CN115701422B - Preparation method of KGP94 - Google Patents

Abstract

The invention provides a preparation method of KGP94, which belongs to the technical field of organic synthesis. The invention starts from common 3-bromobenzoyl chloride, adopts Weinreb amide method to prepare amide compound with structure shown in formula 1, and then utilizes format reagent 3-methoxy phenyl magnesium bromide to couple with amide compound with structure shown in formula 1 to obtain 3-bromo-3' -methoxy-benzophenone. In the present invention, 3-bromo-3' -methoxy-benzophenone is used as an intermediate material and KGP94 is obtained by either a demethylation followed by condensation or a condensation followed by demethylation. The method provided by the invention has the advantages of short synthetic route and high total yield, and the results of examples show that the total yield of the method provided by the invention is 80% or 89%.

Description

A kind of preparation method of KGP94

Technical field

The present invention relates to the technical field of organic synthesis, and in particular to a preparation method of KGP94.

Background technique

KGP94 is a selective, highly active ((IC ₅₀ =131.4μM), low toxicity ((GI ₅₀ =26.9μM)) small molecule inhibitor of cathepsin, which belongs to the substituted benzophenone thiosemicarbazone compounds. KGP94 The treatment of metastatic cancer is currently in preclinical research and attracts much attention.

Currently, there are two main reported synthesis methods of KGP94. The synthesis route of the first method is as follows:

The second method is improved on the basis of the first method. The synthesis route is as follows:

The two reported methods both use cross-coupling reaction as the key step, and finally obtain the target compound through oxidation, condensation, and deprotection. However, they both have the shortcomings of long synthetic routes and low overall yields.

Contents of the invention

In view of this, the purpose of the present invention is to provide a preparation method of KGP94. The preparation method provided by the invention has a short synthesis route and high overall yield.

In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

The invention provides a preparation method of KGP94, which includes the following steps:

(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N,O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with the structure shown in Formula 1:

(2) 3-Methoxyphenylmagnesium bromide is coupled with an amide compound having the structure shown in Formula 1 to obtain 3-bromo-3'-methoxy-benzophenone;

(3) 3-bromo-3'-methoxy-benzophenone is subjected to the first route or the second route to obtain KGP94;

The first route includes: performing a first condensation reaction with thiosemicarbazone and p-toluenesulfonic acid to obtain a compound having the structure shown in Formula 2:

The compound having the structure shown in Formula 2 undergoes a first demethylation reaction with boron tribromide to obtain KGP94;

The second route includes: 3-bromo-3'-methoxy-benzophenone and boron tribromide are subjected to a second demethylation reaction to obtain 3-bromo-3'-hydroxy-benzophenone ;

3-Bromo-3'-hydroxy-benzophenone undergoes a second condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.

Preferably, in the step (1), the molar ratio of the 3-bromobenzoyl chloride to N,O-dimethylhydroxylamine hydrochloride and potassium carbonate is 1:1.5:2.5.

Preferably, the temperature of the nucleophilic substitution reaction is 0-30°C and the time is 5-7 hours.

Preferably, in the step (2), the molar ratio of the 3-methoxyphenyl magnesium bromide to the amide compound having the structure shown in Formula 1 is 1.5 to 2.5:1.

Preferably, the coupling reaction temperature is 0-30°C and the time is 5-7 hours.

Preferably, in the first route, the molar ratio of 3-bromo-3'-methoxy-benzophenone to thiosemicarbazone and p-toluenesulfonic acid is 1:(3~3.5):1;

The temperature of the first condensation reaction is 75-85°C, and the time is 20-24 hours.

Preferably, in the first route, the molar ratio of the compound having the structure shown in Formula 2 to boron tribromide is (0.8~1.2):0.6;

The temperature of the first demethylation reaction is 0-30°C, and the time is 5-7 hours.

Preferably, in the second route, the molar ratio of 3-bromo-3'-methoxy-benzophenone and boron tribromide is 1:0.3~0.5;

The temperature of the second demethylation reaction is 0-30°C, and the time is 5-7 hours.

Preferably, in the second route, the molar ratio of 3-bromo-3'-hydroxy-benzophenone to thiosemicarbazone and p-toluenesulfonic acid is 1:(3~4):(1~1.2);

The temperature of the second condensation reaction is 75-85°C, and the time is 18-24 hours.

The invention provides a preparation method of KGP94, which includes the following steps: (1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo a nucleophilic substitution reaction to obtain The amide compound with the structure shown in Formula 1: (2) 3-methoxyphenyl magnesium bromide and the amide compound with the structure shown in Formula 1 are subjected to a coupling reaction to obtain 3-bromo-3'-methoxy-bis Benzophenone; (3) 3-bromo-3'-methoxy-benzophenone is carried out through the first route or the second route to obtain KGP94; the first route includes: with thiosemicarbazide, p-toluenesulfonic acid The first condensation reaction is performed to obtain a compound with the structure shown in Formula 2: the compound with the structure shown in Formula 2 is subjected to a first demethylation reaction with boron tribromide to obtain KGP94; the second route includes: 3- Bromo-3'-methoxy-benzophenone undergoes a second demethylation reaction with boron tribromide to obtain 3-bromo-3'-hydroxy-benzophenone; 3-bromo-3'-hydroxy -The second condensation reaction of benzophenone with thiosemicarbazide and p-toluenesulfonic acid gives KGP94. The present invention starts from ordinary 3-bromobenzoyl chloride, adopts Weinreb amide method to prepare amide compounds with the structure shown in Formula 1, and then uses Grignard reagent 3-methoxyphenyl magnesium bromide and amide compounds with the structure shown in Formula 1 The amide compound is coupled to obtain 3-bromo-3'-methoxy-benzophenone. In the present invention, 3-bromo-3'-methoxy-benzophenone is used as an intermediate raw material, and KGP94 is obtained by first demethylating and then condensing, or by first condensing and then demethylating. The method provided by the invention has a short synthesis route and high overall yield. The results of the examples show that the overall yield of the method provided by the invention is 80% or 89%.

Description of drawings

Figure 1 shows the synthesis roadmap of KGP94.

Detailed ways

The invention provides a preparation method of KGP94, which includes the following steps:

(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo a nucleophilic substitution reaction to obtain an amide compound with the structure shown in Formula 1:

(2) 3-Methoxyphenylmagnesium bromide is coupled with an amide compound having the structure shown in Formula 1 to obtain 3-bromo-3'-methoxy-benzophenone;

(3) 3-bromo-3'-methoxy-benzophenone is subjected to the first route or the second route to obtain KGP94;

The first route includes: performing a first condensation reaction with thiosemicarbazone and p-toluenesulfonic acid to obtain a compound having the structure shown in Formula 2:

The compound having the structure shown in Formula 2 undergoes a first demethylation reaction with boron tribromide to obtain KGP94;

The second route includes: 3-bromo-3'-methoxy-benzophenone and boron tribromide are subjected to a second demethylation reaction to obtain 3-bromo-3'-hydroxy-benzophenone ;

3-Bromo-3'-hydroxy-benzophenone undergoes a second condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.

In the present invention, unless otherwise specified, all reactions are carried out under an inert atmosphere.

In the present invention, under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound having the structure shown in Formula 1. In the present invention, the solvent used in the nucleophilic substitution reaction is preferably chloroform and water, and the volume ratio of chloroform and water is preferably 1:1.

In the present invention, the molar ratio of the 3-bromobenzoyl chloride to N,O-dimethylhydroxylamine hydrochloride and potassium carbonate is preferably 1:(1～2):(2～3), more preferably 1:1.5:2.5. In the present invention, the temperature of the nucleophilic substitution reaction is preferably 0 to 30°C, and the time is preferably 5 to 7 hours, and more preferably 6 hours.

In the present invention, the nucleophilic substitution reaction is preferably:

Mix potassium carbonate, N,O-dimethylhydroxylamine hydrochloride and a solvent, add 3-bromobenzoyl chloride while stirring at 0°C, and raise the temperature to room temperature to perform a nucleophilic substitution reaction. In the present invention, the reaction time of the nucleophilic substitution reaction is calculated from the temperature rise of 0°C.

After the nucleophilic substitution reaction is completed, the present invention preferably performs post-processing on the obtained nucleophilic substitution reaction solution, and the post-processing preferably includes the following steps:

Dilute the nucleophilic substitution reaction solution with chloroform and water, and separate to obtain the first organic phase;

Extract the aqueous phase with chloroform to obtain a second organic phase, combine the first organic phase and the second organic phase to obtain a combined organic phase;

The combined organic phases are sequentially washed with alkali and dried to obtain an amide compound having the structure shown in Formula 1.

In the present invention, the alkali liquid used in the alkali cleaning is preferably a NaOH solution with a concentration of 6M; in the present invention, the desiccant used in the drying is preferably anhydrous Na ₂ SO ₄ . After said drying, the present invention preferably evaporates the solvent in the solid to dryness in a vacuum.

After obtaining the amide compound with the structure shown in Formula 1, 3-methoxyphenyl magnesium bromide and the amide compound with the structure shown in Formula 1 are coupled to obtain 3-bromo-3'-methoxy -Benzophenone. In the present invention, the organic solvent used in the coupling reaction is preferably one or more of tetrahydrofuran, toluene, diethylene glycol, 2-methacrolein and cyclopentyl methyl ether. In the present invention, the molar ratio of the 3-methoxyphenyl magnesium bromide to the amide compound having the structure shown in Formula 1 is preferably 1.5 to 2.5:1, more preferably 2:1, and the coupling reaction The temperature is preferably 0 to 30°C, and the time is preferably 5 to 7 hours, more preferably 6 hours.

In the present invention, the coupling reaction is preferably:

Mix 3-methoxyphenylmagnesium bromide with the amide compound having the structure shown in Formula 1 and an organic solvent, and heat the mixture from 0°C to room temperature to perform a coupling reaction. In the present invention, the reaction time of the coupling reaction is calculated from the time when the temperature rises to 0°C.

After the coupling reaction is completed, the present invention preferably performs post-treatment on the obtained coupling reaction liquid. In the present invention, the post-treatment preferably includes the following steps:

The coupling reaction solution was quenched, extracted with an organic solvent, washed and dried in order to obtain pure 3-bromo-3'-methoxy-benzophenone.

In the present invention, it is preferred to use ice water for the quenching. In the present invention, the organic solvent used in the extraction is preferably ethyl acetate. In the present invention, after the extraction, the aqueous phase is preferably extracted again with ethyl acetate and the organic phases are combined. In the present invention, the detergent for washing is preferably brine. In the present invention, the desiccant used for drying is preferably anhydrous Na ₂ SO ₄ .

After obtaining the 3-bromo-3'-methoxy-benzophenone, in the first route, 3-bromo-3'-methoxy-benzophenone is carried out with thiosemicarbazone and p-toluenesulfonic acid. The first condensation reaction yields a compound having the structure shown in Formula 2.

In the present invention, the molar ratio of the 3-bromo-3'-methoxy-benzophenone to thiosemicarbazone and p-toluenesulfonic acid is preferably 1:3.5:1. In the present invention, the organic solvent used in the first condensation reaction is preferably one or more of absolute ethanol, methanol and tetrahydrofuran. In the present invention, the temperature of the first condensation reaction is preferably 75-85°C, more preferably 80°C, and the time is preferably 20-24h, more preferably 22h.

After the first condensation reaction, the present invention preferably performs post-treatment on the obtained first condensation reaction liquid, and the post-treatment preferably includes the following steps:

The organic solvent in the first condensation reaction solution is evaporated, the remaining residue is diluted with water, and extraction, washing, drying, concentration and column chromatography are performed sequentially to obtain a pure compound having the structure shown in Formula 2.

In the present invention, the organic solvent used in the extraction is preferably ethyl acetate. In the present invention, after the extraction, the aqueous phase is preferably extracted again with ethyl acetate and the organic phases are combined. In the present invention, the detergent for washing is preferably a NaHCO ₃ solution, and the desiccant used for drying is preferably anhydrous Na ₂ SO ₄ . The present invention has no special requirements for the concentration method, and any concentration method well known to those skilled in the art can be used.

In the present invention, the mobile phase used in the column chromatography is preferably petroleum ether:ethyl acetate, and the volume ratio of petroleum ether:ethyl acetate is preferably 20:3.5-5.0.

After obtaining the compound having the structure represented by Formula 2, the compound having the structure represented by Formula 2 is subjected to a first demethylation reaction with boron tribromide to obtain KGP94. In the present invention, the organic solvent used in the first demethylation reaction is preferably dichloromethane and/or chloroform. In the present invention, the molar ratio of the compound having the structure shown in Formula 2 to boron tribromide is preferably 0.8-1.2:0.6, more preferably 1:0.6. In the present invention, the temperature of the first demethylation reaction is preferably 0 to 30°C, and the time is preferably 5 to 7 hours, and more preferably 6 hours.

In the present invention, the first demethylation reaction is preferably:

The compound having the structure shown in Formula 2 and the organic solvent are mixed at 0°C, boron tribromide is added, the temperature is raised to room temperature, and the first demethylation reaction is performed. In the present invention, the reaction time of the first demethylation reaction is calculated from the time when the temperature is raised to 0°C.

After the first demethylation reaction, the present invention preferably performs post-processing on the obtained first demethylation reaction liquid, and the post-processing preferably includes the following steps:

The first demethylation reaction solution is sequentially quenched, extracted with an organic solvent, washed, dried, concentrated and column chromatographed to obtain pure 3-bromo-3'-methoxy-benzophenone.

In the present invention, it is preferred to use ice water for the quenching. In the present invention, the organic solvent used in the extraction is preferably methylene chloride. After the extraction, the present invention preferably uses dichloromethane to extract the obtained aqueous phase again, and combine the organic phases. In the present invention, the detergent for washing is preferably NaHCO ₃ solution and brine solution, and the desiccant used for drying is preferably anhydrous Na ₂ SO ₄ . The present invention has no special requirements for the concentration method, and any concentration method well known to those skilled in the art can be used.

In the present invention, the mobile phase used in the column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether and ethyl acetate is preferably 20:5-6.

After obtaining the 3-bromo-3'-methoxy-benzophenone, in the second route, 3-bromo-3'-methoxy-benzophenone and boron tribromide undergo the second demethylation Kylation reaction gives 3-bromo-3'-hydroxy-benzophenone;

3-Bromo-3'-hydroxy-benzophenone undergoes a second condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.

In the present invention, the organic solvent used in the second demethylation is preferably dichloromethane and/or chloroform. In the present invention, the molar ratio of 3-bromo-3'-methoxy-benzophenone and boron tribromide is preferably 1:0.3-0.5, more preferably 1:0.4. In the present invention, the temperature of the second demethylation reaction is preferably 0 to 30°C, and the time is preferably 5 to 7 hours, and more preferably 6 hours.

In the present invention, the second demethylation reaction is preferably:

Mix 3-bromo-3'-methoxy-benzophenone and an organic solvent at 0°C, add boron tribromide, raise the temperature to room temperature, and perform the first demethylation reaction. In the present invention, the reaction time of the second demethylation reaction is calculated from the temperature rise of 0°C.

After the second demethylation reaction, the present invention preferably performs post-processing on the obtained second demethylation reaction liquid. The post-processing method is preferably the same as the post-processing method of the first demethylation reaction liquid. I won’t go into details here.

After obtaining the 3-bromo-3'-hydroxy-benzophenone, 3-bromo-3'-hydroxy-benzophenone is subjected to a second condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94. In the present invention, the organic solvent used in the second condensation reaction is preferably absolute ethanol. In the present invention, the molar ratio of the 3-bromo-3'-hydroxy-benzophenone to thiosemicarbazone and p-toluenesulfonic acid is preferably 1:(3~4):(1~1.2), more preferably is 1:3.5:1. In the present invention, the temperature of the second condensation reaction is preferably 75-85°C, more preferably 80°C, and the time is preferably 18-24h, more preferably 20h.

In the present invention, after the second condensation reaction, the present invention preferably performs post-treatment on the obtained second condensation reaction liquid. The post-treatment method is preferably the same as the post-treatment method of the first condensation reaction liquid, which will not be repeated here. Repeat.

In the present invention, the synthetic route diagram of KGP94 is shown in Figure 1.

The preparation method of KGP94 provided by the present invention will be described in detail below with reference to the examples, but they should not be understood as limiting the protection scope of the present invention.

In the following examples, unless otherwise stated, all reactions were carried out under an inert atmosphere.

The hydrogen nuclear magnetic resonance spectrum (1H-NMR) was measured at 400MHz with a ruker Avance 400 spectrometer, and the carbon nuclear magnetic resonance spectrum (13C-NMR) was measured at 100MHz. Residual acetone (δ2.05; 206.6, 29.9), chloroform (δ7.24; 77.2) and dimethyl sulfoxide (δ2.50; 39.5) are used as internal references for the solvent peaks of hydrogen and carbon spectra, and tetramethylsilane (TMS ) as the internal standard, the peak shape indicates: s (single peak), d (double peak), t (triple peak), q (quadruple peak), dd (double doublet), ddd (triple doublet), m ( double peak), brs (broad single peak). The coupling constant is expressed as J (unit: Hz), and the chemical shift is expressed as δ (unit: ppm). High-resolution mass spectrometry was detected by Agilent 6540q-TOF (electrospray ionization, ESI-TOF) mass spectrometer. Column chromatography uses 200 to 300 mesh silica gel. Thin layer chromatography uses HSGF254 silica gel plate, and UV light (254nm) or potassium permanganate is used for color development.

Example 1

(1) Preparation of amide compounds having the structure shown in Formula 1

Dissolve N,O-dimethylhydroxylamine hydrochloride (2.053g, 21.051mmol, 1.5eq., 98%) and potassium carbonate (4.849g, 35.086mmol, 2.5eq., 99%) in chloroform (15.0mL) and water (15.0 mL), add 3-bromobenzoyl chloride 3 (3.080g, 14.034mmol, 1.0eq., 97%) dropwise with stirring at 0°C, and gradually warm to room temperature after 10 minutes, continue Stir the reaction. After 6 hours, dilute the reaction solution with chloroform and water, separate the organic phase, further extract the aqueous phase with chloroform, combine the organic phases, wash with 6M NaOH solution, separate the organic phase, and dry over anhydrous Na ₂ SO ₄ . After the solvent was evaporated to dryness in a vacuum, the Weinreb amide compound (3.392g, yield 99%) with the structure shown in Formula 1 was obtained as a colorless liquid.

¹ H-NMR (400MHz, CDCl ₃ ) δ7.74 (s, 1H, Ar-H), 7.54-7.49 (m, 2H, 2xAr-H), 7.20 (t, J＝7.8Hz, 1H, Ar-H ),3.47(s,3H,OCH ₃ ),3.27(s,3H,NCH ₃ ); ¹³ C-NMR(100MHz,CDCl ₃ )δ168.1(C＝O),135.9(C),133.5(CH) ,131.2(CH),129.6(CH),126.7(CH),122.0(C),61.2(OCH ₃ ),33.5(NCH ₃ ); HRMS(ESI)calcd.for C ₉ H ₁₀ BrNO ₂ [M+H ] ⁺ 243.9968,found 243.9969.

The reaction process is shown in formula A:

(2) Preparation of 3-bromo-3'-methoxy-benzophenone

Under argon protection at 0°C, 3-methoxyphenylmagnesium bromide (1.0M, 28mL, 27.793mmol, 2.0eq., 98% tetrahydrofuran solution) was added to the mixture, stirred, degassed and dissolved. The solution of the amide compound (3.392g, 13.896mmol, 1.0eq.) in dry tetrahydrofuran was stirred at 0°C for 30 minutes and then gradually raised to room temperature to continue stirring the reaction. After 4 hours, the reaction was quenched with ice water, extracted with ethyl acetate, and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate, the organic phases were combined, then washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated, and column chromatographed ( Petroleum ether: ethyl acetate, gradient 20:0.5 to 20:1.5) was purified to obtain a light yellow product, which was 3-bromo-3'-methoxy-benzophenone (3.860g, yield 95%).

¹ H-NMR (400MHz, CDCl ₃ ) δ7.85 (s, 1H, Ar-H), 7.64-7.62 (dd, J = 6.2, 1.5Hz, 2H, 2xAr-H), 7.33-7.22 (m, 4H , 4xAr-H), 7.08-7.06 (dd, J=6.0, 1.8Hz, 1H, Ar-H), 3.78 (s, 3H, OCH ₃ ); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 194.9 ( C＝O),159.6(C),139.5(C),138.1(C),135.2(CH),132.7(CH),129.8(CH),129.4(CH),128.5(CH),122.8(C), 122.5(CH),119.3(CH),114.2(CH),55.5(OCH ₃ ); HRMS(ESI)calcd.for C ₁₄ H ₁₁ BrO ₂ [M+H] ⁺ 291.0015, found 291.0017.

The reaction process is shown in formula B:

(3) Preparation of compounds having the structure shown in Formula 2

3-Bromo-3'-methoxy-benzophenone (1.000g, 3.434mmol, 1.0eq.), thiosemicarbazide (1.095g, 12.021mmol, 3.5eq., 99%) and p-toluenesulfonic acid Monohydrate (0.653, 3.434 mmol, 1.0 eq., 98%) was dissolved in absolute ethanol (45 mL), and the reaction was heated to reflux at 80°C for 22 hours. After the reaction was completed, the ethanol was evaporated in vacuo. Then the residue was diluted with water, extracted with ethyl acetate, the organic phase was separated, the aqueous phase was further extracted with ethyl acetate, the organic phases were combined, washed with NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ , concentrated, and column chromatography (petroleum ether: Purification (ethyl acetate, gradient, petroleum ether:ethyl acetate, gradient, 20:3.5 to 20:5.0) gave the product as white crystals (1.239 g, yield 99%).

¹ H-NMR (400MHz, (CD ₃ ) ₂ CO) δ8.57(brs,1H,NH),8.23(brs,1H,NH),7.97(s,1H,Ar-H),7.78(brs,1H ,NH),7.63-7.56(3H,m,Ar-H),7.31(t,J＝7.9Hz,1H,Ar-H),7.19(dd,J＝8.4,1.9Hz,1H,Ar-H) ,6.96-6.94(m,2H,Ar-H)3.88(s,3H,OCH ₃ ); ¹³ C-NMR(100MHz,(CD ₃ ) ₂ CO)δ180.4(C=S),161.7(C) ,148.3(C＝N),139.8(C),133.3(CH),133.1(C),132.2(CH),131.1(CH),130.5(CH),127.6(CH),123.1(C),121.0( CH),116.7(CH),114.5(CH),55.9(OCH ₃ ); HRMS(ESI)calcd.for C ₁₅ H ₁₄ BrN ₃ OS[M+H] ⁺ 364.0114,found 364.0119.

The reaction process is shown in formula C:

(4) Preparation of KGP94

The compound with the structure shown in Formula 2 (0.500g, 1.372mmol, 1.0eq.) was dissolved in anhydrous dichloromethane (15mL) and cooled to 0°C, and then boron tribromide (1.0M, 0.8 mL, 0.6eq., 99.9% methylene chloride solution), gradually returned to room temperature and continued to stir the reaction. After 6 hours, the reaction solution was quenched with ice water, the organic phase was separated by extraction with dichloromethane, the aqueous phase was further extracted with dichloromethane, the organic phases were combined, washed with NaHCO ₃ solution and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate, gradient 20:5.0 to 20:6.0) gave a white solid product, which was KGP94 (0.461g, yield 96%), E:Z=4.5:1.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.98(s,1H,OH),8.68(brs,1H,NH),8.55(brs,1H,NH),8.42(brs,1H,NH), 8.05(s,1H,Ar-H),7.57(ddd,J＝7.7,1.95,1.0Hz,1H,Ar-H),7.78-7.44(m,2H,2x Ar-H),7.31(t,J ＝7.9Hz,1H,Ar-H),7.02(dd,J＝6.5,1.7Hz,1H,Ar-H),6.73-6.71(m,1H,Ar-H),6.66-6.65(m,1H, Ar-H). ¹³ C-NMR (100MHz, DMSO-d ₆ ,) δ177.8(C＝S), 158.5(C), 147.3(C＝N), 138.5(C), 132.3(CH), 131.6 (C),131.3(CH),130.4(CH),129.3(CH),126.9(CH),122.1(C),118.3(CH),117.2(CH),114.5(CH); HRMS(ESI)calcd. forC ₁₄ H ₁₂ BrN ₃ OS[M+H]+349.9957,found 349.9964.

The reaction process is shown in formula D:

The imine (C=N) double bond of KGP94 is mainly in the E configuration in solution. This configuration is determined by combining ROESY (Rotating-Frame Overhauser Spectroscopy), HMBC (Heteronuclear Multiple Bond Correlation) and COSY (Correlation Spectroscopy) spectra. . In the ROESY spectrum, NH (δ8.42) is significantly correlated with C-H (δ6.73) and C-H (δ6.66); in the HMB spectrum, NH (δ8.42) is strongly correlated with C=S (177.8) ( 2J (strong)), weakly correlated with C=N (147.3) (3J (weak)); in the COSY spectrum, two protons of NHaHb (δ8.68, 8.55) can be found respectively. The E and Z configurations of KGP94 and its analog compound 2 can quickly convert into each other and cannot be separated separately. The E:Z ratio is determined by integrating the characteristic signals of two isomeric protons in the 1H-NMR spectrum of the purified mixture. Sure.

Example 2

The amide compound having the structure shown in Formula 1 and 3-bromo-3'-methoxy-benzophenone were prepared in the same manner as in Example 1.

(1) Preparation of 3-bromo-3'-hydroxy-benzophenone

Dissolve 3-bromo-3'-methoxy-benzophenone (2.860g, 9.823mmol, 1.0eq.) in anhydrous dichloromethane (40mL) solution, and add boron tribromide ( 1.0M, 4.2mL, 0.4eq., 99.9% dichloromethane solution), stir the reaction at room temperature for 6 hours, slowly transfer the mixture to ice water, and then extract with dichloromethane, separate the organic phase, and further extract with dichloromethane The aqueous phase was combined with the organic phase, washed with NaHCO ₃ solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated, and purified by column chromatography (petroleum ether: ethyl acetate, gradient 20:2.0 to 20:4.0) to obtain white The solid product was 3-bromo-3'-hydroxy-benzophenone (2.391 g, yield 88%).

¹ H-NMR (400MHz, CDCl ₃ ) δ7.84 (brs, 1H, Ar-H), 7.61 (dd, J＝6.7, 1.1Hz, 2H, 2x Ar-H), 7.26 (t, J＝7.9Hz ,3H,3x Ar-H),7.20(d,J＝7.7Hz,1H,Ar-H),7.05(dd,J＝7.9,1.7Hz,1H,Ar-H),6.43(brs,1H,OH ), ¹³ C-NMR (100MHz, CDCl ₃ ) δ194.7(C＝O),155.1(C),138.1(C),137.0(C),134.5(CH),131.8(CH),128.8(CH) ,128.7(CH),127.6(CH),121.8(CH),121.5(C),119.5(CH),115.4(CH); HRMS(ESI)calcd.for C ₁₃ H ₉ BrO ₂ [M+H] ⁺ 276.9859,found276.9860.

The reaction process is shown in Formula E:

(2) Preparation of KGP94

3-Bromo-3'-hydroxy-benzophenone (2.391g, 8.628mmol, 1.0eq.), thiosemicarbazide (2.751g, 30.198mmol, 3.5eq., 99%) and p-toluenesulfonic acid monohydrate The compound (1.6411g, 8.628mmol, 1.0eq., 98%) was dissolved in absolute ethanol (60.0mL). After ultrasonic treatment for 10 minutes, the reaction was refluxed at 80°C under argon protection for 20 hours. After the reaction was completed, the ethanol was removed under reduced pressure, and the residual liquid was extracted with ethyl acetate, and the aqueous phase was further extracted, the organic phases were combined, washed with NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ , concentrated, and column chromatographed (petroleum ether : Ethyl acetate, gradient, 20:4.0 to 20:6.0) was purified to obtain a white solid product (2.930g, yield 97%), E:Z=4.5:1.

¹ H-NMR (400MHz, (CD ₃ ) ₂ CO) δ8.93(brs,1H,OH),8.61(brs,1H,NH),8.24(brs,1H,NH),7.97(s,1H,Ar -H),7.78(brs,1H,NH),7.58-7.50(3H,m,Ar-H),7.31(t,J＝7.7Hz,1H,Ar-H),7.10(d,J＝7.5Hz ,1H,Ar-H),6.85-6.83(m,2H,Ar-H); ¹³ C-NMR(100MHz,(CD ₃ ) ₂ CO)δ180.4(C=S),159.5(C),148.5 (C＝N),139.9(C),133.3(CH),133.1(C),132.3(CH),131.1(CH),130.6(CH),127.7(CH),123.1(C),120.0(CH) ,118.3(CH),115.8(CH);HRMS(ESI)calcd.for C ₁₄ H ₁₂ BrN ₃ OS[M+H] ⁺ 349.9957,found 349.9963.

The reaction process is shown in Formula F:

The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.

Claims (9)

1. A process for the preparation of KGP94 comprising the steps of:

(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1:

(2) Performing a coupling reaction on 3-methoxy phenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;

(3) 3-bromo-3' -methoxy-benzophenone to obtain KGP94;

the first route includes: carrying out a first condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain a compound with a structure shown in a formula 2:

carrying out a first demethylation reaction on a compound with a structure shown in a formula 2 and boron tribromide to obtain KGP94;

the second route includes: carrying out a second demethylation reaction on the 3-bromo-3 '-methoxy-benzophenone and boron tribromide to obtain 3-bromo-3' -hydroxy-benzophenone;

and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.

2. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the 3-bromobenzoyl chloride to the N, O-dimethylhydroxylamine hydrochloride to the potassium carbonate is 1 (1-2): 2-3.

3. The method according to claim 1, wherein the nucleophilic substitution reaction is carried out at a temperature of 0 to 30 ℃ for a time of 5 to 7 hours.

4. The method according to claim 1, wherein in the step (2), the molar ratio of the 3-methoxyphenylmagnesium bromide to the amide compound having the structure represented by formula 1 is 1.5 to 2.5:1.

5. the preparation method according to claim 1, wherein the coupling reaction is carried out at a temperature of 0 to 30 ℃ for a time of 5 to 7 hours.

6. The preparation method according to claim 1, wherein in the first route, the molar ratio of 3-bromo-3' -methoxy-benzophenone to thiosemicarbazide to p-toluenesulfonic acid is 1 (3-3.5): 1;

the temperature of the first condensation reaction is 75-85 ℃ and the time is 20-24 h.

7. The method according to claim 1, wherein in the first route, the molar ratio of the compound having the structure represented by formula 2 to boron tribromide is (0.8 to 1.2): 0.6;

the temperature of the first demethylation reaction is 0-30 ℃ and the time is 5-7 h.

8. The method of claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -methoxy-benzophenone to boron tribromide is 1:0.3-0.5;

the temperature of the second demethylation reaction is 0-30 ℃ and the time is 5-7 h.

9. The preparation method according to claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -hydroxy-benzophenone to thiosemicarbazide to p-toluenesulfonic acid is 1 (3-4): 1-1.2;

the temperature of the second condensation reaction is 75-85 ℃ and the time is 18-24 h.