Supported catalysts and methods for their preparation, galnac intermediates and methods for their preparation and use

Abstract

The application provides a supported catalyst and a preparation method thereof, a GalNAc intermediate and a preparation method and application thereof. The supported catalyst comprises a carrier and a Lewis acid catalyst supported on the carrier, and the carrier is a strong acid cation exchange resin. After the carrier in the application is modified by the Lewis acid catalyst, the Lewis acid catalyst reacts with functional groups (such as sulfonic acid groups) of the ion exchange resin to form new strong acid centers, and the catalytic performance can be significantly improved. The supported catalyst can be recovered by filtration after the reaction, repeatedly used for catalytic reaction for multiple times, and after multiple uses, the catalytic performance of the supported catalyst does not obviously decrease. Compared with the catalysts in the prior art, the supported catalyst is more economical and environmentally friendly. The supported catalyst can be used for synthesizing the GalNAc intermediate, and can not only improve the catalytic efficiency but also effectively improve the yield and purity of the GalNAc intermediate.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of fine chemicals, in particular to a supported catalyst and a preparation method thereof, a GalNAc intermediate and a preparation method and application thereof. BACKGROUND

[0002] GalNAc (N-acetylated galactosamine) conjugation modification is the most commonly used small nucleic acid drug delivery system at present. GalNAc-siRNA drugs use GalNAc modification. By covalently coupling GalNAc to the 3' end of the sense strand of siRNA in a trivalent manner, a polysaccharide-siRNA monoconjugate is formed. GalNAc-siRNA optimized by chemical modification has better stability and interference efficiency. Such siRNA conjugates have better application potential in the treatment of liver-related diseases involving abnormal high expression of genes.

[0003] is an important intermediate in the chemical synthesis of GalNAc, and is a necessary stage in the synthesis of GalNAc. Therefore, the synthesis of the intermediate is also very important. Chinese Patent Publication No. CN109661233A discloses a synthesis method for synthesizing the above-mentioned intermediate catalyzed by TMSOTf. This method is a relatively mature synthesis method at present. However, due to the irritancy, self-ignition, and sensitization of TMSOTf, this method usually causes greater harm to the human body during the scale-up process, and the yield is relatively low (63.5%). SUMMARY

[0004] The main purpose of the present application is to provide a supported catalyst and a preparation method thereof, a GalNAc intermediate and a preparation method and application thereof, so as to solve the problem of low yield of the preparation of the GalNAc intermediate in the prior art.

[0005] In order to achieve the above-mentioned purpose, according to one aspect of the present application, a supported catalyst is provided, which comprises a carrier and a Lewis acid catalyst supported on the carrier, and the carrier is a strong acid cation exchange resin.

[0006] Further, the Lewis acid catalyst is a metal salt, preferably the metal salt is SnCl4 and / or FeCl3, preferably SnCl4, preferably the carrier is a D072 type strong acid cation exchange resin and / or a NKC-9 type strong acid cation exchange resin, and preferably the Lewis acid catalyst accounts for 1.0-3.0% of the total weight of the supported catalyst.

[0007] In order to achieve the above object, according to one aspect of the present application, a preparation method of the supported catalyst is provided, and the preparation method of the supported catalyst comprises: pretreating a carrier to obtain an activated carrier; mixing the activated carrier with a Lewis acid catalyst solution to obtain the supported catalyst after drying.

[0008] Further, the pretreating step comprises: soaking the carrier with an organic solvent, then filtering, and washing to neutral to obtain the pretreated carrier; and activating the pretreated carrier to obtain the activated carrier; preferably, the organic solvent is ethanol and / or methanol; preferably, the activation uses a hydrochloric acid solution, and preferably, the mass concentration of the hydrochloric acid solution is 5-10%.

[0009] Further, the solvent in the Lewis acid catalyst solution comprises anhydrous methanol and / or anhydrous ethanol, preferably, the concentration of the Lewis acid catalyst solution is 0.03-0.07 mol / mL, and preferably, the ratio of the volume of the Lewis acid catalyst to the mass of the activated carrier is 9-12.

[0010] According to another aspect of the present application, a preparation method of a GalNAc intermediate is provided, and the preparation method comprises: step S1, dissolving a first compound to obtain a first solution, and performing a catalytic reaction on the first solution by using the supported catalyst to obtain a second compound; and step S2, mixing the second compound with a third compound to perform a nucleophilic substitution reaction to obtain the GalNAc intermediate; the general formula of the first compound is the general formula of the second compound is the general formula of the third compound is the general formula of the GalNAc intermediate is

[0011] Further, in step S1, the first compound is dissolved in a second solvent, and the second solvent comprises dichloromethane and / or 1,2-dichloroethane, preferably dichloromethane, and more preferably, the ratio of the volume of the second solvent to the mass of the first compound is 4-5:1, and preferably, the mass ratio of the first compound to the supported catalyst is 1:0.08-1:0.15, and more preferably, 1:0.1.

[0012] Further, the temperature of the catalytic reaction is 20-50°C, and preferably 20-30°C; and preferably, the time of the catalytic reaction is 3-10h, and preferably 3-5h.

[0013] Further, the molar ratio of the third compound to the first compound is (1.1-1.3):1, and preferably 1.1:1.

[0014] Further, the temperature of the nucleophilic substitution is 20-50°C, and preferably 20-30°C; and preferably, the time of the nucleophilic substitution is 20-30h.

[0015] According to another aspect of the present application, there is provided a GalNAc intermediate prepared according to the above method for preparing a GalNAc intermediate.

[0016] According to still another aspect of the present application, there is provided a use of a GalNAc intermediate for preparing a GalNAc.

[0017] According to the technical solution of the present application, the carrier in the present application adopts a strong acid cation exchange resin, which is a high molecular material containing an acidic functional active ingredient and has strong catalytic ability for esterification, aldehyde ketone condensation, etherification, etc. After modification by a Lewis acid catalyst, the Lewis acid catalyst reacts with the functional groups (such as sulfonic acid groups) of the ion exchange resin to form new strong acid centers, which can significantly improve the catalytic performance. The supported catalyst can be filtered and recovered after the reaction and repeatedly used for catalytic reactions multiple times, and after multiple uses, the catalytic performance of the supported catalyst does not decrease significantly. Compared with the catalysts in the prior art, the supported catalyst is more economical and environmentally friendly. The supported catalyst can be used for synthesizing a GalNAc intermediate, which can not only improve the catalytic efficiency but also effectively improve the yield and purity of the GalNAc intermediate. DETAILED DESCRIPTION

[0018] It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. The present application will be described in detail below with reference to the embodiments.

[0019] As analyzed in the background art, the current relatively mature synthesis method is mainly a TMSOTf catalysis method for synthesizing a GalNAc intermediate. However, TMSOTf is used in this method, and TMSOTf has strong irritability, allergenicity, and self-ignition. In general, it is more harmful to the human body and has higher risk in the process of scale-up, and the yield is relatively low (about 63.5%).

[0020] In a typical embodiment of the present application, a supported catalyst is provided, which includes a carrier and a Lewis acid catalyst supported on the carrier, and the carrier is a strong acid cation exchange resin.

[0021] The carrier in the present application adopts a strong acid cation exchange resin. The strong acid cation exchange resin is a high molecular material containing an acid functional active ingredient, and has strong catalytic capacity for esterification, aldehyde ketone condensation, etherification and the like. After modification by a Lewis acid catalyst, the Lewis acid catalyst reacts with the functional groups (such as sulfonic acid groups) of the ion exchange resin to form new strong acid centers, which can significantly improve the catalytic performance. The supported catalyst can be filtered and recovered after the reaction, and repeatedly used for catalytic reaction multiple times, and after multiple uses, the catalytic performance of the supported catalyst does not decrease significantly. Compared with the catalysts in the prior art, the supported catalyst is more economical and environmentally friendly. The supported catalyst can be used for synthesizing GalNAc intermediates, which can not only improve the catalytic efficiency but also effectively improve the yield and purity of the GalNAc intermediates.

[0022] In order to form new strong acid centers between the Lewis acid catalyst and the carrier, thereby improving the catalytic performance of the supported catalyst, in some embodiments, the Lewis acid catalyst is a metal salt, preferably the metal salt is SnCl4 and / or FeCl3, preferably SnCl4. The carrier preferably includes a D072 type strong acid cation exchange resin and / or an NKC-9 type strong acid cation exchange resin. Both of the above strong acid cation exchange resins have a high acid functional active ingredient, which is beneficial to combination with the above metal salt. The Lewis acid catalyst preferably accounts for 1.0% to 3.0% of the total weight of the supported catalyst. Too much Lewis acid catalyst will cause the catalyst to accumulate, and the active center is not easy to expose, resulting in low catalyst utilization rate; too little Lewis acid catalyst will result in reduced catalytic efficiency.

[0023] In another typical embodiment of the present application, a preparation method of the above supported catalyst is provided, and the preparation method of the supported catalyst includes: activating the carrier to obtain an activated carrier; mixing the activated carrier with a Lewis acid catalyst solution, and drying to obtain the supported catalyst.

[0024] The method for preparing the above supported catalyst according to the present application is relatively simple and has low cost. The carrier is first activated, and then loaded. The supported catalyst prepared by the above preparation method has high catalytic performance, and can be recycled and reused.

[0025] Since the ion exchange resin usually contains a small amount of impurities, when the resin is in contact with the solution, the above-mentioned impurities will be transferred into the solution, affecting the quality of the water, therefore, the strong acid cation exchange resin needs to be pretreated before use. In some embodiments, the carrier is soaked with an organic solvent, then filtered, washed to neutral to obtain a pretreated carrier; the pretreated carrier is activated to obtain an activated carrier. Preferably, the neutralization is carried out with deionized water. Preferably, the organic solvent is ethanol and / or methanol; preferably, the activation is carried out with a hydrochloric acid solution, preferably the hydrochloric acid solution is an aqueous hydrochloric acid solution, preferably the mass concentration of the hydrochloric acid solution is 5-10%. First, the organic impurities in the carrier are removed by using an organic solvent, in order to prevent the ion exchange capacity from being reduced due to the contact of the carrier with a strong oxidant, etc., the resin also needs to be activated by using hydrochloric acid. The carrier is activated by using a hydrochloric acid solution with a suitable concentration, which can avoid the pollution of the carrier by organic matter or metal (such as iron, etc.).

[0026] In order to fully load the Lewis acid catalyst on the carrier, in some embodiments, the solvent in the Lewis acid catalyst solution is anhydrous methanol and / or anhydrous ethanol, preferably the concentration of the Lewis acid catalyst solution is 0.03-0.07 mol / mL, preferably the ratio of the volume of the Lewis acid catalyst to the mass of the activated carrier is 9-12.

[0027] In another typical embodiment of the present application, a preparation method of a GalNAc intermediate is provided, which comprises: step S1, dissolving a first compound to obtain a first solution, and catalyzing the first solution by using the above-mentioned supported catalyst to obtain a second compound; step S2, carrying out a nucleophilic substitution reaction on the mixture of the second compound and a third compound to obtain the GalNAc intermediate; the general formula of the first compound is the general formula of the second compound is the general formula of the third compound is the general formula of the GalNAc intermediate is

[0028] The present application uses the above-mentioned supported catalyst to catalytically synthesize the GalNAc intermediate by one-pot method, which has a lower reaction cost, a mild reaction condition, and a higher product yield and purity. Compared with the TMSOTf catalysis method commonly used in the prior art, the present application has a lower toxicity and is harmless to the human body, and the supported catalyst can be directly recovered after the reaction by filtration, which not only has a higher economic benefit, but also is suitable for scale-up production.

[0029] In some embodiments, in step S1, the first compound is dissolved in a second solvent, and the second solvent comprises dichloromethane and / or 1,2-dichloroethane, preferably dichloromethane, and more preferably the volume of the second solvent is used in an amount of 4-5:1 relative to the mass of the first compound, and preferably the mass ratio of the first compound to the supported catalyst is 1:0.08-1:0.15, preferably 1:0.1.

[0030] In order to improve the efficiency of the catalytic reaction, in some embodiments, the temperature of the catalytic reaction is 20-50°C, preferably 20-30°C, and preferably the time of the catalytic reaction is 3-10h, preferably 3-5h. Due to the use of the catalyst of the present application, the catalytic reaction can be carried out at a lower temperature and for a shorter time.

[0031] In order to improve the efficiency of the reaction of the first compound and the third compound and to avoid the generation of by-products, in some embodiments, the molar ratio of the third compound to the first compound is (1.1-1.3):1, preferably 1.1:1.

[0032] In order to improve the efficiency of the nucleophilic substitution, in some embodiments, the temperature of the nucleophilic substitution is 20-50°C, preferably 20-30°C, and preferably the time of the nucleophilic substitution is 20-30h.

[0033] In some embodiments, the method for preparing the GalNAc intermediate further comprises a post-treatment of the GalNAc intermediate. The post-treatment step can refer to the post-treatment method commonly used in the art. In order to improve the purity and yield of the GalNAc intermediate, in some embodiments, the post-treatment step comprises: washing the GalNAc intermediate with a base, washing with water to obtain a wet GalNAc intermediate, then concentrating the wet GalNAc intermediate under reduced pressure to obtain a solid GalNAc intermediate, and recrystallizing the solid GalNAc intermediate to obtain a refined GalNAc intermediate.

[0034] In some embodiments, in order to sufficiently remove the impurities of the GalNAc intermediate, the solute used in the base washing is preferably one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate.

[0035] In order to improve the purity of the refined GalNAc intermediate, the recrystallization solvent is a mixture of ethyl acetate and n-heptane, and the volume ratio is (2-3):1, preferably 3:1; the volume of the recrystallization solvent is used in an amount of (12-16):1 relative to the mass of the first compound (galactosamine pentaacetate), preferably 16:1, and the recrystallization temperature is 30-60°C, preferably 40-50°C.

[0036] In another typical embodiment of the present application, a GalNAc intermediate is provided, which is prepared according to the above-mentioned method for preparing a GalNAc intermediate.

[0037] The GalNAc intermediate prepared according to the above-mentioned preparation method has high yield and purity.

[0038] In another typical embodiment of the present application, a use of a GalNAc intermediate for preparing a GalNAc is provided.

[0039] The above-mentioned GalNAc intermediate is an important intermediate in the chemical synthesis of GalNAc, and is a necessary stage for the synthesis of GalNAc.

[0040] The present application will be further described in detail below in conjunction with specific examples, which should not be construed as limiting the scope of the present application.

[0041] The examples and comparative examples of the present application are reacted according to the following reaction formula:

[0042]

[0043] Preparation of SnCl4 supported catalyst

[0044] 10 g of commercially available D072 strong acid cation exchange resin was soaked in ethanol for 12 h, then filtered, washed with deionized water until neutral, then activated with 7% hydrochloric acid aqueous solution for 12 h, filtered, washed with deionized water again until neutral, filtered, dried, ground, and sieved through a 200 mesh sieve to obtain an activated carrier. 100 mL of SnCl4 solution with a concentration of 0.05 mol / mL was added to the above-mentioned activated carrier, and stirred at 25-30°C for 4 h. Then filtered, dried, and sealed for use, to obtain a SnCl4 supported catalyst, in which SnCl4 accounts for 2.7% of the total weight of the above-mentioned SnCl4 supported catalyst.

[0045] Preparation of FeCl3 supported catalyst

[0046] Take 10 g of commercially available D072 strong acid cation exchange resin, soak in ethanol for 12 h, then filter, wash with deionized water until neutral, then activate with 7% hydrochloric acid solution for 12 h, filter, wash with deionized water again until neutral, filter, dry, grind, pass through a 200-mesh sieve, and obtain the activated carrier. Add 10 g of the above-activated carrier to a 250 mL round-bottom flask, add 100 mL of a 0.05 mol / L FeCl3 solution, and stir at 25-30°C for 4 h. Then filter, dry, seal, and obtain the FeCl3 supported catalyst. The FeCl3 accounts for 2.0% of the total weight of the above FeCl3 supported catalyst.

[0047] Example 1

[0048] (1) Add 80 mL of dichloromethane, 20.0 g of galactosamine pentaacetate (compound of formula I, 51.4 mmol, 1 eq) to a 500 mL reaction flask, stir until dissolved, add SnCl4 supported catalyst 2.0 g at 20-30°C, and react for 4 hours to obtain a 2-methyl-(3,4,6-triacetyloxy-1,2-dideoxy-α-D-galactopyranoside) [2,1-d]-2-oxazoline solution (compound of formula II).

[0049] (2) Add dichloromethane 80 mL to the above-obtained 2-oxazoline compound (formula II) solution and continue stirring for 0.5 h. Add compound of formula III 17.4 g (56.5 mmol, 1.1 eq) and continue to react at 20-30°C for 24 h.

[0050] (3) Filter the system, recover the SnCl4 supported catalyst, dry, and wait for recovery for reuse. Wash the filtrate with saturated sodium bicarbonate solution and water in turn, concentrate the organic phase under reduced pressure to obtain a residue. Add ethyl acetate 240 mL to the above residue, warm to 40-50°C, and add n-heptane 80 mL dropwise with stirring. After dropping, warm and stir for 1 h, cool to 15-25°C to crystallize, suction filter, rinse with n-heptane, and dry at ≤40°C to obtain white solid IV 27.7 g (HPLC purity: 99.51%; yield: 84.5%).

[0051] Example 2

[0052] (1) Add 80 mL of dichloromethane, 20.0 g of galactosamine pentaacetate (compound of formula I, 51.4 mmol, 1 eq) to a 500 mL reaction flask, stir until dissolved, add SnCl4 supported catalyst 2.0 g at 20-30°C, and react for 4 hours to obtain a 2-methyl-(3,4,6-triacetyloxy-1,2-dideoxy-α-D-galactopyranoside) [2,1-d]-2-oxazoline solution (compound of formula II).

[0053] (2) To the above obtained 2-oxazoline compound (Formula II) solution, dichloromethane 80 mL was added and stirring was continued for 0.5 hour. Formula III compound 17.4 g (56.5 mmol, 1.1 eq) was added and the reaction was continued for 24 hours at 20-30 °C.

[0054] (3) The system was filtered and the recovered FeCl3supported catalyst was dried and reserved for reuse. The filtrate was washed successively with saturated sodium bicarbonate solution and water, and the organic phase was concentrated under reduced pressure to obtain a residue. Ethyl acetate 240 mL was added to the above residue, and the temperature was raised to 40-50 °C. Heptane 80 mL was added dropwise with stirring, and after the dropping was completed, the system was stirred for 1 hour. The temperature was lowered to 15-25 °C, and the product was crystallized. The product was filtered and washed with heptane, and the white solid IV 26.3 g was obtained (HPLC purity: 99.22%; yield: 80.3%, as shown in Table 1).

[0055] Example 3

[0056] Different from Example 1, the recovered SnCl4supported catalyst after four uses was selected for use, and the GalNAc intermediate product was obtained (HPLC purity: 99.50%; yield: 83.2%).

[0057] Example 4

[0058] Different from Example 2, the recovered FeCl3supported catalyst after four uses was selected for use, and the GalNAc intermediate product was obtained (HPLC purity: 99.00%; yield: 78.2%).

[0059] Example 5

[0060] (1) Into a 500 mL reaction flask, 100 mL of dichloromethane and 20.0 g of galactosamine pentaacetate (Formula I compound, 51.4 mmol, 1 eq) were added, and the mixture was stirred until dissolved. SnCl4supported catalyst 1.6 g was added at 20-30 °C, and the reaction was continued for 10 hours to obtain a 2-methyl-(3,4,6-triacetoxy-1,2-dideoxy-α-D-galactopyranosyl)[2,1-d]-2-oxazoline solution (Formula II compound).

[0061] (2) To the above obtained 2-oxazoline compound (Formula II) solution, dichloromethane 80 mL was added and stirring was continued for 0.5 hour. Formula III compound 17.4 g (56.5 mmol, 1.1 eq) was added and the reaction was continued for 24 hours at 20-30 °C.

[0062] (3) The system was filtered, the SnCl4 supported catalyst was recovered and dried, and was ready for recycling. The filtrate was washed successively with saturated sodium bicarbonate solution and water, and the organic phase was concentrated under reduced pressure to obtain a residue. Ethyl acetate 240 mL was added to the above residue, and the temperature was raised to 40-50°C. Heptane 80 mL was added dropwise with stirring, and after the dropping was completed, the mixture was stirred for 1 hour. The temperature was lowered to 15-25°C, and the product was crystallized. The product was filtered, washed with heptane, and dried at ≤40°C to obtain white solid IV 24.9 g (HPLC purity: 99.06%; yield: 76.0%, as shown in Table 1).

[0063] Example 6

[0064] (1) Into a 500 mL reaction flask, 90 mL of dichloromethane and 20.0 g of galactosamine pentaacetate (compound of formula I, 51.4 mmol, 1 eq) were added, and the mixture was stirred until dissolved. SnCl4 supported catalyst 3 g was added under temperature control at 20-30°C, and the reaction was carried out for 3 hours to obtain a solution of 2-methyl-(3,4,6-triacetoxy-1,2-dideoxy-α-D-galactopyranosyl)[2,1-d]-2-oxazoline (compound of formula II).

[0065] (2) To the above obtained solution of 2-oxazoline compound (formula II), dichloromethane 80 mL was added, and the stirring was continued for 0.5 hours. Compound of formula III 19.0 g (61.6 mmol, 1.2 eq) was added, and the reaction was continued for 30 hours under temperature control at 20-30°C.

[0066] (3) The system was filtered, the SnCl4 supported catalyst was recovered and dried, and was ready for recycling. The filtrate was washed successively with saturated sodium bicarbonate solution and water, and the organic phase was concentrated under reduced pressure to obtain a residue. Ethyl acetate 240 mL was added to the above residue, and the temperature was raised to 40-50°C. Heptane 80 mL was added dropwise with stirring, and after the dropping was completed, the mixture was stirred for 1 hour. The temperature was lowered to 15-25°C, and the product was crystallized. The product was filtered, washed with heptane, and dried at ≤40°C to obtain white solid IV 24.9 g (HPLC purity: 99.06%; yield: 76.0%, as shown in Table 1).

[0067] Example 7

[0068] Different from Example 1, in step (1), SnCl4 supported catalyst 1 g was added, and after drying, white solid IV 21.2 g (HPLC purity: 90.11%; yield: 64.7%) was obtained.

[0069] Example 8

[0070] Different from Example 1, in step (2), 22 g of compound III was added, and after drying, white solid IV 27.0 g (HPLC purity: 97.80%; yield: 82.4%) was obtained.

[0071] Example 9

[0072] Different from Example 1, in step (3), 16 g of compound III was added, and after drying, white solid IV 25.3 g was obtained (HPLC purity: 94.67%; yield: 77.2%).

[0073] Comparative Example 1

[0074] Different from Example 1, SnCl4 was used as a catalyst, and no GalNAc intermediate product was generated.

[0075] Comparative Example 2

[0076] Different from Example 1, SnCl4 was loaded on ZSM-25 molecular sieve as a catalyst, and no GalNAc intermediate product was generated.

[0077] The yield and purity of the GalNAc intermediate product obtained in the above examples and comparative examples are shown in Table 1.

[0078] Table 1

[0079] Examples / Comparative Examples Yield (%) Purity (%) Example 1 84.5 99.51 Example 2 80.3 99.22 Example 3 83.2 99.50 Example 4 78.2 99.00 Example 5 76.0 99.06 Example 6 82.2 99.00 Example 7 64.7 90.11 Example 8 82.4 97.80 Example 9 77.2 94.67 Comparative Example 1 / / Comparative Example 2 / /

[0080] From the above description, it can be seen that the above-mentioned embodiments of the present application achieve the following technical effects: the carrier in the present application uses a strong acid cation exchange resin, which is a high molecular material containing an acidic functional active ingredient and has strong catalytic ability for esterification, aldehyde ketone condensation, etherification, etc. After modification by a Lewis acid catalyst, the Lewis acid catalyst reacts with the functional groups (such as sulfonic acid groups) of the ion exchange resin to form new strong acid centers, which can significantly improve the catalytic performance. The supported catalyst can be filtered and recovered after the reaction and repeatedly used for catalytic reaction multiple times, and after multiple uses, the catalytic performance of the supported catalyst does not decrease significantly. Compared with the catalysts in the prior art, the supported catalyst is more economical and environmentally friendly. The supported catalyst can be used for synthesizing GalNAc intermediates, which not only can improve the catalytic efficiency but also can effectively improve the yield and purity of GalNAc intermediates.

[0081] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method of preparing a GalNAc intermediate, characterized in that, The preparation method comprises: S1, dissolving a first compound to obtain a first solution, and performing a catalytic reaction on the first solution by using a supported catalyst to obtain a second compound; S2, performing a nucleophilic substitution reaction on a mixture of the second compound and a third compound to obtain the GalNAc intermediate; The first compound has a general formula of , The second compound has a general formula of , The third compound has a general formula of , The general formula of the GalNAc intermediate is ; The supported catalyst comprises a carrier and a Lewis acid catalyst supported on the carrier, the carrier is a strong acid cation exchange resin; wherein the Lewis acid catalyst is a metal salt, the metal salt is SnCl4 and / or FeCl3; the carrier is a D072 type strong acid cation exchange resin and / or a NKC-9 type strong acid cation exchange resin; the Lewis acid catalyst accounts for 1.0-3.0% of the total weight of the supported catalyst.

2. The process for the preparation of GalNAc intermediate according to claim 1, characterized in that, In the step S1, the first compound is dissolved in a second solvent, the second solvent comprises dichloromethane and / or 1,2-dichloroethane, and / or the volume dosage of the second solvent to the mass dosage of the first compound is 4-5:1, and / or the mass ratio of the first compound to the supported catalyst is 1:0.08-1:0.

15.

3. The process for the preparation of GalNAc intermediate as claimed in claim 1, wherein, The temperature of the catalytic reaction is 20-50℃; and / or the time of the catalytic reaction is 3-10 h.

4. The process for the preparation of GalNAc intermediate as claimed in claim 1, wherein, The molar ratio of the third compound to the first compound is (1.1-1.3):

1.

5. The method of claim 1, wherein the GalNAc intermediate is prepared by, The temperature of the nucleophilic substitution is 20-50℃; and / or the time of the nucleophilic substitution is 20-30 h.

6. The method of claim 1, wherein the GalNAc intermediate is prepared by, The preparation method of the supported catalyst comprises: pretreating the carrier to obtain an activated carrier; mixing the activated carrier with a Lewis acid catalyst solution, and drying to obtain the supported catalyst.

7. The method of claim 6, wherein the GalNAc intermediate is prepared by, The pretreatment step comprises: immersing the carrier in an organic solvent, then filtering, and washing to neutral to obtain a pretreated carrier; activating the pretreated carrier to obtain the activated carrier; the organic solvent is ethanol and / or methanol; the activation uses a hydrochloric acid solution, and the mass concentration of the hydrochloric acid solution is 5-10%.

8. The process for the preparation of a GalNAc intermediate according to claim 7, characterized in that, The solvent in the Lewis acid catalyst solution comprises anhydrous methanol and / or anhydrous ethanol, the concentration of the Lewis acid catalyst solution is 0.03-0.07 mol / mL, and the ratio of the volume dosage of the Lewis acid catalyst solution to the mass dosage of the activated carrier is 9-12.

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