CN115583898A - A kind of preparation method of aryl isothiocyanate - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of aryl isothiocyanate. The aryl bromide and the cyanation reagent are used as raw materials to carry out cyanation reaction, aryl nitrile is obtained through a one-step method, and then aryl isothiocyanate is generated through reaction with a non-thiophosgene reagent. The preparation process of the invention does not need protection of acetyl protecting group, thus reducing reaction steps and greatly improving atom economy and total reaction yield; and a technical scheme for preparing aryl isothiocyanate by removing thiophosgene is provided in the reaction process, so that the method is more environment-friendly and is suitable for industrial large-scale production.

Description

A kind of preparation method of aryl isothiocyanate

technical field

The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of aryl isothiocyanate.

Background technique

Aryl isothiocyanate is a class of important pharmaceutical intermediates, widely used in the preparation of androgen receptor antagonists of thiohydantoin structure, such as enzalutamide (Enzalutamide), apalutamide ( Apalutamide) and Pruxelutamide.

The compound of formula A is an intermediate for preparing Pruxelutamide, and the applicant has disclosed its preparation method in CN103608333B, and the synthetic route is as follows:

In the reaction scheme, compound 11 is used as a raw material to generate the compound of formula A through multi-step reactions. When preparing compound 15, the corresponding amino group must be protected with acetyl group, followed by cyanation and deprotection. Finally, compound 15 reacted with thiophosgene to generate the target product.

The above route has the following defects: 1) the amino group needs to be protected and deprotected during the reaction, and the reaction steps are tedious, resulting in a lower overall yield (compound 11 recorded in the section [0483]-[0493] of the description is passed through bromination, amino The total yield of compound 15 obtained by the four-step reaction of protection, cyanation and deprotection is 75%×85%×80%×90%=45.9%), and the atom economy is poor; 2) Thiophosgene is not friendly to the environment, Not conducive to production scale-up.

The results of clinical trials show that proxalutamide (Pruxelutamide) can be used to treat COVID-19, so it is necessary to overcome the defects in the prior art and provide a route suitable for industrial production to prepare the intermediate isothiocyanate of proxalutamide Acid aryl ester compound, namely formula A compound.

Contents of the invention

The problem to be solved by the invention

In order to solve the problems in the prior art, the present invention provides a kind of method for preparing aryl isothiocyanate, the present invention adopts one-step method to carry out cyanation reaction, does not need to protect amino group; And proposed in the reaction process Eliminate the technical scheme of preparing aryl isothiocyanate from thiophosgene, and the environment is more friendly.

solutions to problems

According to the first aspect of the present invention, the present invention provides a method for preparing compound 15, said method comprising the reaction of compound 12 to generate compound 15 in the presence of a solvent and a cyanation reagent, the reaction equation is as follows:

Preferably, the solvent is a polar organic solvent; the polar organic solvent is selected from any one or more combinations of nitriles, sulfoxides, chain amides or cyclic amides, preferably N, A combination of any one or more of N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone, more preferably N,N-dimethyl base formamide.

Preferably, the cyanation agent is selected from any of KCN, NaCN, CuCN, Zn(CN) ₂ , Ni(CN) ₂ , K ₄ [Fe(CN) ₆ ] or K ₃ [Fe(CN) ₆ ] One, more preferably CuCN.

Preferably, the solvent is N,N-dimethylformamide, and the cyanation agent is CuCN.

Preferably, the method includes adding compound 12 dropwise into a system of a solvent (preferably N,N-dimethylformamide) and a cyanation agent (preferably CuCN), and heating up the reaction after the dropwise addition.

Preferably, the system temperature is controlled during the dropping process; more preferably, the system temperature is 10-50°C, preferably 10-40°C or 15-35°C, further preferably 20-30°C.

Preferably, the molar amount of the cyanation reagent is 1.0-1.5 times that of compound 12, preferably 1.1, 1.2, 1.3 or 1.4 times, more preferably 1.1 times.

Preferably, the reaction temperature is 110-140°C, preferably 110-130°C, more preferably 120-130°C.

Preferably, the method further includes a post-treatment step, and the post-treatment step includes: adding an organic phase solvent and an aqueous phase solvent to the reaction system, extracting, washing, and concentrating the organic phase to obtain the product. Preferably, the organic phase solvent is chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is water.

Preferably, the post-processing step includes: adding an organic phase solvent and an aqueous phase solvent to the reaction system, extracting, washing, concentrating the organic phase, and beating to obtain the product. Preferably, the organic phase solvent is a chlorinated hydrocarbon, preferably dichloromethane; the aqueous phase solvent is ammonia water; and the beating is done using alkanes, preferably n-heptane.

Compound 15 can be obtained from compound 12 through one-step reaction by adjusting the order of addition, method of addition, dropwise addition temperature, and reaction temperature in this step reaction, and the yield of this step reaction is greatly improved. Moreover, the inventor optimized the post-processing steps, and adopted the extraction and beating process by adding ammonia water, so that the purity of the product was also greatly improved under the premise of ensuring a high yield.

Further, in the method for preparing compound 15, the preparation method of compound 12 comprises: reacting compound 11 in the presence of an organic solvent and a brominating reagent to generate compound 12, and the reaction equation is as follows:

Preferably, the organic solvent is any one or a combination of chain or cyclic amides, preferably one or more of N,N-dimethylformamide or N,N-dimethylacetamide A combination of the two, more preferably N,N-dimethylformamide.

Preferably, the bromination reagent is N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBH), 3,5-dibromobenzaldehyde (DBBA), N-bromophthalimide (NBP) or 1,3,5-tribromo-1,3,5-triazine-2,4,6-trione (TBCA).

Preferably, the method comprises adding a bromination reagent (preferably NBS) or a system of a bromination reagent and an organic solvent (preferably a system of NBS and N,N-dimethylformamide) to compound 11 and an organic solvent (preferably N,N-dimethylformamide) system, after the dropwise addition, the temperature rises to react.

Preferably, the temperature of the system is controlled during the dropwise addition; more preferably, the temperature of the system is -5-5°C, further preferably 0°C (for example, an ice bath).

Preferably, the method further includes a post-treatment step, and the post-treatment step includes: adding an aqueous solution of a quencher and an organic phase solvent to the reaction system, extracting, and concentrating the organic phase to obtain the product. Preferably, the quenching agent is bisulfite, preferably sodium bisulfite; the organic phase solvent is ester, preferably ethyl acetate.

However, in CN103608333B, the dropping process of this step reaction is not temperature-controlled, and is carried out at room temperature, and the final yield of this step reaction is only 75%. Moreover, the post-treatment step is to add diethyl ether for dilution, and then wash with brine, which does not quench the excess NBS. If the cyanation reaction is carried out directly without purifying compound 12, the excess NBS may remain in the cyanation reaction. affect the yield in the reaction.

Further, the specific steps of the method for preparing compound 15 are:

Add N,N-dimethylformamide and compound 11 to the reaction flask, stir to dissolve, add NBS N,N-dimethylformamide solution dropwise under ice bath conditions, and naturally warm up to room temperature after the addition; After the reaction was completed, an aqueous solution of sodium bisulfite was added dropwise, extracted with ethyl acetate, the organic phase was collected and concentrated under reduced pressure to obtain compound 12;

Add CuCN and N,N-dimethylformamide to the reaction flask, stir, add the compound 12 obtained in the above steps into the reaction flask dropwise, control the temperature of the system and the time of dropping, and raise the temperature to react after the addition; Cool down to room temperature, add ammonia solution and dichloromethane, stir, extract, collect the dichloromethane layer, wash the dichloromethane layer with saturated brine, collect the organic layer, and concentrate to obtain a crude product, which is beaten with n-heptane to obtain compound 15;

Preferably, the parameters such as reaction temperature, reaction time, and molar ratio of reagents in the above specific steps are as defined in the aforementioned methods for preparing compound 12 and compound 15.

According to the second aspect of the present invention, the present invention provides a method for preparing the compound represented by formula A, the method comprising: reacting compound 15 with a non-thiophosgene reagent in a solvent or a non-solvent to generate the compound represented by formula A , the reaction equation is:

Preferably, the compound 15 can be prepared by the method described in the first aspect.

Preferably, the non-thiophosgene reagent is any one of N,N'-thiocarbonyldiimidazole, carbon disulfide, N,N-dimethylthiocarbamoyl chloride or phenyl thiochloroformate.

According to the third aspect of the present invention, the present invention provides another method for preparing the compound shown in formula A, said method comprising reacting compound 12 in the presence of a solvent and a cyanation reagent to generate compound 15, compound 15 and non- Thiophosgene reagent reacts under solvent or non-solvent to generate the compound shown in formula A, and the reaction equation is as follows:

Preferably, the compound 15 can be prepared by the method in the first aspect.

Preferably, the non-thiophosgene reagent refers to N,N'-thiocarbonyldiimidazole, carbon disulfide, N,N-dimethylthiocarbamoyl chloride or phenylthiochloroformate, and the reaction equation is as follows:

In addition, the applicant found in the previous research that by controlling the reaction conditions, compound 15 and non-thiophosgene reagents can generate a new ring-closing product: the compound shown in formula I or the compound shown in formula II. Therefore, the present invention also provides the use of compound 15 in preparing the compound shown in formula I or the compound shown in formula II, wherein the compound 15 is prepared by the method described in the first aspect.

Using compound 15 as a raw material and N,N'-thiocarbonyldiimidazole as a reagent, react in a reaction system of an organic base and an organic solvent to generate a compound shown in formula I. The reaction equation is as follows:

Preferably, the compound 15 can be prepared by the method described in the first aspect.

Preferably, the organic base is a nitrogen-containing organic base; preferably, the nitrogen-containing organic base is N,N-diisopropylethylamine (DIPEA), N,N-diisopropylaniline, 4-di Any one or more of methylaminopyridine (DMAP), lutidine, imidazole, triethylamine or pyridine, preferably triethylamine and/or DMAP.

Preferably, the organic solvent is halogenated hydrocarbon, aromatic hydrocarbon, C2-C6 nitrile, preferably toluene and/or acetonitrile.

Preferably, the molar amount of N,N'-thiocarbonyldiimidazole is 1-3 times, preferably 2 times, that of compound 15.

Preferably, the molar amount of the organic base is 0.1-5 times, preferably 3 times, that of compound 15.

Preferably, the reaction temperature is from 0°C to below the boiling point, preferably from 40°C to below the boiling point, such as 50-90°C, 50-80°C, 60-70°C or 80-90°C.

Similarly, compound 15 is used as a raw material, and carbon disulfide is used as a reagent to react under the reaction system of an organic base and an organic solvent to generate a compound shown in formula II, and the reaction equation is as follows:

Preferably, the compound 15 can be prepared by the method described in the first aspect.

Preferably, the organic base is triethylamine, pyridine, N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]nonane -5-ene (DBN), 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), N-methylmorpholine , tetramethylethylenediamine or a mixture thereof, more preferably triethylenediamine.

Preferably, the organic solvent is an alkyl ketone, preferably the alkyl ketone is acetone, butanone or methyl isobutyl ketone, preferably acetone.

Preferably, the molar ratio of carbon disulfide to compound 15 is 1-3 times, such as 1.2, 1.5 or 2.0 times, more preferably 1.2 times.

Preferably, the molar ratio of the organic base to compound 15 is 0.1-1 times, more preferably 0.2-0.8 times (eg 0.2, 0.4, 0.6, 0.8), further preferably 0.4-0.5 times.

The compound shown in the above formula I or the compound shown in the formula II can be used as the impurity produced in the preparation process of the compound shown in the formula A for the quality control of the target product of the compound shown in the formula A, and monitor the compound shown in the formula I or the formula II in the target product The content of the indicated compounds was used to evaluate the quality of the target product. Therefore, the present invention also provides the application of the compound represented by the above formula I or the compound represented by the formula II or the preparation method thereof in the product quality control of the compound represented by the formula A.

According to a fourth aspect of the present invention, the present invention provides another method for preparing the compound shown in formula A, said method comprising the steps of:

Wherein, P is an amino protecting group;

1) compound 15 generates compound 15-1 in the presence of thiocyanate and amino protecting agent;

Preferably, the compound 15 can be prepared by the method described in the first aspect;

Preferably, the thiocyanate is any one of ammonium thiocyanate, sodium thiocyanate, potassium thiocyanate, magnesium thiocyanate or manganese thiocyanate, preferably ammonium thiocyanate;

Preferably, the amino-protecting group is any one of alkoxycarbonyl, acyl or alkyl; further, the alkoxycarbonyl in the amino-protecting group may be substituted or unsubstituted, and the substituent It can be an aryl group, an alkenyl group or an alkylsilyl group; the alkyl group in the amino protecting group can be substituted or unsubstituted by a substituent, and the substituent can be an aryl group or an aryl group substituted by an alkoxy group; Furthermore, the alkoxycarbonyl group is any one of benzyloxycarbonyl Cbz, tert-butoxycarbonyl Boc, fluorenylmethoxycarbonyl Fmoc, allyloxycarbonyl Alloc or trimethylsilylethoxycarbonyl Teoc; the acyl group is Any one of phthaloyl Pht, p-toluenesulfonyl Tos, trifluoroacetyl Tfa or benzoyl Bz, preferably benzoyl Bz; the alkyl group is trityl Trt, 2,4- Any one of dimethoxybenzyl Dmb, p-methoxybenzyl Pmb or benzyl Bn;

2) Compound 15-1 removes the amino protecting group to generate compound 15-2;

Those skilled in the art can use different deprotecting group systems according to different protecting groups; preferably, compound 15-1 can remove the amino protecting group in a system of base and solvent; the base is an inorganic base, preferably a base Metal hydroxide, more preferably sodium hydroxide or potassium hydroxide; The solvent is an alcoholic solvent, preferably methanol, ethanol or isopropanol, etc.;

3) Compound 15-2 removes ammonia to generate a compound of formula A;

Ammonia can be removed by heating in high-boiling organic solvents, such as toluene, xylene, chlorinated benzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone to remove ammonia; it is also possible to add acid salts (sodium bisulfate, potassium bisulfate, sodium bisulfite, potassium bisulfite, dihydrogen phosphate in a mixed system of organic solvent and water) One or more of sodium, potassium dihydrogen phosphate, sodium hydrogen oxalate, potassium hydrogen oxalate, etc.) catalytic reaction to remove ammonia.

According to a fifth aspect of the present invention, the present invention provides another method for preparing the compound shown in formula A, the method comprising: reacting compound 12 in the presence of a solvent and a cyanation reagent to generate compound 15, and compound 15 is passed through The method described in the fourth aspect generates the compound shown in formula A, and the reaction equation is as follows:

Wherein, P is an amino protecting group.

Preferably, the compound 15 can be prepared by the method in the first aspect.

The effect of the invention

Compared with prior art, the present invention has following advantage:

1) The present invention uses compound 12 as a raw material, adopts a direct cyanation method, and prepares compound 15 through a one-step reaction; the protection of the acyl protecting group is removed, the reaction steps are reduced, and the atom economy is greatly improved; According to the conditions such as feeding order, feeding method, feeding temperature, reaction temperature and post-treatment in the two-step reaction of alkylation, the total yield of reaction can reach 80%, which is far higher than the total yield in CN103608333B (bromo, acyl protection, The total yield of cyanation and deprotection four-step reaction is 45.9%); especially the post-treatment of cyanation reaction has adopted the steps of ammonia water extraction washing and n-heptane thermal beating, which removes a large amount of impurities and ensures high yield Under the premise, the product purity has also been greatly improved.

2) The present invention uses reagents such as N,N'-thiocarbonyldiimidazole, carbon disulfide, N,N-dimethylthiocarbamoyl chloride, phenyl thiochloroformate or thiocyanate to prepare the compound of formula A, replacing Thiophosgene solves the disadvantages of thiophosgene that pollutes the environment and is not conducive to production scale-up. At the same time, the present invention also provides a new ring-closing product that compound 15 can form with reagents such as N,N'-thiocarbonyldiimidazole or carbon disulfide under specific reaction conditions. The ring-closing product or its preparation method can be applied to In the quality control of formula A compound product.

Description of drawings

Figure 1 is the HPLC spectrum of the compound prepared in Example 1 of the present invention.

Figure 2 is the LC-MS spectrum of the compound prepared in Example 2 of the present invention.

Figure 3 is the H NMR spectrum of the compound prepared in Example 2 of the present invention.

Figure 4 is the LC-MS spectrum of the compound prepared in Example 3 of the present invention.

detailed description

"Compound of formula A", "compound shown in formula A" or "aryl isothiocyanate compound shown in formula A" in the present invention all refer to the compound with the following structure, which is Proxelutamide (Pruxelutamide) intermediates.

The invention can be further understood by the examples, however, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described herein and claimed below.

The HPLC detection method of compound 15 is as follows:

Chromatographic column: C18, 150×4.6mm; column temperature: 25°C; flow rate: 1.0mL/min; injection volume: 5μL;

Detection wavelength: 220nm;

Mobile phase: binary mobile phase system: mobile phase A is 0.02V% acetic acid aqueous solution; mobile phase B is acetonitrile;

Elution mode: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 90%, and the minimum volume percentage is 0%).

The preparation of embodiment 1 compound 15

Add 60ml of the organic solvent N,N-dimethylformamide and 12g of the compound of formula 11 into the reaction flask, stir to dissolve, and add 40ml of NBS N,N-dimethylformamide solution dropwise under ice bath conditions (NBS is the formula 11 1.05 times the molar weight of the compound), naturally warmed up to room temperature after the dropwise addition, and reacted for 16-24h; after the reaction was finished, aqueous sodium bisulfite solution was added dropwise to quench excess NBS, extracted with ethyl acetate (3 × 60ml), and the organic phase, concentrated under reduced pressure to obtain compound 12 as an oil.

Add CuCN (1.1 times the molar amount of the compound of formula 11) and 50ml of N,N-dimethylformamide into the reaction flask, stir, and drop all the compound 12 obtained in the above steps into the reaction flask at 20-30°C, Control the dropwise addition time for 1-2h. After the dropwise addition, raise the temperature to 120-130°C for 6-8h; Chloromethane layer, then wash the dichloromethane layer with saturated brine, collect the organic layer, concentrate until no distillate is evaporated to obtain a crude product, which is stirred and beaten with 60ml of n-heptane at 40-50°C for 6-8h, then filtered, Dry to obtain 10.8g of compound 15 (the HPLC area normalization method measures its purity to be 99.5%, and the retention time is 8.39min, and the HPLC collection is shown in Figure 1), and the yield is 80.0% (calculated based on the compound 11 charging amount, and the compound 15 Purity is calculated as 100%).

The applicant did not optimize the post-treatment in the early stage. During the post-treatment process, dichloromethane and water were added, extracted and concentrated. The purity of the product obtained was only 83.3%, and the yield was basically the same as the above method. Therefore, post-treatment using ammonia water combined with n-heptane beating can significantly improve product purity with less product loss.

Example 2

Add compound 15 (1.0g, 4.9mmol), N,N'-thiocarbonyldiimidazole (1.75g, 9.8mmol), 10ml of toluene and triethylamine (1.49g, 14.7mmol) into the reaction flask, stir to dissolve, and raise the temperature Reaction at 80°C for 6h, sampling by TLC monitoring, the reaction was complete, stop heating, and cool down to room temperature.

Toluene was removed by rotary evaporation, and column purification (PE:EA=2:1, R _f =0.2-0.3) was used to obtain the compound represented by formula I (1.13g), with a yield of 73.4%.

LC-MS: m/z 295.05[M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d6): δ8.73(s, 1H), 8.41(d, J＝8.4Hz, 1H), 8.30(d, J＝8.4Hz, 1H), 8.12(s, 1H) ,7.28(s,1H).

Example 3

Add compound 15 (2.0g, 10mmol), carbon disulfide (0.91g, 12mmol), 20ml of acetone and 0.5ml of triethylenediamine (0.45 times the molar amount of compound 15) into the reaction flask, stir to dissolve, and heat up to 40-50 After reacting at ℃ for 6-8h, sampling TLC monitoring, the reaction is complete, stop heating, and cool down to room temperature.

Acetone was removed by rotary evaporation, and column purification (PE:EA=2:1, R _f =0.2-0.3) was used to obtain the compound represented by formula II.

LC-MS: m/z 258.92 [M-1] ^- .

Example 4

Compounds of formula A, wherein P is benzoyl, are prepared as above. The specific steps are:

1) Compound 15 was reacted in the presence of ammonium thiocyanate and benzoyl chloride, and post-treated to obtain compound 15-1;

2) Compound 15-1 removes the benzoyl group with sodium hydroxide as the base and methanol as the solvent, followed by post-treatment to obtain Compound 15-2;

3) Compound 15-2 is heated in a solvent system of chlorobenzene to remove ammonia to generate the target compound of formula A.

Claims (12)

1. A method for preparing compound 15, said method comprising: compound 12 reacts to generate compound 15 in the presence of solvent and cyanation reagent,

2. The method according to claim 1, characterized in that: The solvent is a polar organic solvent, and the polar organic solvent is preferably a combination of any one or more of nitriles, sulfoxides, chain amides or cyclic amides, more preferably N,N- Any one or more combinations of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone; The cyanation reagent is selected from any one of KCN, NaCN, CuCN, Zn(CN) ₂ , Ni(CN) ₂ , K ₄ [Fe(CN) ₆ ] or K ₃ [Fe(CN) ₆ ]. 3. The method according to claim 2, characterized in that: The solvent is N,N-dimethylformamide, and the cyanation reagent is CuCN. 4. The method according to any one of claims 1-3, characterized in that: The method comprises: adding the compound 12 dropwise into the system of the solvent and the cyanation reagent, and raising the temperature to react after the dropping; Preferably, the temperature of the system is controlled during the dropping process; More preferably, the temperature of the system is 10-50°C, further preferably 20-30°C. 5. The method according to claim 4, characterized in that: The molar amount of the cyanation reagent is 1.0-1.5 times that of the compound 12, preferably 1.1, 1.2, 1.3 or 1.4 times, more preferably 1.1 times; Preferably, the reaction temperature is 110-140°C, more preferably 120-130°C. 6. The method according to claim 4 or 5, characterized in that: The method also includes a post-treatment step, which includes: adding an organic phase solvent and an aqueous phase solvent to the reaction system, extracting, washing, and concentrating the organic phase to obtain; preferably, the organic phase solvent It is a chlorinated hydrocarbon, preferably methylene chloride; the aqueous phase solvent is water; Preferably, the step of post-processing includes: adding an organic phase solvent and an aqueous phase solvent to the reaction system, extracting, washing, concentrating the organic phase, beating, and obtaining that product; preferably, the organic phase solvent is a chlorinated hydrocarbon, Dichloromethane is preferred; the aqueous phase solvent is ammonia water; the beating is accomplished with alkanes, preferably n-heptane. 7. The method of claim 1, wherein: The preparation method of the compound 12 comprises: reacting the compound 11 to generate the compound 12 in the presence of an organic solvent and a brominating reagent,

Preferably, the organic solvent is any one or a combination of chain or cyclic amides, preferably one or more of N,N-dimethylformamide or N,N-dimethylacetamide a combination of the two; Preferably, the bromination reagent is NBS, DBH, DBBA, NBP or TBCA; More preferably, the organic solvent is N,N-dimethylformamide, and the bromination reagent is NBS; Preferably, the method comprises: adding the bromination reagent or the system of the bromination reagent and the organic solvent dropwise to the system of the compound 11 and the organic solvent, and heating up the reaction after the dropwise addition; Preferably, the temperature of the system is controlled during the dropping process; more preferably, the temperature of the system is -5 to 5°C, further preferably 0°C. 8. The method according to claims 1-7, characterized in that: The concrete steps of described method are: Add N,N-dimethylformamide and compound 11 to the reaction flask, stir to dissolve, add NBS N,N-dimethylformamide solution dropwise under ice bath conditions, and naturally warm up to room temperature after the addition; After the reaction was completed, aqueous sodium bisulfite solution was added dropwise, extracted with ethyl acetate, the organic phase was collected and concentrated under reduced pressure to obtain compound 12; Add CuCN and N,N-dimethylformamide to the reaction flask, stir, add the compound 12 obtained in the above steps into the reaction flask dropwise, control the time and temperature of the dropwise addition, and raise the temperature to react after the dropwise addition; Cool down to room temperature, add ammonia and dichloromethane, stir, extract, collect the dichloromethane layer, wash the dichloromethane layer with saturated brine, collect the organic layer, and concentrate to obtain a crude product, which is beaten with n-heptane to obtain compound 15. 9. A method for preparing an aryl isothiocyanate compound shown in formula A, comprising the steps of:

Wherein, P is an amino protecting group; 1) Compound 15 generates compound 15-1 in the presence of thiocyanate and amino protecting agent; preferably, said compound 15 is prepared by the method according to any one of claims 1-8; 2) Compound 15-1 removes the amino protecting group to generate compound 15-2; 3) Compound 15-2 removes ammonia to generate a compound of formula A; Preferably, the thiocyanate is any one of ammonium thiocyanate, sodium thiocyanate, potassium thiocyanate, magnesium thiocyanate or manganese thiocyanate, more preferably ammonium thiocyanate; Preferably, the amino protecting group is any one of alkoxycarbonyl, acyl or alkyl; further preferably, the alkoxycarbonyl is benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxy Any one of carbonyl or trimethylsilylethoxycarbonyl; said acyl is any one of phthaloyl, p-toluenesulfonyl, trifluoroacetyl or benzoyl, more preferably benzoyl; said The alkyl group is any one of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl. 10. A method for preparing an aryl isothiocyanate compound shown in formula A, said method comprising: compound 12 reacts to generate compound 15 in the presence of a solvent and a cyanation reagent, and compound 15 passes through according to claim 9 Described method generates the compound shown in formula A,

Preferably, the compound 15 is prepared by the method according to any one of claims 1-8. 11. The use of compound 15 in the preparation of compounds having the structure shown in formula I or formula II, wherein the compound 15 is prepared by the method according to any one of claims 1-8:

12. A method for preparing a compound shown in formula II, said method comprising: using compound 15 as a raw material, taking carbon disulfide as a reagent, reacting to generate a compound shown in formula II in the presence of an organic base and an organic solvent,

Preferably, the compound 15 is prepared by the method according to any one of claims 1-8; Preferably, the organic base is triethylamine, pyridine, N,N-diisopropylethylamine, triethylenediamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1 , At least one of 8-diazabispiro[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, more preferably Triethylenediamine; Preferably, the organic solvent is an alkyl ketone, more preferably acetone, butanone or methyl isobutyl ketone, more preferably acetone; Preferably, the molar amount of carbon disulfide is 1-3 times that of compound 15, more preferably 1.2, 1.5 or 2.0 times, further preferably 1.2 times; Preferably, the molar amount of the organic base is 0.1-1 times that of the compound 15, more preferably 0.2-0.8 times, further preferably 0.4-0.5 times.

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