CN107540598B

CN107540598B - Method for preparing N-difluoromethylthio phthalimide compound

Info

Publication number: CN107540598B
Application number: CN201610469651.4A
Authority: CN
Inventors: 沈其龙; 吕龙; 朱佃虎
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2016-06-23
Filing date: 2016-06-23
Publication date: 2020-05-12
Anticipated expiration: 2036-06-23
Also published as: CN107540598A

Abstract

本发明公开了一种制备N‑二氟甲硫基邻苯酰亚胺类化合物的方法。该方法包括下列步骤：如式3所示的N‑二氟甲硫基邻苯酰亚胺的制备方法，其包括下列步骤：有机溶剂中，将二氟甲硫氯与如式1所示的化合物进行如下所示的二氟甲硫基化反应，即可。本发明的制备方法操作简便、步骤少、适用底物范围广、反应条件温和、转化率高、收率高、成本低、适合于工业化生产。

The invention discloses a method for preparing N-difluoromethylthio o-phenylimide compounds. The method comprises the following steps: the preparation method of N-difluoromethylthio o-phenylimide shown in formula 3, which comprises the following steps: in an organic solvent, mixing difluoromethylthio chloride with the formula shown in formula 1 The compound may be subjected to the difluoromethylthiolation reaction shown below. The preparation method of the invention has the advantages of simple operation, few steps, wide range of applicable substrates, mild reaction conditions, high conversion rate, high yield and low cost, and is suitable for industrial production.

Description

Method for preparing N-difluoromethylthio phthalimide compound

Technical Field

The invention relates to a method for preparing N-difluoromethylthio phthalimide compounds.

Background

In the field of medicines and pesticides, fluorine-containing and fluoroalkyl functional groups are important structural units, and introduction of the fluorine functional groups can effectively increase the metabolic stability of the medicine, improve the lipid solubility of the medicine, better permeate cell membranes and improve the medicine effect.

Difluoromethylthio (SCF)₂H) Is one of fluoroalkyl groups, has important application in the fields of medicine and pesticide, and is becoming a hot point of research for chemists in recent years. In one aspect, SCF₂Compared with other fluorine-containing groups, the H has smaller electron-withdrawing performance and poorer stability, and the characteristics show advantages in the aspects of special selectivity of the medicine and shorter biological metabolism; in another aspect, SCF₂H has a moderate Hansch lipophilicity coefficient pi (table 1), which offers the possibility for drug modulation of lipid solubility.

TABLE 1 Hansch lipophilicity index (π) for some substituents

Substituent group	CH₃	CF₃	SCH₃	SCF₃	OCF₃	OCF₂H	SCF₂H	SO₂CF₃
									π	0.56	0.88	0.61	1.44	1.04	0.58	0.68	0.56

Further, SCF₂H contains a difluoromethyl group (CF)₂H) It has weak acidity and is unstable and easy to decompose under strong alkaline conditions. Difluoromethyl group due to its acid-base and electrical similarity to OH or NH, SCF₂H is also easy to generate secondary interaction such as hydrogen bonds and the like in molecules and among molecules, and the metabolic stability in organisms is increased.

The unique properties of difluoromethylthio make it an important group in the fields of medicine and pesticides. The compound I is a phenylpyrazole pesticide developed by Mitsubishi chemical corporation, is a homolog of fipronil, reduces toxicity to bees and aquatic animals, and becomes a novel broad-spectrum pesticide (modern pesticide, 2013,12(1), 1); the compound II is a sulfonamide herbicide developed by japan combinatorial chemistry industries, mainly used for preventing preemergence weeds in paddy fields, which is an acetolactate synthase inhibitor (modern pesticide, 2013,12(1), 1); compounds III and IV are useful as antibiotics (j. fluorine Chem,2011,132,792) and against HIV-1 virus (j. fluorine Chem,2000,102,369), respectively.

The methods for introducing difluoromethylthio group in the prior art mainly comprise the following methods:

(1) by XeF₂Fluorination methods introduce difluoromethylthio into the molecule (j. fluorine Chem,1976,8, 305).

(2) The classical method is that the insertion of difluorocarbene p-mercaptan or sulfur salt generated on site is utilized to grab the proton in the system and introduce difluoromethylthio into the molecule.

ClCF₂H (F-22) (reference Tetrahedron Letters,1965,7, 403);

BrCF₂P(O)(OEt)₂(reference Tetrahedron,2009,65, 5278);

ClCF₂CO₂na (SCDA) (ref)Org.Lett.,2013,15,5036)；

FSO₂CF₂CO₂H (ref.J. fluorine Chem,1989,44, 433);

FSO₂CF₂CO₂tms (tfda) (ref j. fluorine Chem,2015,171,133);

n-Bu₃N⁺(CF₂H)Cl^-(reference chinese. j. chem.2011,29,2717);

TMSCF₂br (ref angelw.chem., int.ed.,2013,52, 12390);

(reference org.lett.,2009,11, 2109);

HCF₂OTf (reference angelw.chem.int.ed.2013, 52,2092);

CHF₃(reference j.org.chem.2013,78,8904);

Ph₃P⁺CF₂CO₂ ^-(PDFA) (reference chem. commun.,2015,51, 8805).

(3) Prepared by reacting a thiol with an electrophilic difluoromethyl reagent (Tetrahedron lett.2008,49,5006; j.fluorine chem.2011,132,792) or a reagent capable of generating a difluoromethyl radical (j.am. chem.soc.2012,134, 1494).

All the methods need to be carried out under strong alkali, and the compatibility of functional groups is poor; meanwhile, the preparation of thiol or thiophenol containing sulfydryl and other substrates is required, which is a challenge for complex molecules, so the development of a method for introducing difluoromethylthio is greatly limited.

(4) In 2015, the Goosen group of Germany utilized organosulfur cyanide and [ CuCF ] generated in situ₂H]By reaction, a difluoromethylthio group-containing compound (angelw.chem.int.ed.2015, 54,5753) can be prepared. The disadvantage of the reaction is that the substrate is limited to organosulfur cyanides.

(5) Shenchinong topic group of Shanghai institute of Chinese academy of sciences reports an azacarbene-complexed difluoromethyl silver compound SIPRAGSCF₂H ([ SIPr ═ 1, 3-bis (2, 6-diisopropylphenyl) imidazole)]). It is a nucleophilic difluoromethylthiolation reagent that can undergo Sandmeyer-difluoromethylthiolation of copper-mediated aryl/heteroaromatic diazo compounds (angew. chem. int. ed.2015,54,7648) and also the first palladium-catalyzed difluoromethylthiolation of heterocyclic iodides/bromides/OTf and aryl iodides (chem. sci.,2016, DOI:10.1039/C6SC 00082G). The disadvantage of the reaction is the use of the silver reagent in equivalent amounts of difluoromethylthio group.

R is phenyl, methoxy, phenoxy, bromine, iodine, formyl, ester group, nitro, etc

This subject group subsequently reports a first stable electrophilic difluoromethylthioylating agent, N-difluoromethylthiomethylthiophthalimide 3, prepared by the following process: in toluene, N-Thiophthalimide with SIPRAGCF₂H ([ SIPr ═ 1, 3-bis (2, 6-diisopropylphenyl) imidazole)]) Nucleophilic substitution reaction was carried out, and difluoromethylthioylating agent 3(j.am.chem.soc.2015,137,10547) was obtained in a yield of 66%. Wherein SIPRAGCF₂H can be prepared according to the method reported in literature NatureCommunications, 2014, 5, 5405.

The method has the advantages of complicated preparation steps and higher cost, and is not suitable for industrial production.

Therefore, the search for a preparation method of the compound containing the difluoromethylthio group, which has the advantages of simple operation, few steps, wide range of applicable substrates, mild reaction conditions, high conversion rate, high yield, low cost and suitability for industrial production, is a technical problem to be solved at present.

Disclosure of Invention

The invention aims to overcome the defects of complicated steps, complex operation, harsh reaction conditions, narrow substrate application range, low yield, low conversion rate, inapplicability to industrial production and the like of the conventional preparation method of the compound containing the difluoromethylthio group, and provides a method for preparing the N-difluoromethylthio phthalimide compound. The preparation method has the advantages of simple operation, few steps, wide range of applicable substrates, mild reaction conditions, high conversion rate, high yield and low cost, and is suitable for industrial production.

In the prior art to HCF₂SCl has fewer studies, its boiling point is lower (25-35 ℃) (J.org.chem.1979,44,1708), toxicity is not reported, and there are few reports on its application, except that it can be used for pyriprole synthesis as mentioned in WO2002010153, probably due to HCF₂There are potential safety hazards to SCl. In the course of their research, the inventors of the present application found that the use of HCF generated in situ₂SCl, without isolation, gave difluoromethylthiolation reagent 3 in a good condition.

The invention provides a preparation method of N-difluoromethylthio phthalimide shown as a formula 3, which comprises the following steps: in an organic solvent, difluoromethylthiochloride (HCF)₂Cl) and a compound shown as a formula 1 are subjected to difluoro methylation reaction shown as follows;

in the compound of formula 1, M⁺Being alkali metal ions (e.g. Li)⁺、Na⁺、K⁺Or Cs⁺) (ii) a In the compound shown as the formula 1 or the formula 3, R is hydrogen or nitro.

The N-difluoro shown in the formula 3In the preparation method of the methylthio phthalimide, the organic solvent is preferably one or more of halogenated alkane solvents, halogenated aromatic solvents, nitrile solvents and aromatic solvents. The halogenated alkane solvent is preferably monochloromethane, dichloromethane or trichloromethane (CHCl)₃) Tetrachloromethane and 1, 2-dichloroethane, and further preferably chloroform. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, dichlorobenzene and trichlorobenzene, and is further preferably chlorobenzene. The nitrile solvent is preferably acetonitrile. The aromatic hydrocarbon solvent is preferably toluene. The amount of the organic solvent is not particularly limited as long as the reaction is not affected, and the volume-to-mass ratio of the organic solvent to the compound represented by formula 1 is preferably 1mL/g to 20mL/g, more preferably 1mL/g to 10mL/g (e.g., 3mL/g to 5 mL/g). The dosage of the difluoromethoxy chloride and the compound shown as the formula 1 can be the dosage which is conventional in the field of organic synthesis in the reaction, and the molar ratio of the difluoromethoxy chloride to the compound shown as the formula 1 is preferably 0.9:1-2:1, and more preferably 1: 1-1.1: 1. The temperature of the difluoromethylthiolation reaction may be a temperature conventional for such reactions in the field of organic synthesis, preferably-78 ℃ to 30 ℃, and more preferably-20 ℃ to 30 ℃ (e.g., room temperature). The progress of the difluoromethylation reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC, HNMR or GC), and is generally determined as the end point of the reaction when the compound of formula 1 disappears. The time of the difluoromethylation reaction is preferably 0.5 to 24 hours, and more preferably 1 to 10 hours.

In a preferred embodiment of the present invention, the difluoromethylthiolation reaction comprises the steps of: mixing HCF₂And mixing the mixed solution formed by SCl and an organic solvent with a compound shown as a formula 1 to perform the difluoromethylthio reaction. The temperature of the mixing is preferably-78 deg.C to 30 deg.C, and more preferably-20 deg.C to 0 deg.C (e.g. -10 deg.C).

After the difluoromethylation reaction is finished, the method can further comprise the operation of post-treatment. The operation of the post-treatment can be the operation which is conventional in the field of post-treatment in organic synthesis, and preferably comprises the following steps: the reaction solution after the termination of the difluoromethylation reaction is subjected to solid-liquid separation (preferably filtration), the organic solvent in the filtrate is removed (preferably desolventizing under reduced pressure), and the resulting product is separated and purified by silica gel column chromatography (preferably flash silica gel chromatography, and the eluent preferably ethyl acetate and petroleum ether (preferably ethyl acetate: petroleum ether (V: V) ═ 1: 4)).

The preparation method of the N-difluoromethylthio phthalimide shown in the formula 3 can further comprise the following steps: in an organic solvent, a compound shown as a formula 2 and chlorine gas are subjected to chlorination reaction shown as the following to prepare difluoromethylthiochloride (HCF)₂Cl)；

In the preparation method of the difluoromethylthio chloride, the chlorination reaction conditions can be the conditions conventional in the organic synthesis field. The organic solvent is preferably one or more of halogenated alkane solvents, halogenated aromatic solvents, nitrile solvents and aromatic solvents. The halogenated alkane solvent is preferably monochloromethane, dichloromethane or trichloromethane (CHCl)₃) Tetrachloromethane and 1, 2-dichloroethane, and further preferably chloroform. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, dichlorobenzene and trichlorobenzene, and is further preferably chlorobenzene. The nitrile solvent is preferably acetonitrile. The aromatic hydrocarbon solvent is preferably toluene. The amount of the organic solvent used is not particularly limited as long as the reaction is not affected, and the volume-to-mass ratio of the organic solvent to the compound represented by the formula 2 is preferably 1.0mL/g to 30mL/g, and more preferably 1mL/g to 10mL/g (e.g., 4mL/g to 8 mL/g). The dosage of the chlorine is the dosage which is conventional in the field of organic synthesis reaction, and the molar ratio of the chlorine to the compound shown as the formula 2 is preferably 0.9:1-2:1, and further preferably 1:1. The temperature of the chlorination reaction may be a temperature conventional for such reactions in the field of organic synthesis, preferably-78 ℃ to 30 ℃, and more preferably-20 ℃ to 0 ℃ (e.g., -10 ℃). The progress of the chlorination reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC, HNMR, or GC), and generallyThe end point of the reaction was determined when the compound represented by the formula 2 disappeared. The time of the chlorination reaction is preferably 10 minutes to 6 hours, and more preferably 0.5 hour to 1.5 hours.

In a preferred embodiment of the present invention, the process for the preparation of difluoromethylthiochloride comprises the steps of: mixing an organic solution containing chlorine (namely, a solution formed by dissolving chlorine in the organic solvent) with a compound shown as a formula 2, and carrying out the chlorination reaction. The temperature of the mixing is preferably-78 deg.C to 30 deg.C, and more preferably-20 deg.C to 0 deg.C (e.g. -10 deg.C).

In a preferred embodiment of the present invention, the preparation method of N-difluoromethylthio phthalimide represented by the formula 3 comprises the following steps:

(1) in an organic solvent, a compound shown as a formula 2 and chlorine gas are subjected to chlorination reaction shown as the following to prepare HCF₂SCl；

(2) Mixing the reaction solution obtained after the reaction in the step (1) with a compound shown as a formula 1 without post-treatment, and carrying out a difluoromethylthio reaction shown as follows;

in the compound of formula 1, M⁺Is an alkali metal ion; in the compound shown as the formula 1 or the formula 3, R is hydrogen or nitro. The conditions of the chlorination reaction in the step (1) and the difluoromethylation reaction in the step (2) are the same as those described above.

When the reaction solution after the reaction in the step (1) is finished is directly added with the compound shown in the formula 1 without post-treatment, and the difluoromethylthio reaction is performed, the amount of the compound shown in the formula 1 is calculated by the amount of the compound shown in the formula 2, and the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is not particularly limited as long as the reaction is not affected, and is preferably 1:5-3:1, and more preferably 1:1.1-1:0.9 (for example, 1: 1).

In a preferred embodiment of the present invention, the step (2) preferably comprises the steps of: and (2) adding a compound shown as a formula 1 into the reaction liquid after the reaction in the step (1), and carrying out the difluoromethylthio reaction. The temperature of the addition is preferably-78 deg.C to 30 deg.C, and more preferably-20 deg.C to 0 deg.C (e.g. -10 deg.C).

The preparation method of the N-difluoromethylthio phthalimide shown in the formula 3 can further comprise the following steps: in an organic solvent, under the action of alkali, carrying out difluorocarbene intercalation reaction on a compound shown as a formula A and a difluorocarbene precursor as shown in the specification to prepare the compound shown as a formula 2;

the difluorocarbene precursor is preferably any one of the following compounds: ClCF₂H(F-22)、BrCF₂P(O)(OEt)₂、ClCF₂CO₂Na(SCDA)、FSO₂CF₂CO₂H、FSO₂CF₂CO₂TMS(TFDA)、n-Bu₃N⁺(CF₂H)Cl^-、TMSCF₂Br、

HCF₂OTf、CHF₃Or Ph₃P⁺CF₂CO₂ ^-(PDFA)。

In the preparation method of the compound shown in the formula 2, the organic solvent can be a solvent which is conventional in the reaction in the field of organic synthesis, and preferably water and/or an organic solvent. The organic solvent is preferably one or more of alkane solvents, ether solvents, ketone solvents and nitrile solvents. The alkane solvent is preferably a naphthenic solvent, and is further preferably one or more of n-hexane, n-pentane and petroleum ether. The ether solvent is preferably 1, 4-dioxane. The ketone solvent is preferably acetone. The nitrile solvent is preferably acetonitrile. The amount of the organic solvent used is not particularly limited as long as the reaction is not affected, and the organic solvent and the compound represented by the formula AThe volume-to-mass ratio of the compound is preferably 25 to 250 mL/g. The base may be a base conventional to such reactions in the field of organic synthesis, and is preferably one or more of alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal monohydrogen phosphate, and alkali metal dihydrogen phosphate. The alkali metal hydroxide is preferably one or more of LiOH, NaOH, KOH and CsOH. The alkali metal carbonate is preferably Li₂CO₃、Na₂CO₃、K₂CO₃And Cs₂CO₃One or more of (a). The alkali metal bicarbonate is preferably NaHCO₃And/or KHCO₃. The alkali metal phosphate is preferably Na₃PO₄And/or K₃PO₄. The alkali metal monohydrogen phosphate is preferably Na₂HPO₄And/or K₂HPO₄. The alkali metal dihydrogen phosphate is preferably NaH₂PO₄And/or KH₂PO₄. The dosage of the alkali can be the dosage which is conventional in the field of organic synthesis reaction, and the molar ratio of the alkali to the compound shown in the formula A is preferably 1-30. The molar ratio of the difluorocarbene precursor to the compound of formula a may be selected as is conventional in the art, preferably from 1 to 4. The reaction temperature may be a temperature which is conventional for such a reaction in the field of organic synthesis, and is preferably-80 to 80 ℃ and more preferably 10 to 60 ℃. The progress of the reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC, HNMR or GC), and is generally determined as the end point of the reaction when the compound of formula A is eliminated. The reaction time is preferably 1 to 8 hours, more preferably 1 to 4 hours.

In a preferred embodiment of the present invention, the reaction of difluorocarbene insertion may be carried out in the presence of a phase transfer catalyst. The phase transfer catalyst may be a phase transfer catalyst conventional for such reactions in the field of organic synthesis, preferably tris (3, 6-dioxaheptyl) amine. The amount of the phase transfer catalyst can be the amount conventionally used in such reactions in the field of organic synthesis, and is generally a catalytic amount, which is generally 1% to 15%, preferably 5%, of the molar amount of the compound represented by formula 2.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

In the present invention, room temperature means 10 to 30 ℃.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

the preparation method is simple and convenient, the benzyl mercaptan is used as a raw material, the N-difluoromethylthiomethylthio phthalimide 3 can be prepared by only two-step reaction, and the preparation method is greatly simplified compared with the prior preparation methods (J.Am.chem.Soc.2015,137 and 10547); in addition, the cost is low, the resource utilization of F-22 is realized, the reaction condition is mild, the reaction conversion rate is high, the yield is high, the purity of the prepared product is good, and the industrial production and commercialization prospect is wide.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1N-Difluoromethylthio-phthalimide 3

1) Preparation of difluoromethyl-substituted benzylthiol 2

The first method,

N-hexane (1500mL) was added to a three-necked flask, placed in a-78 ℃ cold bath with stirring, chlorodifluoromethane (F-22, 750mmol) slowly bubbled in, NaOH (50g, 1250mmol), tris (3, 6-dioxaheptyl) amine (TDA-1, 8.1g, 25mmol) and benzyl mercaptan (62.1g, 500mmol) were added at-78 ℃ and then slowly raised to 60 ℃ to react for 2-4h under dry ice-acetone condensation. The reaction solution was filtered, desolventized under reduced pressure, and subjected to flash silica gel column chromatography to obtain 53g of a pale pink oily liquid with a yield of 61% and a purity of more than 98% as shown by hydrogen chromatography.

The second method,

KOH (168g, 3000mmol), acetonitrile/water (1400mL, 1:1) and benzyl mercaptan (18.6g, 150mmol) were added to a three-necked flask, stirred in a-78 ℃ cold bath, diethyl bromodifluorophosphate (80.1g, 300mmol) was added in one portion, and the mixture was slowly warmed to room temperature for reaction for 4-6 h. The reaction solution is extracted by 2000mL of ether, the water phase is extracted twice by ether, the organic phases are combined, dried by anhydrous sodium sulfate, decompressed and desolventized, and separated by flash silica gel column chromatography to obtain 22.5g of light pink oily liquid, the yield is 86.2 percent, and the purity is more than 98 percent by hydrogen spectrum.

Difluoromethyl-substituted benzylthiol (benzyl (difluoromethyl) sulfone):¹H NMR(400MHz,CDCl₃,293K,TMS)δ7.35(s,2H),7.34(t,J＝1.2Hz,2H),7.27-7.30(m,1H),6.73(t,J＝56.0Hz,1H)；¹⁹F NMR(375MHz,CDCl₃)δ-94.4(d,J＝56.2Hz,2F)；¹³C NMR(125MHz,CDCl₃,293K,TMS)δ136.2,128.9,128.8,127.6,120.2(t,J＝271.2Hz),31.8ppm.

2) preparation of N-difluoromethylthio phthalimide 3

98mLCl is added into a three-neck flask₂/CHCl₃Solution (1.232mol/L, 120mmol), the flask was placed in a-10 ℃ cold bath and stirred, difluoromethyl-substituted benzyl mercaptan 2(20.9g, 120mmol) was added and reacted for 1h (using¹⁹F NMR was monitored and F spectral yield 80%). Potassium phthalimide salt (22.3g, 120mmol) was added rapidly at-10 ℃ in a cold bath, and the reaction was allowed to warm to room temperature for 10 h. The reaction solution was filtered, desolventized under reduced pressure, and separated by flash silica gel column chromatography to obtain 18.9g of a white solid with a yield of 69% and a purity of over 98% by hydrogen chromatography.

N-difluoromethylthiophthalimide (N- (difluoromethylthio) phthalimide):¹H NMR(400MHz,CDCl₃,293K,TMS)δ7.97(dd,J＝4.0,4.0Hz,2H),7.83(dd,J＝4.0,4.0Hz,2H),6.80(t,J＝56.0Hz,1H)ppm；¹⁹F NMR(375MHz,CDCl₃)δ-98.6(d,J＝56.2Hz,2F)ppm；¹³C NMR(100.7MHz,CDCl₃,293K,TMS)δ166.76,135.13,131.69,124.42(t,J＝224.5Hz),118.76ppm.IR(KBr):ν＝3089,3003,1784,1746,1718,1470,1363,1346,1281,1088,1057,1041,868,798,786,714,696,688,572,526,441cm^-1.MS(EI)：m/z(％)229,196,179(100),162,147,130,104,90,76,63,50,39.

the other conditions are the same as above, and the specific data of the reaction of difluoromethyl benzyl mercaptan 2, chlorine and phthalimide potassium salt for 10 hours under different temperatures, solvents and feeding amounts and conditions are shown in the following table.

Example 2N-difluoromethylthio-4-nitrophthalimide 3

98mLCl is added into a three-neck flask₂/CHCl₃Solution (1.232mol/L, 120mmol), placing the flask in a-10 deg.C cold bath, stirring, adding difluoromethyl substituted benzyl mercaptan 2(20.9g, 120mmol), and reacting for 1h (using¹⁹F NMR for monitoring). 4-Nitrophthalimide potassium salt (27.6g, 120mmol) was added rapidly at-10 ℃ in a cold bath and allowed to warm to room temperature for 10 h. The reaction solution was filtered, desolventized under reduced pressure, and separated by flash silica gel column chromatography to obtain 19.7g of a white solid with a yield of 60% and a purity of more than 98% by hydrogen chromatography.

N-difluoromethylthio-4-nitrophthalimide (N- (difluoromethylthio) -4-nitrophthalimide):¹H NMR(400MHz,CDCl₃,293K,TMS)δ8.82(d,J＝5.2Hz,1H),8.74(dd,J＝8.2,1.8Hz,1H),8.24(d,J＝8.2Hz,1H),6.80(t,J＝56.0Hz,1H)ppm；¹⁹F NMR(375MHz,CDCl₃)δ-98.1(d,J＝56.2Hz,2F)ppm；¹³C NMR(100.7MHz,CDCl₃,293K,TMS)δ164.1,163.8,152.5,135.7,132.9,130.5,126.3,124.8(t,J＝224.5Hz),120.2ppm.

example 3N-trifluoromethylthio-o-phthalimide

The method comprises the following steps: CF was bubbled through 1, 2-dichloroethane of potassium phthalimide salt (3.7g, 20mmol) at 0 deg.C₃SCl gas, then reacting the reaction solution for 7h at room temperature (25 ℃) (a reflux condenser tube with the temperature of-20 ℃) is arranged, filtering is carried out after the reaction is finished, and recrystallization is carried out after the filtrate is desolventized, thus obtaining 0.5g of white solid, the yield is 10%, and the purity of hydrogen spectrum display is more than 98%.

The second method comprises the following steps: CF was bubbled through 1, 2-dichloroethane of potassium phthalimide salt (3.7g, 20mmol) at 0 deg.C₃SCl gas, then reacting the reaction solution at 90-100 ℃ for 7h (a reflux condenser tube at-20 ℃ is arranged), cooling to room temperature after the reaction is finished, filtering, and recrystallizing the filtrate after desolventizing to obtain 3.2g of white solid, wherein the yield is 65%, and the purity is more than 98% by hydrogen spectrum.

N- (trifluoromethylthio) phthalimide (N- (trifluoromethylthio) phthalimide):¹H NMR(400MHz,CDCl₃)δ8.00(dd,J＝5.5,3.1Hz,2H),7.87(dd,J＝5.5,3.1Hz,2 H)ppm；¹⁹F NMR(376 MHz,CDCl₃)δ-48.97(s,3 F)ppm；¹³C NMR(101 MHz,CDCl₃)δ166.00,135.40,131.39,127.84(q,J＝316.6 Hz),124.66 ppm。

Claims

1. a preparation method of N-difluoromethylthio o-phenylimide as shown in formula 3, it comprises the following steps: (1) in organic solvent, compound as shown in formula 2 and chlorine are carried out as follows The chlorination reaction shown produces HCF ₂ SCl;

(2) directly add the compound shown in formula 1 to the reaction solution after the reaction in step (1) without post-treatment, and carry out the difluoromethylthiolation reaction as shown below;

In the compound shown in formula 1, M is K; in the compound shown in formula 1 or formula 3, R is hydrogen or nitro;

In step (1), in the preparation method of described difluoromethyl thiochloride, described organic solvent is one or more in halogenated alkane solvent, halogenated aromatic hydrocarbon solvent, nitrile solvent and aromatic hydrocarbon solvent ; Described halogenated alkane solvent is one or more in dichloromethane, trichloromethane, tetrachloromethane and 1,2-dichloroethane;

In step (1), the temperature of described chlorination reaction is -78 ℃-30 ℃;

In step (2), the temperature of the difluoromethylthiolation reaction is -78°C-30°C.

2. preparation method as claimed in claim 1, is characterized in that,

In step (2), the volume-to-mass ratio of the reaction solution and the compound shown in formula 1 is 1mL/g-20mL/g;

And/or, in step (2), the molar ratio of the difluoromethylthio chloride to the compound shown in formula 1 is 0.9:1 to 2:1;

And/or, in step (2), the time of the difluoromethylthiolation reaction is 0.5-24 hours.

3. preparation method as claimed in claim 2, is characterized in that,

In step (2), the volume-to-mass ratio of the reaction solution and the compound shown in formula 1 is 1mL/g-10mL/g;

And/or, in step (2), the molar ratio of the difluoromethylthio chloride to the compound shown in formula 1 is 1:1 to 1.1:1;

And/or, in step (2), the temperature of the difluoromethylthiolation reaction is -20°C-30°C;

And/or, in step (2), the time of the difluoromethylthiolation reaction is 1-10 hours.

4. The preparation method of claim 3, wherein in step (2), the volume-to-mass ratio of the reaction solution to the compound shown in formula 1 is 3mL/g-5mL/g.

5. preparation method as claimed in claim 1 is characterized in that,

In step (1), in the preparation method of described difluoromethylthio chloride, the volume-to-mass ratio of described organic solvent and compound shown in formula 2 is 1.0mL/g-30mL/g;

And/or, in step (1), in the preparation method of described difluoromethyl sulfide chlorine, the mol ratio of described chlorine and the compound shown in formula 2 is 0.9:1-2:1;

And/or, in step (1), in the preparation method of difluoromethylthio chloride, the time of the chlorination reaction is 10 minutes to 6 hours.

6. preparation method as claimed in claim 5 is characterized in that,

In step (1), in the preparation method of described difluoromethyl thiochloride, when described organic solvent is halogenated aromatic hydrocarbon solvent, described halogenated aromatic hydrocarbon solvent is chlorobenzene, dichlorobenzene and trichlorobenzene. One or more of chlorobenzene;

And/or, in the step (1), in the preparation method of difluoromethyl thiochloride, when the organic solvent is a nitrile solvent, the nitrile solvent is acetonitrile;

And/or, in step (1), in the preparation method of described difluoromethyl sulfide, when described organic solvent is aromatic hydrocarbon solvent, described aromatic hydrocarbon solvent is toluene;

And/or, in step (1), in the preparation method of described difluoromethyl thiochloride, the volume mass ratio of described organic solvent and compound shown in formula 2 is 1mL/g-10mL/g;

And/or, in step (1), in the preparation method of described difluoromethyl sulfide chlorine, the mol ratio of described chlorine and the compound shown in formula 2 is 1:1;

And/or, in step (1), in the preparation method of difluoromethylthio chloride, the temperature of the chlorination reaction is -20°C-0°C;

And/or, in step (1), in the preparation method of difluoromethylthio chloride, the time of the chlorination reaction is 0.5 hour to 1.5 hour.

7. preparation method as claimed in claim 6, is characterized in that,

In step (1), in the preparation method of difluoromethylthio chloride, the volume-to-mass ratio of the organic solvent to the compound shown in formula 2 is 4mL/g-8mL/g.

8. preparation method as claimed in claim 1 is characterized in that, the preparation method of described difluoromethyl thiochloride comprises the following steps: mix the organic solution containing chlorine gas with the compound shown in formula 2, carry out the The chlorination reaction described; the temperature of the mixing is -78 ℃-30 ℃.

9. The preparation method according to claim 8, wherein the temperature of the mixing is -20°C-0°C.

10. preparation method as claimed in claim 4, is characterized in that, step (2) comprises the following steps: add the compound shown in formula 1 in the reaction solution after step (1) reaction finishes, carry out described two Fluoromethylthiolation reaction is enough; the temperature of the addition is -78°C-30°C.

11. The preparation method according to claim 10, wherein the temperature of the addition is -20°C-0°C.

12. preparation method as described in any one of claim 1-11, is characterized in that, the preparation method of described N-difluoromethylthio o-phenylimide shown in formula 3, also further comprises following Step: in an organic solvent, under the action of a base, the compound shown in formula A is subjected to the reaction of difluorocarbene insertion as shown below with a difluorocarbene precursor to obtain the compound shown in formula 2. compound;

The difluorocarbene precursor is any of the following compounds: ClCF ₂ H or BrCF ₂ P(O)(OEt) ₂ ,

Described alkali is alkali metal hydroxide;

The organic solvent is water and/or an organic solvent, and the organic solvent is an alkane solvent and/or a nitrile solvent.

13. preparation method as claimed in claim 12, is characterized in that, in the preparation method of described compound shown in formula 2:

The volume-to-mass ratio of the organic solvent and the compound shown in formula A is 25-250mL/g;

And/or, the molar ratio of the base and the compound shown in formula A is 1-30;

And/or, the molar ratio of the difluorocarbene precursor to the compound of formula A is 1-4;

And/or, the temperature of the reaction is -80-80°C.

14. The preparation method of claim 12, wherein the reaction of the difluorocarbene insertion is carried out in the presence of a phase transfer catalyst.

15. The preparation method of claim 14, wherein the transfer catalyst is tris(3,6-dioxeptyl)amine;

And/or, the phase transfer catalyst is 1%-15% of the molar amount of the compound shown in formula 2.

16 . The preparation method according to claim 15 , wherein the phase transfer catalyst is 5% of the molar amount of the compound represented by formula 2. 17 .