.2008,37, 320-. At present, about 20% -25% of the medicine molecular structures contain fluorine elements, and common fluorine-containing functional groups comprise fluorine atoms F and trifluoromethyl CF3Trifluoromethyl thio group SCF3trifluoromethoxyOCF3And the like. In general, the introduction of fluorine atoms alters the lipophilicity, hydrogen bonding, metabolic stability, bioavailability, etc. of the compounds. In recent years, difluoromethyl CF2The frequency with which the H structure appears in the active compound is significantly increased, it not only being a hydrogen bond donor function, but also being able to modulate the lipophilicity of the molecule. The following are active difluoro (methylene) -containing compounds:
in 2012, Caosan et al reported a novel synthesis method of difluoromethyl isocyanide building blocks for the first time, and utilized Ugi reaction to synthesize a pseudopeptide compound with difluoromethyl (Cao, S.; org. Biomol. chem.,2010,8, 2386-. The method takes thiophenol as a raw material, sequentially carries out nucleophilic substitution, ammonolysis, reduction, amidation, dehydration and other steps to obtain a target product, and has the following synthetic route:
when the lithium aluminum hydride in the route is used for reducing difluoromethyleneamide, fluorine atoms are also very easy to reduce, a byproduct diphenyl-thio-ethylamine is easily generated, the yield of a target product 2, 2-difluoro-phenylthio-ethylamine is only 45%, excessive flammable and high-risk lithium aluminum hydride is used as a reducing agent, the reduction selectivity is poor, the post-treatment is complicated, and the large-scale production of difluoromethyl isocyanide is restricted.
Disclosure of Invention
Aiming at the defects of the method for synthesizing the difluoromethyl isocyanide compound reported in the prior art, such as low difluoromethyl amide reduction efficiency, high danger of lithium aluminum hydride, poor selectivity and complex post-treatment. The technical scheme of the invention aims to provide a method for synthesizing 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compounds by taking 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compounds as raw materials through steps of reduction, oxidation, alcohol amination, formylation, dehydration and the like in sequence. The method avoids using high-risk and low-selectivity lithium aluminum hydride to reduce the low-activity difluoromethyl amide, and uses a mild reducing agent sodium borohydride to reduce the high-activity 2, 2-difluoro-2- (phenylthio) ethyl acetate compounds, so that the reduction yield and selectivity are greatly improved, the operation is simple, the reaction yield is good, the product property is stable, and the large-scale production is favorably realized.
In order to achieve the technical purpose, the invention provides a synthesis method of a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound, which comprises the following steps:
1) 2, 2-difluoro-2- (phenylthio) ethyl acetate compounds with the structure of formula 1 and NaBH4Carrying out reduction reaction to obtain an intermediate of a formula 2;
2) carrying out oxidation reaction on the intermediate of the formula 2 and hydrogen peroxide to obtain an intermediate of a formula 3;
3) reacting the intermediate shown in the formula 3 with trifluoromethanesulfonic anhydride, pyridine and triethylamine to obtain an intermediate shown in a formula 4;
4) carrying out formylation reaction on the intermediate of the formula 4 and a formylation reagent to obtain an intermediate of a formula 5;
5) the intermediate of the formula 5 is subjected to dehydration reaction under the action of phosphorus oxychloride to obtain a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound with a structure of a formula 6;
wherein R is1Hydrogen, alkyl, halogen substituent, nitro, amino or hydroxyl.
In the 2, 2-difluoro-2- (phenylthio) ethyl acetate compound and various intermediate compounds, the influence on the reaction of the substituent on the benzene ring is not obvious, and the substituent can be hydrogen or common substituents such as alkyl, halogen substituent, nitro, amino or hydroxyl. Alkyl is typically a short-chain alkyl, e.g. C1～C5The alkyl group of (a) may be a straight-chain alkyl group or a branched-chain alkyl group. The halogen substituent is fluorine, chlorine or bromine.
In a preferable scheme, the 2, 2-difluoro-2- (arylthio) ethyl acetate compound and sodium borohydride are stirred and react for 2-4 hours in an ethanol solvent at room temperature.
In a more preferable scheme, the molar ratio of the 2, 2-difluoro-2- (arylthio) ethyl acetate compound to the sodium borohydride is as follows: 1: 4-1: 1; more preferably 1:3 to 1:2.
In the preferred scheme, the intermediate of the formula 2 and hydrogen peroxide are stirred and react for 3-5 hours in an acetic acid-water mixed solvent at the temperature of 100-120 ℃.
In a preferred scheme, the mass percentage concentration of the hydrogen peroxide is 20-40%; the molar ratio of the intermediate in the formula 2 to hydrogen peroxide is 1: 2.5-1: 1; more preferably 1:2.5 to 1: 1.5.
According to the preferable scheme, the intermediate of the formula 3, pyridine and trifluoromethanesulfonic anhydride are stirred and reacted for 1-3 h at room temperature in an acetonitrile solvent, and then triethylamine water solution is added, and stirring and reaction are continued for 24-48 h; wherein, the molar ratio of the intermediate, pyridine and trifluoromethanesulfonic anhydride in formula 3 is 1 (1-2) to 1-2; more preferably 1 (1-1.5) to (1-2). The amount of triethylamine added is an excess of 1 or more times the theoretical molar amount required.
In a preferable scheme, the intermediate of the formula 4 and the formylation reagent are stirred and react for 1-4 h in an organic solvent at the temperature of 80-100 ℃. More preferably, the reaction is carried out at a temperature of 80-100 ℃ for 1-2 hours under stirring.
In a more preferred embodiment, the organic solvent is at least one of methanol, ethanol, propylene glycol, glycerol, t-butanol, ethylene glycol, and hexylene glycol. Most preferably tert-butanol.
In a more preferred embodiment, 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 preferable scheme, the molar ratio of the intermediate of the formula 4 to the formylation reagent is 1: 4-1: 1; more preferably 1:3 to 1: 4.
In the preferable scheme, the intermediate of the formula 5, phosphorus oxychloride and triethylamine are stirred and react for 1-4 h in a dichloromethane solvent at the temperature of-20 ℃. In a more preferable scheme, the intermediate of the formula 5, phosphorus oxychloride and triethylamine are stirred and react for 1-2 hours in a dichloromethane solvent at the temperature of-10 ℃.
The mol ratio of the intermediate, phosphorus oxychloride and triethylamine in the formula 5 is 1 (1-2) to 2-5; more preferably 1 (1-1.5) to 2-4.
The ethyl 2, 2-difluoro-2- (phenylthio) acetate compounds of the invention can be synthesized conventionally according to literature reports known in the prior art, such as: stirring thiophenol or thiophenol derivative and sodium hydride for 1h, dissolving with ethyl difluorobromoacetate in dimethyl sulfoxide solvent, and stirring at 40 deg.C for reaction for 15 h.
The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound skillfully adopts reduction-oxidation-alcohol amination-formylation and dehydration reaction to replace the prior synthesis route of nucleophilic substitution-ammonolysis-reduction-amidation and dehydration, avoids the reduction step of difluoromethyl amide, and avoids the use of a high-risk and poor-selectivity lithium aluminum hydride reducing reagent. The method for reducing the 2, 2-difluoro-2- (phenylthio) ethyl acetate by using the sodium borohydride has high reaction activity and high selectivity, greatly improves the reduction yield, is simple to operate, and is favorable for realizing large-scale production of the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound.
In the synthesis process of synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound, thiophenol or thiophenol derivatives are used as raw materials, such as thiophenol, p-methyl thiophenol, p-methoxy thiophenol, p-nitro thiophenol, p-amino thiophenol, p-bromo thiophenol, o-bromo thiophenol, 2-hydroxy thiophenol and the like.
The synthesis process of the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound comprises the following steps: the raw material of the 2, 2-difluoro-2- (thiophenyl) ethyl acetate compound is obtained by nucleophilic substitution reaction of thiophenol and ethyl difluorobromoacetate according to the literature. The method comprises the following steps of selectively reducing ester groups into alcohol by using sodium borohydride, oxidizing mercapto groups into sulfone by using hydrogen peroxide, aminating under the action of trifluoromethanesulfonic anhydride, pyridine and triethylamine, performing formylation reaction with sodium formate, and performing dehydration reaction under the action of phosphorus oxychloride and triethylamine to obtain a target product, wherein the main reaction steps are as follows:
compared with the prior art, the technical scheme of the invention brings the following technical advantages:
(1) the technical scheme of the invention takes 2, 2-difluoro-2- (phenylthio) ethyl acetate compounds as raw materials, skillfully designs a synthesis route of reduction-oxidation-alcohol amination-formylation and dehydration reaction, directly carries out sodium borohydride reduction on the 2, 2-difluoro-2- (phenylthio) ethyl acetate, avoids the reduction step of difluoromethyl amide, avoids the use of a lithium aluminum hydride reduction reagent with high risk and poor selectivity, improves the reduction yield and selectivity, ensures that the yield of the reduction step can reach 90 percent, and is beneficial to realizing the mass preparation of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone.
(2) The reaction conditions for synthesizing the 2, 2-difluoro-2- (phenylthio) ethyl acetate compound in the technical scheme of the invention are mild, the operation and the treatment are simple, the yield is high (the yield in each step is more than 85%), the product separation is simple, the target product can be obtained at high yield, the product property is stable, and a large amount of difluoro isonitrile intermediates are provided for the drug synthesis.
Drawings
FIG. 1 is ethyl 2, 2-difluoro-2- (phenylthio) acetate1H NMR(400MHz,CDCl3)；
FIG. 2 is ethyl 2, 2-difluoro-2- (phenylthio) acetate19F NMR(376MHz,CDCl3)；
FIG. 3 is an intermediate product prepared in example 21H NMR(400MHz,CDCl3)；
FIG. 4 shows an intermediate product prepared in example 219F NMR(376MHz,CDCl3)；
FIG. 5 is an intermediate product prepared in example 213C NMR(100MHz,CDCl3)；
FIG. 6 is an intermediate product prepared in example 31H NMR(400MHz,CDCl3)；
FIG. 7 is an intermediate product prepared in example 319F NMR(376MHz,CDCl3)；
FIG. 8 is an intermediate product prepared in example 41H NMR(400MHz,D2O)；
FIG. 9 is an intermediate product prepared in example 419F NMR(376MHz,D2O)；
FIG. 10 is an intermediate product prepared in example 51H NMR(400MHz,CDCl3)；
FIG. 11 shows the preparation of the product of example 61H NMR(400MHz,MeOD)；
FIG. 12 shows the preparation of the product of example 619F{1H}NMR(376MHz,MeOD)；
FIG. 13 shows the preparation of the product of example 619F NMR(376MHz,MeOD)；
FIG. 14 shows the preparation of the product of example 613C NMR(100MHz,MeOD)；
FIG. 15 is HRMS product of example 6.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
Example 1
Thiophenol (5.5mL, 1.0equiv) was dissolved in dimethyl sulfoxide (50mL), and sodium hydride (2.4g, 1.1equiv) was added slowly under ice-bath conditions, and the reaction was stirred at 40 ℃ for 1 h. Ethyl difluorobromoacetate (12.0g,1.1equiv) was added to the reaction solution and stirred for 15h, TLC showed complete reaction of the starting materials. Quenching with aqueous ammonium chloride solution and extracting with diethyl ether, washing the organic layer with water and brine in sequence, and then with anhydrous MgSO4Drying and concentration under reduced pressure gave the crude product, 10.7g of product by column chromatography, 86% yield.1H NMR(400MHz,CDCl3)：δ7.57–7.51(m,2H),7.41–7.35(m,1H),7.31(dd,J＝8.2,6.5Hz,3H),4.16(q,J＝7.2Hz,2H),1.16(t,J＝7.1Hz,3H).19F NMR(376MHz,CDCl3)：δ-82.21。
Example 2
Example 3
2, 2-difluoro-2- (phenylthio) ethan-1-ol (10g,1.0eqiv) was dissolved in HOAc: h2O (10: 19mL), and 30% H2O2(3.9g,2.2equiv) was added to the reaction system under N2The reaction was stirred at 120 ℃ for about 4h under protection, the reaction mixture was cooled to room temperature and extracted with EA and the organic phase was extracted with saturated brine and saturated NaHCO3The solution was washed, the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to give a crude product, which was separated by column chromatography (PE: EA ═ 9:1) to give 9.9g of the product in 85% yield.1H NMR(400MHz,CDCl3)δ8.01(d,2H,J＝7.8Hz),7.80(t,1H,J＝7.5Hz),7.65(t,J＝7.9Hz,2H),4.31(t,J＝12.8Hz,2H),2.74(s,1H).19F NMR(376MHz,CDCl3)δ-111.20(t,J＝12.9Hz).
Example 4
Pyridine (2.0g,1.4equiv) was added to a solution of 2, 2-difluoro-2- (benzenesulfonyl) ethan-1-ol (4.0g,1.0equiv) in acetonitrile (33mL), the reaction solution was cooled to 0 ℃ and trifluoromethanesulfonic anhydride (5.23g,1.03equiv) was added, and after stirring the reaction at that temperature for 30min, the temperature was raised to room temperature and the reaction was stirred for 2 h. Subsequently, 28% triethylamine (14mL) was added and the reaction was stirred at room temperature for 48h, extracted three times with DCM, the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give a reddish brown liquid. This was dissolved in 10ml DCM, 2N ethereal hydrochloride was added, the reaction was stirred at room temperature for 10min, filtered and washed with hot ethereal solution to give a reddish brown product 4.4g with 95% yield.1H NMR(400MHz,D2O):δ7.97–7.93(m,2H),7.86–7.81(m,1H),7.65(t,J＝8.0Hz,2H),3.93(t,J＝15.3Hz,2H).19F NMR(376MHz,D2O)δ-107.96(t,J＝15.3Hz).
Example 5
Adding 2, 2-difluoro-2- (benzenesulfonyl) ethyl-1-ammonium chloride (10g,1.0equiv) and sodium formate (7.92g,3.0equiv) into a reaction bottle, adding tert-butyl alcohol (150mL), stirring the reaction mixture at 80 ℃ for 1.5h, concentrating under reduced pressure, extracting with dichloromethane for three times, combining organic phases, washing the organic phases with saturated saline solution, concentrating the organic phases under reduced pressure to obtain a crude product, and separating and purifying by column chromatography (PE: EA is 4:1) to obtain 8.2g of a pure product, wherein the yield is 85%.1H NMR(400MHz,CDCl3)：δ8.30(s,1H),8.02–7.95(m,2H),7.84–7.75(m,1H),7.64(t,J＝7.9Hz,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 (5.0g, 1.0equiv) and sodium formate (3.95g,3.0equiv) were added to a reaction flask, replaced with nitrogen gas for 3 times, methanol was added under nitrogen, the reaction was stirred at 65 ℃ for 1.5h, TLC showed a large amount of remaining starting material and the desired product was formed, and the product was separated by column chromatography at PE: EA ═ 4:1 to give 2.10g, 44% yield. The yield of the obtained target product is low under the conditions of not using tertiary butanol solvent and low temperature.
Comparative example 2
Adding 2, 2-difluoro-2- (benzenesulfonyl) ethyl-1-ammonium chloride (10g,1.0equiv) and sodium formate (5.28g,2.0equiv) into a reaction bottle, adding tert-butyl alcohol (150mL), stirring the reaction mixture at 80 ℃ for 1.5h, concentrating under reduced pressure, extracting with dichloromethane for three times, combining organic phases, washing the organic phases with saturated saline solution, concentrating the organic phases under reduced pressure to obtain a crude product, and separating and purifying by column chromatography (PE: EA is 4:1) to obtain 6.75g of a pure product with the yield of 70%. The molar dosage of the sodium formate is properly increased, and the yield of the target product can be increased.
Comparative example 3
Adding 2, 2-difluoro-2- (benzenesulfonyl) ethyl-1-ammonium chloride (10g,1.0equiv) and sodium formate (7.92g,3.0equiv) into a reaction bottle, adding tert-butyl alcohol (100mL), stirring the reaction mixture at 60 ℃ for 3.0h, concentrating under reduced pressure, extracting with dichloromethane for three times, combining organic phases, washing the organic phase with saturated saline solution, concentrating the organic phase under reduced pressure to obtain a crude product, and separating and purifying by column chromatography (PE: EA is 4:1) to obtain 6.75g of a pure product with the yield of 70%. If the reaction temperature is lower, the yield of the obtained target product is lower.
Comparative example 4
2, 2-difluoro-2- (benzenesulfonyl) ethan-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, and TLC showed a large amount of starting material remaining and yielded 73mg of the product in 15% yield by column chromatography with PE: EA ═ 4: 1. Although ethyl formate can also be used as a formylation reagent, the formylation effect of ethyl formate 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, and potassium persulfate (0.81g,1.5equiv) was added to the reaction system for reflux reaction for 8h, and TLC showed that the reaction system was complicated and no target product was produced. Formamide and potassium persulfate are common formylation reagents in the prior art, but the technical scheme of the invention has difficulty in obtaining the target product of the invention by formamide.
Comparative example 6
2, 2-difluoro-2- (phenylsulfonyl) ethan-1-amine (2.2g,1.0equiv) was added to the reaction system with formic acid (20mL), acetic anhydride (5mL,5.3equiv), and the reaction was stirred at room temperature, and TLC showed no change in the starting materials.
Example 6
0.2N solution of 2, 2-difluoro-2- (benzenesulfonyl) ethyl-1-carboxamide (10g,1.0equiv) in dichloromethane (20ml) was cooled to-10 deg.C and NEt was added3(13.8g,3.4equiv) and slowly adding POCl dropwise3(6.7g,1.1 equiv.) the reaction mixture was stirred at-10 ℃ for 2 h. After the reaction was completed, a 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 isolated by column chromatography (PE: EA ═ 30:1) to give 7.8g of pure product in 85% yield.1H 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)；19F{1H}NMR(376MHz,MeOD)：δ-109.72(t,J＝14.2Hz).19F NMR(376MHz,MeOD):δ-109.72；13C NMR(100MHz,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 C9H8F2NO2S+(M+H)+232.02383,found 232.02390.
Example 7
2, 2-difluoro-2- (p-methylphenylsulfanyl) ethan-1-ol (10.7g,1.0eqiv) was dissolved in HOAc: h2O (11: 20mL), and 30% H2O2(4.2g,2.2equiv) was added to the reaction system under N2The reaction was stirred at 120 ℃ for about 4h under protection, the reaction mixture was cooled to room temperature and extracted with EA and the organic phase was extracted with saturated brine and saturated NaHCO3The solution was washed, the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to give a crude product, which was isolated by column chromatography (PE: EA ═ 9:1) to give 11.7g of the product in 95% yield.1H NMR(400MHz,CDCl3)：δ7.76(d,J＝8.1Hz,2H),7.54(t,J＝8.2Hz,2H),4.31(td,J＝12.8,7.8Hz,2H),2.77(t,J＝7.8Hz,1H),2.60(s,3H).19F NMR(376MHz,CDCl3):δ-111.40(t,J＝12.4Hz).
Example 8
Pyridine (4.0g,1.4equiv) was added to a solution of 2, 2-difluoro-2- (p-toluenesulfonyl) ethan-1-ol (8.5g,1.0equiv) in acetonitrile (60mL), the reaction solution was cooled to 0 ℃ and trifluoromethanesulfonic anhydride (10.5g,1.03equiv) was added, the reaction was stirred at that temperature for 30min, then the temperature was raised to room temperature and the reaction was stirred for 2 h. Subsequently, 28% triethylamine (30mL) was added and the reaction was stirred at room temperature for 48h, extracted three times with DCM, the organic phases were combined, washed with saturated brine and concentrated under reduced pressure to give a reddish brown liquid. This was dissolved in 25 ml of DCM, 2N ethereal hcl was added, the reaction was stirred at room temperature for 10min, filtered and washed with hot ethereal solution to give 9.30g of white solid with 96% yield.1H NMR(400MHz,D2O):δ7.64(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),4.20(td,J＝12.8,8.0Hz,2H),2.66(t,J＝8.0Hz,1H),2.50(s,3H)；19F NMR(376MHz,D2O)δ-111.85(t,J＝12.5Hz).
Example 9
Adding 2, 2-difluoro-2- (p-methyl benzenesulfonyl) ethyl-1-ammonium chloride (5.27g,1.0equiv) and sodium formate (3.96g,3.0equiv) into a reaction bottle, adding tert-butyl alcohol (70mL), stirring the reaction mixture at 80 ℃ for reacting for 2.0h, concentrating under reduced pressure, extracting with dichloromethane for three times, integrating organic phases, washing the organic phases with saturated saline solution, concentrating the organic phases under reduced pressure to obtain a crude product, separating and purifying by using a column chromatography (PE: EA is 5:1) to obtain a pure product 4.48g, wherein the yield is 88%, and directly feeding the pure product into a one-step reaction.
A0.2N solution of 2, 2-difluoro-2- (p-methylbenzenesulfonyl) ethane-1-carboxamide (10.6g,1.0equiv) in dichloromethane (20mL) was cooled to-10 deg.C and NEt was added3(14.2g,3.5equiv) and slowly adding POCl dropwise3(6.7g,1.1 equiv.) the reaction mixture was stirred at-10 ℃ for 2 h. After the reaction was completed, a 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 isolated by column chromatography (PE: EA ═ 30:1) to give 8.76g of pure product, 90% yield.1H NMR(400MHz,MeOD):δ7.85(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),4.62(t,J＝13.8Hz,2H),2.58(s,3H)；19F NMR(376MHz,D2O)δ-113.74(t,J＝12.5Hz)。
Claims (10)
1. A synthetic method of a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound is characterized by comprising the following steps: the method comprises the following steps:
1) carrying out reduction reaction on 2, 2-difluoro-2- (phenylthio) ethyl acetate compounds with a structure shown in a formula 1 and sodium borohydride to obtain an intermediate shown in a formula 2;
2) carrying out oxidation reaction on the intermediate of the formula 2 and hydrogen peroxide to obtain an intermediate of a formula 3;
3) reacting the intermediate shown in the formula 3 with trifluoromethanesulfonic anhydride, pyridine and ammonia water to obtain an intermediate shown in the formula 4;
4) carrying out formylation reaction on the intermediate of the formula 4 and a formylation reagent to obtain an intermediate of a formula 5;
5) the intermediate of the formula 5 is subjected to dehydration reaction under the action of phosphorus oxychloride to obtain a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound with a structure of a formula 6;
formula 1
Formula 2
Formula 3
Formula 4
Formula 5
Formula 6
Wherein R is1Hydrogen, alkyl, halogen, nitro, amino or hydroxyl.
2. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 1, characterized in that: and (3) stirring and reacting the 2, 2-difluoro-2- (phenylthio) ethyl acetate compound and sodium borohydride in an ethanol solvent at room temperature for 2-4 h.
3. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 2, characterized in that: the mol ratio of the 2, 2-difluoro-2- (phenylthio) ethyl acetate compound to the sodium borohydride is as follows: 1:4 to 1:1.
4. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 1, characterized in that: and (3) stirring the intermediate of the formula 2 and hydrogen peroxide in an acetic acid-water mixed solvent for reaction for 3-5 hours at the temperature of 100-120 ℃.
5. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 4, characterized in that: the mass percentage concentration of the hydrogen peroxide is 20-40%; the molar ratio of the intermediate in the formula 2 to hydrogen peroxide is 1: 2.5-1: 1.
6. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 1, characterized in that: stirring the intermediate of the formula 3, pyridine and trifluoromethanesulfonic anhydride in an acetonitrile solvent for reaction for 1-3 h at room temperature, adding an ammonia solution, and continuing stirring for reaction for 24-48 h; wherein, the molar ratio of the intermediate, pyridine and trifluoromethanesulfonic anhydride in formula 3 is 1 (1-2) to 1-2.
7. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 1, characterized in that: stirring the intermediate of the formula 4 and a formylation reagent in an organic solvent at the temperature of 80-100 ℃ for reacting for 1-4 h; the organic solvent is at least one of methanol, ethanol, propylene glycol, glycerol, tert-butyl alcohol, ethylene glycol and hexanediol; the formylation reagent is at least one of sodium formate, formic acid and ethyl formate.
8. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethylphenyl sulfone compound according to claim 7, characterized in that: the molar ratio of the intermediate of the formula 4 to the formylation reagent is 1: 4-1: 1.
9. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound as claimed in claim 1, characterized in that: and (3) stirring the intermediate of the formula 5, phosphorus oxychloride and ammonia water in a dichloromethane solvent for reaction for 1-4 h at the temperature of-20 ℃.
10. The method for synthesizing the 1, 1-difluoro-2-isonitrile-ethylphenyl sulfone compound according to claim 9, characterized in that: the molar ratio of the intermediate of the formula 5, phosphorus oxychloride and ammonia water is 1 (1-2) to 2-5.
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