Preparation method of chloroprocaine hydrochloride

Abstract

The invention discloses a preparation method of chloroprocaine hydrochloride, and belongs to the technical field of chloroprocaine hydrochloride synthesis. Comprising the following steps: (1) preparing 4-amino-2-chlorobenzoic acid: dissolving 2-chloro-4-nitrobenzoic acid in a solvent, and uniformly stirring; adding a ruthenium catalyst Ru / SNC into the system, and carrying out heat preservation reaction in a hydrogen atmosphere; the 4-amino-2-chlorobenzoic acid is obtained through a reaction; (2) preparation of chloroprocaine hydrochloride: dissolving 4-amino-2-chlorobenzoic acid, 2-chloroethyl diethylamine and a solid base catalyst K / r-GO in a reaction solvent, and carrying out an esterification reaction; the 2-(diethylamino)-2-chlorine-4-nitrobenzoic acid ethyl ester is obtained; and then salifying and drying to obtain the chloroprocaine hydrochloride. The catalyst provided by the invention realizes efficient catalytic reaction at lower temperature and pressure, can be recycled for dozens of times, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing chloroprocaine hydrochloride, and belongs to the technical field of chloroprocaine hydrochloride synthesis. Background Art

[0002] Chloroprocaine hydrochloride, its chemical name is 2-(diethylamino)-4-amino-2-chlorobenzoic acid ethyl ester hydrochloride, the molecular formula is C 13 H 19 C1N 2 O 2 , the structural formula is as follows:

[0003]

[0004] Chloroprocaine hydrochloride is a procaine structure with a chlorine atom introduced into it. It is a commonly used ester local anesthetic in clinical practice, mainly used for infiltration anesthesia, obstetric block anesthesia, sacral and epidural anesthesia, etc.

[0005] Regarding the synthesis of chloroprocaine hydrochloride, many synthetic routes have been reported at home and abroad, which can be roughly divided into two categories: reduction first and then esterification, and esterification first and then reduction.

[0006] There are three synthetic routes of reduction followed by esterification: (1) 2-chloro-4-nitrobenzoic acid is reduced to obtain 2-chloro-4-amino-benzoic acid, which is chlorinated with thionyl chloride and then refluxed with diethylaminoethanol to obtain chloroprocaine, which is then acidified with hydrochloric acid to obtain chloroprocaine hydrochloride; (2) Direct esterification method: 2-chloro-4-amino-benzoic acid and diethylaminoethanol are mixed in a ratio of 2:5, heated to 80-85°C for condensation reaction to obtain chloroprocaine, which is then acidified with hydrochloric acid to obtain chloroprocaine hydrochloride; (3) Ester exchange method: 2-chloro-4-aminobenzoic acid methyl ester and diethylaminoethanol are used as raw materials, the generated methanol and excess diethylaminoethanol are evaporated to obtain chloroprocaine, and finally salified with hydrochloric acid to obtain chloroprocaine hydrochloride.

[0007] The route of esterification followed by reduction is: first react 2-chloro-4-nitrobenzoic acid with dichlorothionyl, and then react with diethylaminoethanol to form an ester; or 2-chloro-4-nitrobenzoic acid is directly reacted with diethylaminoethanol to form an ester, and xylene is used to carry water during the reaction to improve the reaction efficiency. Subsequently, the nitro group is reduced to an amino group by chemical method or catalytic hydrogenation method, and finally salified with hydrochloric acid to obtain chloroprocaine hydrochloride.

[0008] Daria Sokolova et al. used 4-nitrobenzoyl chloride and diethylaminoethylamine as raw materials, carried out amidation at room temperature, and then used carbon black-supported hydrogenase to catalyze hydrogenation to synthesize procainamide Nat Commun 15, 7297 (2024).

[0009] Patent CN 105968019 A introduces a method for preparing chloroprocaine hydrochloride, which uses 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine as raw materials, prepares 2-(diethylamino)-2-chloro-4-nitrobenzoic acid ethyl ester aqueous solution under the catalysis of solid-supported liquid acid, then adds ammonium chloride and iron powder to the solution, and post-processes to obtain chloroprocaine hydrochloride with a yield of more than 99%. Patent CN105968019A introduces the use of solid-supported liquid acid or weakly acidic metal salt as a catalyst to catalyze the esterification reaction of o-chloro-p-nitrobenzoic acid and 2-diethylaminoethanol, and then reduces nitrochlorocaine by iron powder to obtain chloroprocaine. The invention has a short direct esterification reaction time, a high total yield of finished products, and low energy consumption. There is less organic solvent residue, which is more suitable for industrial production applications, but it uses iron powder to reduce the nitro group, and there are many purification and post-processing steps.

[0010] Patent CN118108616A introduces the synthesis of nitrochlorocaine by esterification of 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine in the presence of a new solid acid catalyst, followed by the use of hydrogen in the presence of a new supported platinum catalyst to obtain chloroprocaine, and finally salification to obtain chloroprocaine hydrochloride. This invention improves the reaction yield and reduces the reaction cost, and is more suitable for large-scale industrial production. The use of hydrogen catalytic hydrogenation reduces the problems of post-reaction treatment and waste liquid and solid waste, but the cost of the supported platinum catalyst and the reaction conditions of catalytic hydrogenation are still relatively high. Summary of the invention

[0011] The invention provides a method for synthesizing chloroprocaine hydrochloride at relatively low cost and under low reaction conditions.

[0012] The technical solution adopted by the present invention is as follows:

[0013] A method for preparing chloroprocaine hydrochloride, characterized in that it comprises the following steps:

[0014] (1) Preparation of 4-amino-2-chlorobenzoic acid

[0015] Dissolve 2-chloro-4-nitrobenzoic acid in a solvent and stir evenly; add a ruthenium catalyst Ru / SNC into the system and keep warm for reaction under a hydrogen atmosphere; after the reaction is completed, remove the ruthenium catalyst Ru / SNC by centrifugation, and concentrate and dry to obtain 4-amino-2-chlorobenzoic acid;

[0016] (2) Preparation of Chloroprocaine Hydrochloride

[0017] 4-amino-2-chlorobenzoic acid, 2-chloroethyldiethylamine and solid base catalyst K / r-GO are dissolved in a reaction solvent to carry out an esterification reaction; after the reaction is completed, the solid base catalyst K / r-GO is removed by centrifugation, and then the organic solvent is removed and dried to obtain 2-(diethylamino)-2-chloro-4-nitrobenzoic acid ethyl ester; the dried 2-(diethylamino)-4-amino-2-chlorobenzoic acid ethyl ester is dissolved in a hydrochloric acid solution, salified and dried to obtain chloroprocaine hydrochloride.

[0018] Further settings are as follows:

[0019] In step (1):

[0020] The reaction temperature is preferably 40-80°C and the reaction time is 4-10 hours.

[0021] The solvent is any one of ethanol, acetonitrile, tetrahydrofuran and ethanol aqueous solution. Preferably, the solvent is ethanol. The amount of the solvent added is to control the concentration of the reaction solution to be 10-100 g / L, preferably the concentration of the reaction solution is 40-50 g / L.

[0022] The amount of the ruthenium catalyst Ru / SNC is 1-10wt% of 2-chloro-4-nitrobenzoic acid, and preferably the amount of the catalyst is 5-10wt%.

[0023] The ruthenium catalyst Ru / SNC is prepared by the following method: ruthenium acetylacetonate and zinc nitrate are dissolved in methanol to obtain solution A, 2-methylimidazole is dissolved in methanol to obtain solution B, then solution A is added to solution B, and 3-mercaptopropionic acid is dropped into the solution under stirring, and then a high-pressure hydrothermal reaction is carried out at 100-150° C. for 2-6 hours, and after natural cooling, the solution is centrifuged and washed for several times, and vacuum dried, and then the solid is ground into fine powder, which is placed in a tubular furnace with an inert gas flow, and calcined at 800-950° C. for 1-4 hours, and the novel ruthenium catalyst Ru / SNC is obtained after the temperature is lowered.

[0024] In the preparation of the ruthenium catalyst Ru / SNC, the molar ratio of 2-methylimidazole to zinc nitrate can be 4-6 times, preferably 4-5 times, and the mass ratio of zinc nitrate to the precursor ruthenium acetylacetonate can be 10-50 times, preferably 20-30 times.

[0025] In step (1), the ruthenium catalyst Ru / SNC is removed by centrifugation, washed with ethanol and water for several times, dried and then added back into the reaction. The catalyst can be recycled for 5-6 times.

[0026] In step (2):

[0027] The reaction conditions of the esterification reaction are 60-80° C. for 8-20 h, preferably 70-80° C. for 8-12 h.

[0028] The solvent for the esterification reaction is any one of organic solvents such as acetonitrile, dimethylformamide, ethylene glycol dimethyl ether, dichloromethane, etc. Preferably, the amount of the organic solvent added is to control the concentration of the reaction liquid to be 1-200 g / L, preferably 50-100 g / L.

[0029] The solid base catalyst is used in an amount of 10-50 wt % of 4-amino-2-chlorobenzoic acid, preferably 20-30 wt %.

[0030] The solid base catalyst K / r-GO is prepared by a wet impregnation method: first, a thermal reduction method is used to synthesize reduced graphene oxide, and graphene oxide (GO) is calcined at 500-1000° C. for 1-5 h to obtain reduced graphene oxide (r-GO); KNO 3 The method comprises the steps of dissolving the reduced graphene oxide in deionized water, and then adding ethanol, adding the reduced graphene oxide to the solution, and ultrasonicating the reduced graphene oxide to ensure that the reduced graphene oxide is uniformly dispersed in the mixed solution; then stirring the suspension at 60° C. for 12 hours, and then removing the solvent in vacuo to obtain a solid mixture; drying the obtained solid at 60-100° C. for 12-36 hours, and then grinding the dried solid into fine powder, and calcining the powder at 700-900° C. for 1-4 hours in a tubular furnace with an inert gas flow, and obtaining the solid base catalyst K / r-GO after cooling.

[0031] In the preparation of the solid base catalyst, the mass ratio of the graphene to the precursor sodium nitrate is 5-25 times, preferably 10-15 times.

[0032] The calcination under inert gas is carried out by selecting the inert gas from any one of nitrogen, argon and helium, preferably nitrogen or argon. The calcination conditions are as follows: calcination temperature is 800°C, time is 3h, and inert gas flow rate is 50-75mL / min.

[0033] The beneficial effects of the present invention are:

[0034] (1) The present invention provides a method for preparing chloroprocaine hydrochloride, which comprises the following steps: efficiently reducing 2-chloro-4-nitrobenzoic acid to synthesize 4-amino-2-chlorobenzoic acid under the catalysis of a homemade ruthenium catalyst Ru / SNC, then synthesizing chloroprocaine from 4-amino-2-chlorobenzoic acid and 2-chloroethyldiethylamine under the catalysis of a homemade solid base catalyst, and finally acidifying with hydrochloric acid to obtain chloroprocaine hydrochloride.

[0035] Experiments have shown that this new type of ruthenium catalyst introduces sulfur to coordinate with the metal, regulates the electrons of the metal Ru, and achieves H 2The heterolytic activation on the catalyst enables the catalyst to achieve efficient catalytic reaction at lower temperature and pressure. On the other hand, since sulfur and nitrogen are introduced into the catalyst to form strong coordination with metal ruthenium, the metal leaching and agglomeration of the catalyst are greatly reduced, so that it can be recycled and reused dozens of times with the catalyst activity basically unchanged, which is of great significance for reducing reaction costs and being suitable for large-scale industrial production.

[0036] The following drawings and embodiments will enable those skilled in the art to more fully understand the present invention, but will not limit the present invention in any way. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 XRD patterns of the novel ruthenium catalyst Ru / SNC(A) prepared in the examples of the present invention, its precursor Ru / S-ZIF-8 and the ZIF-8 of the control group.

[0038] Figure 2 The solid base catalysts K / r-GO (A) and KNO prepared in the present invention are 3 / r-GO, XRD patterns of graphene oxide (GO) and reduced graphene oxide (r-GO).

[0039] Figure 3 This is the NMR spectrum of 2-chloro-4-nitrobenzoic acid prepared in the embodiment of the present invention.

[0040] Figure 4 This is the NMR spectrum of chloroprocaine hydrochloride prepared in the embodiment of the present invention. DETAILED DESCRIPTION

[0041] The following examples are helpful to further understand the present invention, but the contents of the present invention are not limited thereto.

[0042] The ruthenium catalyst and the solid base catalyst used in the present invention are prepared by the following methods:

[0043] Preparation of ruthenium catalyst:

[0044] 0.05 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 30 μL of 3-mercaptopropionic acid was dropped under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120°C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950°C for 2 h. After cooling, the ruthenium catalyst Ru / SNC (A) was obtained.

[0045] Catalyst structure confirmation:

[0046] Figure 1 The XRD patterns of the novel ruthenium catalyst Ru / SNC(A) prepared in the examples of the present invention, its precursor Ru / S-ZIF-8 and the control group ZIF-8 are shown. Comparison with the standard card of ZIF-8 shows that the zeolite structure of ZIF-8 is successfully synthesized, and the introduction of Ru and sulfur source does not affect the self-assembly of ZIF-8. In addition, after calcining Ru / S-ZIF-8, its structure is destroyed to form a porous nitrogen-doped carbon structure, which is more conducive to catalytic reaction. The XRD pattern of Ru / SNC(A) can only find some weak diffraction peaks of graphite carbon (near 20-25°), which is different from the XRD pattern of ZIF-8. Figure 2 The diffraction peaks of reduced graphene oxide have certain similarities, indicating that its degree of graphitization is high, which makes the catalytic performance of the catalyst excellent, and no diffraction peaks of metal Ru are found, indicating that the metal Ru in the catalyst has good dispersion.

[0047] According to the preparation method of the above-mentioned ruthenium catalyst, the difference lies in: changing the sulfur source, the amount of precursor, the temperature of calcination and hydrothermal reaction, etc., to obtain ruthenium catalysts Ru / SNC(B), Ru / SNC(C), Ru / SNC(D), Ru / SNC(E), Ru / SNC(F), Ru / SNC(G) respectively.

[0048] 0.05 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 0.01 g of thioacetamide was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120 ° C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950 ° C for 2 h. After cooling, the ruthenium catalyst Ru / SNC (B) was obtained.

[0049] 0.05 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2 O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 0.01 g of thiourea was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120 ° C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950 ° C for 2 h. After cooling, the ruthenium catalyst Ru / SNC(C) was obtained.

[0050] 0.1 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2 O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 50 μL of 3-mercaptopropionic acid was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120°C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950°C for 2 h. After cooling, the ruthenium catalyst Ru / SNC(D) was obtained.

[0051] 0.025 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 20 μL of 3-mercaptopropionic acid was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120°C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950°C for 2 h. After cooling, the ruthenium catalyst Ru / SNC(E) was obtained.

[0052] 0.05 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2 O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 30 μL of 3-mercaptopropionic acid was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 100 ° C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 950 ° C for 2 h. After cooling, the ruthenium catalyst Ru / SNC(F) was obtained.

[0053] 0.05 g of ruthenium acetylacetonate (Ru(acac) 3 ) and 1.07 g of Zn(NO 3 ) 2 6H 2 O was dissolved in 15 mL of methanol to obtain solution A, 1.3 g of 2-methylimidazole was dissolved in methanol to obtain solution B, then solution A was added to solution B, and 30 μL of 3-mercaptopropionic acid was added under vigorous stirring, and then stirring was continued for 10 min. After stirring, it was transferred to a high-pressure hydrothermal reactor, hydrothermally reacted at 120°C for 4 h, cooled naturally, centrifuged and washed several times, and vacuum dried. The dried solid was then ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 800°C for 2 h. After cooling, the ruthenium catalyst Ru / SNC(G) was obtained.

[0054] Preparation of solid base catalyst:

[0055] First, reduced graphene oxide (r-GO) was synthesized by thermal reduction method, that is, graphene oxide (GO) was placed in a tube furnace with argon gas flow and calcined at 500 °C for 2 h to obtain reduced graphene oxide (r-GO). 3Dissolve in 15 mL of deionized water, then add 15 mL of ethanol, then add 0.3 g of reduced graphene oxide to the solution, and ultrasonicate for 20 min to ensure that the reduced graphene oxide is evenly dispersed in the mixed solution. Then keep the suspension at 60 ° C and stir for 12 h. After stirring, remove the solvent under vacuum to obtain a solid mixture (KNO 3 / r-GO). The obtained solid was dried at 80°C for 12 hours, and then the dried solid was ground into fine powder and calcined at 800°C for 3 hours in a tube furnace with argon gas flow. After cooling, the solid base catalyst K / r-GO (A) was obtained.

[0056] Solid base catalyst structure confirmation:

[0057] Figure 2 The solid base catalysts K / r-GO (A) and KNO prepared in the present invention are 3 XRD patterns of / r-GO, graphene oxide (GO) and reduced graphene oxide (r-GO). Figure 2 It can be seen that the XRD diffraction peaks of reduced graphene oxide obtained by thermal reduction of graphene oxide are quite different from those of graphene oxide, indicating that the thermal reduction process was successful and reduced graphene oxide was successfully prepared. 3 No other obvious diffraction peaks were found in the XRD pattern of / r-GO, indicating that potassium and its precursors have good dispersion.

[0058] According to the preparation method of the solid base catalyst, adjust KNO 3 The dosages of K / r-GO(B), K / r-GO(C) and K / r-GO(D) were obtained respectively:

[0059] First, reduced graphene oxide (r-GO) was synthesized by thermal reduction method, that is, graphene oxide (GO) was placed in a tube furnace with argon gas flow and calcined at 500 °C for 2 h to obtain reduced graphene oxide (r-GO). 3 Dissolve in 15 mL of deionized water, then add 15 mL of ethanol, then add 0.3 g of reduced graphene oxide to the solution, and ultrasonicate for 20 minutes to ensure that the reduced graphene oxide is evenly dispersed in the mixed solution. Then keep the suspension stirring at 60 ° C for 12 hours, and remove the solvent under vacuum after stirring to obtain a solid mixture. The obtained solid is dried at 80 ° C for 12 hours, and then the dried solid is ground into fine powder and placed in a tubular furnace with argon gas flow and calcined at 800 ° C for 3 hours. After cooling, the solid base catalyst K / r-GO (B) is obtained.

[0060] First, reduced graphene oxide (r-GO) was synthesized by thermal reduction method, that is, graphene oxide (GO) was placed in a tube furnace with argon gas flow and calcined at 500 °C for 2 h to obtain reduced graphene oxide (r-GO). 3 Dissolve in 15 mL of deionized water, then add 15 mL of ethanol, then add 0.3 g of reduced graphene oxide to the solution, and ultrasonicate for 20 minutes to ensure that the reduced graphene oxide is evenly dispersed in the mixed solution. Then keep the suspension stirring at 60 ° C for 12 hours, and remove the solvent under vacuum after stirring to obtain a solid mixture. The obtained solid is dried at 80 ° C for 12 hours, and then the dried solid is ground into fine powder and placed in a tubular furnace with argon gas flow and calcined at 800 ° C for 3 hours. After cooling, the solid base catalyst K / r-GO (C) is obtained.

[0061] First, reduced graphene oxide (r-GO) was synthesized by thermal reduction method, that is, graphene oxide (GO) was placed in a tube furnace with argon gas flow and calcined at 500 °C for 2 h to obtain reduced graphene oxide (r-GO). 3 Dissolve in 15 mL of deionized water, then add 15 mL of ethanol, then add 0.3 g of reduced graphene oxide to the solution, and ultrasonicate for 20 minutes to ensure that the reduced graphene oxide is evenly dispersed in the mixed solution. Then keep the suspension stirring at 60 ° C for 12 hours, and remove the solvent under vacuum after stirring to obtain a solid mixture. The obtained solid is dried at 80 ° C for 12 hours, and then the dried solid is ground into fine powder and placed in a tubular furnace with argon gas flow and calcined at 800 ° C for 3 hours. After cooling, the solid base catalyst K / r-GO (D) is obtained.

[0062] Example 1: Preparation of 4-amino-2-chlorobenzoic acid

[0063] The Ru / SNC(A), Ru / SNC(B), Ru / SNC(C), Ru / SNC(D), Ru / SNC(E), Ru / SNC(F) and Ru / SNC(G) prepared above were used for the preparation of 4-amino-2-chlorobenzoic acid to test the effect of different loaded ruthenium catalysts on the catalytic performance. The specific steps are as follows:

[0064] 1g of 2-chloro-4-nitrobenzoic acid was added to the reactor, 15mL of methanol was added, and then 0.05g of the ruthenium catalyst Ru / SNC prepared above was added to the system. The air in the reactor was replaced 5 times under argon atmosphere, and the argon in the reactor was replaced with hydrogen five times. Then 0.5MPa of hydrogen was filled and reacted at 50°C for 8h. After the reaction, the catalyst was removed by centrifugation, and 4-amino-2-chlorobenzoic acid was obtained after concentration and drying. The yield was determined by nuclear magnetic resonance.

[0065] Table 1 is a comparison of the loading amounts of ruthenium catalysts prepared in different embodiments and their catalytic performance results. From the inductively coupled plasma spectroscopy (ICP-AES) test data in Table 1, it can be seen that the ruthenium catalysts Ru / SNC prepared in different embodiments have a certain influence on the catalytic performance of the new supported ruthenium catalyst from aspects such as the sulfur source, the amount of precursor, and the temperature of calcination and hydrothermal reaction.

[0066] Table 1

[0067] catalyst S content / wt% Ru content / wt% Conversion rate / % Selectivity / % Ru / SNC(A) 0.35 1.03 99 98 Ru / SNC(B) 0.31 1.09 95 97 Ru / SNC(C) 0.27 1.05 93 98 Ru / SNC(D) 0.76 1.97 99 80 Ru / SNC(E) 0.21 0.56 89 98 Ru / SNC(F) 0.28 0.83 92 97 Ru / SNC(G) 0.33 1.07 73 84 .

[0068] analyze:

[0069] 1. By changing the proportion of metal Ru in the catalyst, the new ruthenium catalyst obtained has obvious differences in catalytic performance. We found that when the Ru content is 1.03wt%, the catalytic performance of the catalyst is better, and a higher conversion rate and less dechlorination side reaction can be achieved.

[0070] 2. By changing the sulfur source used in preparing the catalyst, the new ruthenium catalyst obtained has certain differences in catalytic performance, and we found that the catalytic performance is better when mercaptopropionic acid is used as the sulfur source.

[0071] 3. When the solvent thermal reaction temperature and calcination temperature during catalyst preparation are lowered, the performance of the catalyst will be reduced. It may be that lowering the solvent thermal temperature will affect the self-assembly of ZIF-8, and lowering the calcination temperature may affect the thermal decomposition of ZIF-8, thereby affecting the performance of the catalyst.

[0072] Example 2: Catalyst Recycling

[0073] 1g of 2-chloro-4-nitrobenzoic acid was added to a reactor, 15mL of methanol was added, and then 0.05g of the ruthenium catalyst Ru / SNC(A) prepared in the above embodiment was added to the system. The air in the reactor was replaced 5 times under argon atmosphere, and the argon in the reactor was replaced with hydrogen five times. Then, 0.5MPa of hydrogen was filled and reacted at 50°C for 8h. After the reaction, the catalyst was removed by centrifugation, and 4-amino-2-chlorobenzoic acid was obtained after concentration and drying. The yield was determined by nuclear magnetic resonance. The catalyst was washed with ethanol and water several times, dried and reacted again to examine the catalyst reusability. The results are shown in the table below.

[0074] Table 2: Catalyst recycling

[0075] Recycling times / times 1 2 3 4 5 Yield / % 98 98 97 98 97 .

[0076] It can be seen from Table 2 that the catalyst still exhibits high activity after being reused for 5 times, indicating that the Ru / SNC(A) catalyst has good performance in repeated use.

[0077] Example 3: Preparation of Chloroprocaine Hydrochloride

[0078] Take 1g of dried 4-amino-2-chlorobenzoic acid and add it to a round-bottom flask, then add 0.9g of 2-chloroethyldiethylamine and 0.1g of solid base catalyst K / r-GO to the system, then add 30mL of acetonitrile and react at 60°C for 10h. After the reaction, centrifuge to remove the catalyst, concentrate and dry to obtain 2-diethylaminoethyl-4-aminobenzoate. The yield is determined by nuclear magnetic resonance. Finally, the dried 2-diethylaminoethyl-4-aminobenzoate is stirred in a 3mol / L hydrochloric acid solution for 2h, and then evaporated and concentrated to obtain chloroprocaine hydrochloride.

[0079] Table 2 is a comparison of the solid base catalyst loadings and catalytic performance results prepared in different embodiments. From the inductively coupled plasma spectroscopy (ICP-AES) test data in Table 2, it can be seen that the potassium content in the solid base has a certain influence on the catalytic performance.

[0080] Table 2

[0081] Solid Base K content / wt% Conversion rate / % K / r-GO(A) 1.97 95 K / r-GO(B) 1.08 90 K / r-GO(C) 3.74 91 K / r-GO(D) 4.23 82 .

[0082] From Table 2 we can see that:

[0083] 1. By changing the potassium content in the solid base, the catalytic performance has obvious differences, and we found that when the potassium content is 1.97wt%, the catalytic performance of the catalyst is better and a higher conversion rate can be achieved.

[0084] 2. When the amount of precursor increases, the potassium content in the solid alkali will also increase, but the rate of increase gradually decreases. It may be that the reduced graphene oxide has a certain reducing property and reduces the precursor potassium nitrate at high temperature. However, when the amount of precursor is too large, it cannot be reduced well, which reduces the performance of the solid alkali.

Claims

1. A method for preparing chloroprocaine hydrochloride, characterized in that: The following steps are involved: (1) Preparation of 4-amino-2-chlorobenzoic acid Dissolve 2-chloro-4-nitrobenzoic acid in a solvent and stir evenly; add a ruthenium catalyst Ru / SNC into the system and keep warm for reaction under a hydrogen atmosphere; after the reaction is completed, remove the ruthenium catalyst Ru / SNC by centrifugation, and concentrate and dry to obtain 4-amino-2-chlorobenzoic acid; (2) Preparation of Chloroprocaine Hydrochloride 4-amino-2-chlorobenzoic acid, 2-chloroethyldiethylamine and solid base catalyst K / r-GO are dissolved in a reaction solvent to carry out an esterification reaction; after the reaction is completed, the solid base catalyst K / r-GO is removed by centrifugation, and then the organic solvent is removed and dried to obtain 2-(diethylamino)-2-chloro-4-nitrobenzoic acid ethyl ester; the dried 2-(diethylamino)-4-amino-2-chlorobenzoic acid ethyl ester is dissolved in a hydrochloric acid solution, salified and dried to obtain chloroprocaine hydrochloride.

2. The method for preparing chloroprocaine hydrochloride according to claim 1, characterized in that: In step (1): the reaction temperature is 40-80°C and the reaction time is 4-10h.

3. The method for preparing chloroprocaine hydrochloride according to claim 1, characterized in that: In step (1), the solvent is any one of ethanol, acetonitrile, tetrahydrofuran and ethanol aqueous solution, and the amount of the organic solvent added is to control the concentration of the reaction solution to be 10-100 g / L.

4. The method for preparing chloroprocaine hydrochloride according to claim 1, characterized in that: In step (1): the amount of the ruthenium catalyst Ru / SNC is 1-10wt% of 2-chloro-4-nitrobenzoic acid.

5. The method for preparing chloroprocaine hydrochloride according to claim 1, characterized in that: In step (1): the ruthenium catalyst Ru / SNC is prepared by the following method: ruthenium acetylacetonate and zinc nitrate are dissolved in methanol to obtain solution A, 2-methylimidazole is dissolved in methanol to obtain solution B, then solution A is added to solution B, and 3-mercaptopropionic acid is added dropwise under stirring, and then in a high-pressure hydrothermal reactor, a hydrothermal reaction is carried out at 100-150° C. for 2-6 hours, after natural cooling, centrifugal washing is performed several times, vacuum drying is performed, and then the solid is ground into fine powder, placed in a tubular furnace with an inert gas flow, and calcined at 800-950° C. for 1-4 hours, and the novel ruthenium catalyst Ru / SNC is obtained after cooling.

6. A method for preparing chloroprocaine hydrochloride according to claim 1, characterized in that: In step (1), the ruthenium catalyst Ru / SNC is removed by centrifugation, washed with ethanol and water for several times, dried and then added back into the reaction. The catalyst can be recycled for 5-6 times.

7. A method for preparing chloroprocaine hydrochloride according to claim 6, characterized in that: In step (2): the reaction conditions of the esterification reaction are 60-80° C. and the reaction time is 8-20 hours.

8. The method for preparing chloroprocaine hydrochloride according to claim 6, characterized in that: In step (2), the solvent for the esterification reaction is any one of organic solvents such as acetonitrile, dimethylformamide, ethylene glycol dimethyl ether, and dichloromethane, and the amount of the organic solvent added is to control the concentration of the reaction solution to be 1-200 g / L.

9. The method for preparing chloroprocaine hydrochloride according to claim 6, characterized in that: In step (2): the amount of the solid base catalyst is 10-50wt% of 4-amino-2-chlorobenzoic acid.

10. The method for preparing chloroprocaine hydrochloride according to claim 6, characterized in that: In step (2): the solid base catalyst K / r-GO is prepared by the following method: first, a thermal reduction method is used to synthesize reduced graphene oxide, and the graphene oxide GO is calcined at 500-1000°C for 1-5h to obtain reduced graphene oxide r-GO; KNO3 is dissolved in deionized water, and then ethanol is added, and the reduced graphene oxide is added to the solution, and ultrasound is performed to ensure that the reduced graphene oxide is uniformly dispersed in the mixed solution; then the suspension is stirred at 60°C for 12h, and then the solvent is removed in vacuo to obtain a solid mixture; the obtained solid is dried at 60-100°C for 12-36h, and then the dried solid is ground into fine powder, and then placed in a tubular furnace with an inert gas flow and calcined at 700-900°C for 1-4h, and the solid base catalyst K / r-GO is obtained after cooling.

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