CN112341416A - Method for preparing benzo oxygen-containing aliphatic heterocyclic derivative - Google Patents
Method for preparing benzo oxygen-containing aliphatic heterocyclic derivative Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present application relates to a process for the preparation of benzoxaoxylipid heterocyclic derivatives, in particular comprising the steps of: (1) subjecting the compound of formula I-1 to a nitration reaction to obtain a compound of formula I-2; (2) subjecting the compound of formula I-2 to a reduction reaction to obtain a compound of formula I-3; (3) halogenating the compound of formula I-3 to obtain a compound of formula I-4; (4) carrying out diazotization reaction on the compound of the formula I-4, and further reacting the obtained product with halogenated metal salt to generate the compound of the formula I;
Description
Technical Field
The application relates to the field of synthesis of drug intermediates, in particular to a method for preparing benzo-oxygen-containing lipid heterocyclic derivatives.
Background
US 2015/0152075 a1 discloses diphenylmethane derivatives which exhibit excellent inhibitory effect on sodium-dependent glucose cotransporter 2(SGLT2) and significantly reduce urinary sugar excretion in animals compared to the well-known SGLT2 inhibitor Dapagliflozin (Dapagliflozin). Example 172 et al disclose that 2-nitro-3-methoxybenzoic acid was used as a starting material, and a dihydrobenzofuran intermediate was prepared by 20 steps of reaction, followed by 7 steps of preparation to obtain SGLT2 inhibitor c 28. The method adopts a linear synthesis route, once an error occurs in the middle, the process needs to be started again, the route is complex, and the yield is low.
An improved process for the synthesis of diphenylmethane derivatives is disclosed in WO 2017/2177792 a. In example 1 and the like, it is disclosed that 2-nitro-3-methoxybenzoic acid is used as a starting material, and each main group is synthesized separately by a convergent synthesis method and then coupled to each other, whereby a final product c28 is obtained. Although the yield of the method is improved, the overall yield is still low, and the reaction route is long. In addition, in the process of constructing the benzo-linked oxygen-containing aliphatic heterocycle c34 (shown below), osmium tetroxide or ozone is needed, osmium tetroxide is an agent prohibited from being sold in China, and ozone has special requirements on production equipment and is not beneficial to amplification.
Disclosure of Invention
In order to solve the problems, the inventor develops a new route for synthesizing the benzo oxygen-containing lipid heterocyclic derivative shown as the compound c34, no special reagent is needed in the reaction process, the route is short, the yield is high, the raw materials are all commercially available and are easy to obtain, and the method has a high industrial production prospect.
In particular, the present application provides a process for preparing a compound of formula I below, comprising the steps of:
(1) subjecting the compound of formula I-1 to a nitration reaction to obtain a compound of formula I-2;
(2) subjecting the compound of formula I-2 to a reduction reaction to obtain a compound of formula I-3;
(3) halogenating the compound of formula I-3 to obtain a compound of formula I-4;
(4) carrying out diazotization reaction on the compound of the formula I-4, and further reacting the obtained product with halogenated metal salt to generate the compound of the formula I;
wherein, in the above-mentioned compounds,
R1selected from cyano, C1-6Ester group and C2-6Alkenyl (e.g. C)2-4Alkenyl);
x and X' are each independently selected from halogen (e.g., Cl, Br, or I);
n is 1 or 2.
In some embodiments, R in the compound1Is selected from C1-4Ester group, preferably C1-2Ester group, more preferably-COOCH3。
In some embodiments, X in the compound is Br or I.
In some embodiments, X' in the compound is Cl.
In some embodiments, n in the compound is 1.
In some embodiments, the method of synthesis of the compound of formula I-1 comprises the steps of:
a. performing iodination reaction on the compound of the formula I-4 to obtain a compound of a formula I-5;
b. carrying out a alkylation reaction on the compound of the formula I-5 to obtain a compound of a formula I-6; and/or
c. Cyclizing the compound of formula I-6 and reducing the carbon-carbon double bond of the furan ring in the product;
wherein R is2Selected from cyano, carboxyl and C2-6An alkenyl group;
n is 1 or 2.
In some embodiments, when R is in said compound2In the case of a carboxyl group, the method further comprises a step of esterifying the carboxyl group before or after the step a.
In another aspect, the present application provides the use of a compound of formula I for the preparation of a compound of formula II, wherein the compound of formula I is prepared by a process according to any one of the preceding claims;
the compound of formula II has the following structure:
wherein A is O or S;
x' is halogen or C1-7An alkyl group;
ring B is
Wherein Ra, Rb, Rc, Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7Alkyl radical, C1-7Alkylthio radical, C2-7Alkenyl radical, C2-7Alkynyl, C1-7Alkoxy radical, C1-7alkoxy-C1-7Alkyl radical, C2-7alkenyl-C1-7Alkoxy radical, C2-7alkynyl-C1-7Alkoxy radical, C3-10Cycloalkyl radical, C3-7Cycloalkylthio radical, C5-10Cycloalkenyl radical, C3-10Cycloalkoxy, C3-10cycloalkoxy-C1-7Alkoxy, phenyl-C1-7Alkyl radical, C1-7Alkylthio-phenyl, phenyl-C1-7Alkoxy, mono C1-7Alkylamino or di-C1-7Alkylamino radical, mono C1-7alkylamino-C1-7Alkyl or di-C1-7alkylamino-C1-7Alkyl radical, C1-7Alkanoyl radical, C1-7Alkanoylamino, C1-7Alkylcarbonyl group, C1-7Alkoxycarbonyl, carbamoyl, mono-C1-7Alkylcarbamoyl or di-C1-7Alkylcarbamoyl, C1-7Alkylsulfonylamino, phenylsulfonylamino, C1-7Alkylsulfinyl radical, C6-14Arylsulfanyl group, C6-14Arylsulfonyl radical, C6-14Aryl, 5-to 13-membered heteroaryl, 5-to 10-membered heterocycloalkyl-C1-7Alkyl or 5-to 10-membered heterocycloalkyl-C1-7An alkoxy group;
ring C is C3-10Cycloalkyl radical, C5-10Cycloalkenyl radical, C6-14Aryl, 5-to 13-membered heteroaryl, or 5-to 10-membered heterocycloalkyl;
the alkyl, alkenyl, alkynyl and alkoxy groups are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7Alkyl and C2-7Substituent substitution of alkynyl;
the ringThe alkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4Alkyl and C1-7Substituent substitution of alkoxy; and is
The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from N, S and O;
n is 1 or 2.
In some embodiments, the compound of formula II is
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise indicated, each reaction described herein may be performed according to the teaching of a textbook or the general technical knowledge of a person skilled in the art.
The invention has the advantages of
The application develops a new route for synthesizing the benzo-oxygen-containing aliphatic heterocyclic derivative, the route does not need to use special reagents, the route is short, the yield is high, raw materials are all commercially available and are easy to obtain, and the method has a relatively high industrial application prospect.
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, the present invention is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.
EXAMPLE 13 Synthesis of hydroxy-4-iodobenzoic acid
20g of the compound 1, 6g of sodium hydroxide and 23g of sodium iodide were added to 250ml of methanol, and the system was cooled to 0 ℃. To the above system was added dropwise 132g of a sodium hypochlorite solution. The reaction was stirred at 25-30 ℃ for 72 hours. TLC monitors that the raw material reaction is complete, methanol in the system is evaporated, the pH value of the residual solution is adjusted to be less than 2 at 10 ℃, the temperature is controlled and the stirring is carried out for 2 to 3 hours after the pH value is adjusted, the product is filtered and collected, and the product is dried in vacuum to obtain 35g of white solid with the yield of 92 percent.
EXAMPLE 23 preparation of hydroxy-4-trimethylsilylbenzoic acid
5.22g of the compound 2, 3.71mL of trimethylsilylalkyne, 386mg of palladium dichloride ditriphenylphosphine and 54mg of cuprous iodide were added to a mixed solution of 20mL of THF and 40mL of chloroform, 8.14mL of triethylamine was added to the system, the reaction system was repeatedly evacuated three times and introduced with nitrogen, and the reaction solution was heated to 50 to 60 ℃ for 4 hours of reaction. TLC monitors the reaction is complete, the reaction solution is diluted with 60ml chloroform and washed with 5% dilute hydrochloric acid, the organic phase is separated and dried, and the crude product is separated by column chromatography to obtain 4g yellow product with yield of 90%.
1H NMR(400MHz，CDCl3)δ0.29(s，9H)，5.93(bs，1H)，7.39(d，J＝8Hz，1H)，7.54(d，J＝8Hz，1H)，7.61(s，1H)。
EXAMPLE 36 preparation of benzofuran carboxylic acid
3g of Compound 3 was dissolved in 30ml of a solution of ethanol and triethylamine (volume ratio: 1), 114mg of cuprous iodide was added to the reaction system, and the reaction mixture was heated to 75 to 85 ℃ and stirred for 3 hours. TLC monitored completion of the reaction, 1g of activated carbon and 15ml of methanol were added to the system, and the reaction was refluxed for 1 hour. Then filtering diatomite in the reaction system, adding 24ml of 3N sodium hydroxide solution into the filtrate, distilling off the organic solvent in the filtrate, regulating the pH of the residual water phase with dilute hydrochloric acid to be less than 2, precipitating yellow solid, filtering and collecting the solid, and drying to obtain the product1.8g, yield 92%.1H NMR(400MHz，DMSO-d6)δ7.07(m，1H)，7.75(m，1H)，7.86(m，1H)，8.12(s，1H)，8.19(m，1H)，13.05(bs，1H)。
EXAMPLE 46 preparation of methyl benzofurancarboxylate
Dissolving 4g of the compound 4 in 40mL of methanol, dropwise adding 1mL of concentrated sulfuric acid into the reaction system, stirring the reaction solution at room temperature overnight, after the reaction is completed, concentrating the methanol, dissolving the residue in ethyl acetate, washing the organic phase with saturated saline solution to be neutral, separating the organic phase, drying, and concentrating to obtain 4.2g of a product with the yield of 96%.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，7.07(m，1H)，7.75(m，1H)，7.86(m，1H)，8.12(s，1H)，8.19(m，1H)。
Example 52 preparation of methyl 3, 3-dihydrobenzofuran-6-carboxylate
18g of compound 5 and 2g of 10% wet palladium on carbon are added into 200ml of methanol, the reaction system is reacted for 2 to 3 hours at 30 to 40 ℃ under 50psi of hydrogen, TLC monitors the reaction for completion, the reaction system is filtered through kieselguhr, and the filtrate is concentrated to obtain 17g of product with the yield of 94%.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，2.97(t，2H)，4.27(t，2H)，7.07(m，1H)，7.43(m，1H)，7.45(m，1H)。
EXAMPLE 67 preparation of methyl-nitro-2, 3-dihydrobenzofuran-6-carboxylate
Adding 4.1g of compound 6 into 20ml of concentrated sulfuric acid, dropwise adding 2.13g of nitric acid into the system under the condition of controlling the temperature to be 0 ℃, stirring the reaction solution at the temperature of 0 ℃ for 1-2 hours, slowly adding the reaction system into 200ml of ice-water mixture after the reaction is completed, filtering and collecting solids, and drying in vacuum to obtain 4g of a product with the yield of 78%.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，2.97(t，2H)，4.27(t，2H)，7.51(m，1H)，7.74(m，1H)。
EXAMPLE 77 preparation of methyl amino-2, 3-dihydrobenzofuran-6-carboxylate
30g of the compound 7 and 3g of 10% wet palladium carbon are added into 300ml of methanol, stirred overnight at 20-30 ℃ under a hydrogen atmosphere, after the reaction is completed, the system is filtered through kieselguhr, and the filtrate is concentrated to dryness to obtain 25.9g of a product with 99% yield.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，2.97(t，2H)，4.02(br，2H)，4.27(t，2H)，6.48(m，1H)，7.23(m，1H)。
EXAMPLE 84 preparation of methyl bromo-7-amino-2, 3-dihydrobenzofuran-6-carboxylate
At 0 ℃, adding 17.8g of NBS in 19.3g of the compound 8, 200ml of DMF and a mixed system in batches, stirring the mixture at 0 ℃ for 30 minutes for reaction, completely reacting, diluting the reaction system with 400ml of water, extracting with 200ml of X2 ethyl acetate, separating an organic phase, drying and concentrating, and purifying the product by column chromatography to obtain 24.5g of the product with the yield of 90%.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，2.97(t，2H)，4.15(br，2H)，4.27(t，2H)，7.41(m，1H)。
EXAMPLE 94 preparation of methyl bromo-7-chloro-2, 3-dihydrobenzofuran-6-carboxylate
27.2g of Compound 9 was added to 140ml of an aqueous hydrochloric acid solution (concentrated hydrochloric acid and water in a volume ratio of 1: 1), and the reaction system was lowered to 0 ℃. 21g NaNO2Dissolved in 50ml of water, added dropwise to the above reaction system, and stirred at a controlled temperature of 0 ℃ for 1 hour. Dissolving 10g of cuprous chloride into 80ml of hydrochloric acid, slowly and dropwise adding the cuprous chloride into the reaction system at 0 ℃, stirring the reaction solution at 25-30 ℃ overnight, diluting the reaction system with 300ml of water, extracting with 500ml of ethyl acetate, separating the organic phase, drying, and concentrating to obtain 29g of a product with the yield of 99%.
1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，2.97(t，2H)，4.27(t，2H)，7.41(m，1H)。
While specific embodiments of the invention have been described in detail, those skilled in the art will understand that: various modifications and changes in detail can be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (9)
1. A process for preparing a compound of formula I, comprising the steps of:
(1) subjecting the compound of formula I-1 to a nitration reaction to obtain a compound of formula I-2;
(2) subjecting the compound of formula I-2 to a reduction reaction to obtain a compound of formula I-3;
(3) halogenating the compound of formula I-3 to obtain a compound of formula I-4;
(4) carrying out diazotization reaction on the compound of the formula I-4, and further reacting the obtained product with halogenated metal salt to generate the compound of the formula I;
wherein, in the above-mentioned compounds,
R1selected from cyano, C1-6Ester group and C2-6Alkenyl (e.g. C)2-4Alkenyl);
x and X' are each independently selected from halogen (e.g., Cl, Br, or I);
n is 1 or 2.
2. The method of claim 1, wherein R is1Is selected from C1-4An ester group;
preferably, R1Is selected from C1-2An ester group;
preferably, R1is-COOCH3。
3. The method of claim 1 or 2, wherein X is Br or I.
4. The method of any one of claims 1-3, wherein X' is Cl.
5. The method of any one of claims 1-4, wherein n is 1.
6. The method of any one of claims 1-5, wherein the method of synthesis of the compound of formula I-1 comprises the steps of:
a. performing iodination reaction on the compound of the formula I-4 to obtain a compound of a formula I-5;
b. carrying out a alkylation reaction on the compound of the formula I-5 to obtain a compound of a formula I-6; and/or
c. Cyclizing the compound of formula I-6 and reducing the carbon-carbon double bond of the furan ring in the product;
wherein R is2Selected from cyano, carboxyl and C2-6An alkenyl group;
n is 1 or 2.
7. The method of claim 6, when R is2When the carboxyl group is a carboxyl group, the method further comprises adding the carboxyl group to the mixture before or after the step a or the step cAnd (3) carrying out esterification.
8. Use of a compound of formula I for the preparation of a compound of formula II, wherein said compound of formula I is prepared by a process according to any one of claims 1 to 7;
the compound of formula II has the following structure:
wherein A is O or S;
x' is halogen or C1-7An alkyl group;
ring B is
Wherein Ra, Rb, Rc, Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7Alkyl radical, C1-7Alkylthio radical, C2-7Alkenyl radical, C2-7Alkynyl, C1-7Alkoxy radical, C1-7alkoxy-C1-7Alkyl radical, C2-7alkenyl-C1-7Alkoxy radical, C2-7alkynyl-C1-7Alkoxy radical, C3-10Cycloalkyl radical, C3-7Cycloalkylthio radical, C5-10Cycloalkenyl radical, C3-10Cycloalkoxy, C3-10cycloalkoxy-C1-7Alkoxy, phenyl-C1-7Alkyl radical, C1-7Alkylthio-phenyl, phenyl-C1-7Alkoxy, mono C1-7Alkylamino or di-C1-7Alkylamino radical, mono C1-7alkylamino-C1-7Alkyl or di-C1-7alkylamino-C1-7Alkyl radical, C1-7Alkanoyl radical, C1-7Alkanoylamino, C1-7Alkylcarbonyl group, C1-7Alkoxycarbonyl, carbamoyl, mono-C1-7Alkylcarbamoyl or di-C1-7Alkylcarbamoyl, C1-7Alkylsulfonylamino, phenylsulfonylamino, C1-7Alkylsulfinyl radical, C6-14Aryl sulfurAlkyl radical, C6-14Arylsulfonyl radical, C6-14Aryl, 5-to 13-membered heteroaryl, 5-to 10-membered heterocycloalkyl-C1-7Alkyl or 5-to 10-membered heterocycloalkyl-C1-7An alkoxy group;
ring C is C3-10Cycloalkyl radical, C5-10Cycloalkenyl radical, C6-14Aryl, 5-to 13-membered heteroaryl, or 5-to 10-membered heterocycloalkyl;
the alkyl, alkenyl, alkynyl and alkoxy groups are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7Alkyl and C2-7Substituent substitution of alkynyl;
said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl being unsubstituted or substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4Alkyl and C1-7Substituent substitution of alkoxy; and is
The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from N, S and O;
n is 1 or 2.
9. The use of claim 6, wherein the compound of formula II is
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024072109A1 (en) * | 2022-09-28 | 2024-04-04 | 주식회사 대웅제약 | Novel co-crystal of enavogliflozin |
| WO2024072108A1 (en) * | 2022-09-28 | 2024-04-04 | 주식회사 대웅제약 | Novel crystalline form of enavogliflozin, and preparation method therefor |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555369A (en) * | 2001-07-13 | 2004-12-15 | ����ҩƷ��ҵ��ʽ���� | Method for producing benzofuran derivative |
| CN101687842A (en) * | 2007-05-09 | 2010-03-31 | 沃泰克斯药物股份有限公司 | The CFTR conditioning agent |
| CN101899011A (en) * | 2009-05-26 | 2010-12-01 | 北京大学 | Dithiocarbamates compound, preparation method and application thereof |
| US20150152075A1 (en) * | 2011-06-01 | 2015-06-04 | Green Cross Corporation | Novel diphenylmethane derivatives as sglt2 inhibitors |
| CN108467375A (en) * | 2018-05-14 | 2018-08-31 | 刘可 | A kind of preparation method of dry eye drugs intermediate |
| CN109311861A (en) * | 2016-06-17 | 2019-02-05 | 株式会社大熊制药 | The method for being used to prepare diphenylmethane derivatives |
-
2019
- 2019-08-09 CN CN201910756094.8A patent/CN112341416A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555369A (en) * | 2001-07-13 | 2004-12-15 | ����ҩƷ��ҵ��ʽ���� | Method for producing benzofuran derivative |
| CN101687842A (en) * | 2007-05-09 | 2010-03-31 | 沃泰克斯药物股份有限公司 | The CFTR conditioning agent |
| CN101899011A (en) * | 2009-05-26 | 2010-12-01 | 北京大学 | Dithiocarbamates compound, preparation method and application thereof |
| US20150152075A1 (en) * | 2011-06-01 | 2015-06-04 | Green Cross Corporation | Novel diphenylmethane derivatives as sglt2 inhibitors |
| CN109311861A (en) * | 2016-06-17 | 2019-02-05 | 株式会社大熊制药 | The method for being used to prepare diphenylmethane derivatives |
| CN108467375A (en) * | 2018-05-14 | 2018-08-31 | 刘可 | A kind of preparation method of dry eye drugs intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 沈宁等: "2-氨基-5-氟苯甲酸甲酯的合成", 《应用化工》, vol. 37, no. 11, pages 1389 - 1390 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024072109A1 (en) * | 2022-09-28 | 2024-04-04 | 주식회사 대웅제약 | Novel co-crystal of enavogliflozin |
| WO2024072108A1 (en) * | 2022-09-28 | 2024-04-04 | 주식회사 대웅제약 | Novel crystalline form of enavogliflozin, and preparation method therefor |
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