CN113999200A - Synthetic method of thiodiazaspiro compound, intermediate and synthetic method thereof - Google Patents
Synthetic method of thiodiazaspiro compound, intermediate and synthetic method thereof Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The application discloses a method for preparing a thiodiazaspiro compound or a pharmaceutically acceptable salt thereof, which comprises the following steps, wherein the reaction conditions of the steps are mild, no other special equipment requirements exist, and the method is suitable for industrial production. The application also provides an intermediate compound, which is simple and convenient in preparation process, high in yield and purity and beneficial to high yield and high purity of subsequent products.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a thiodiazaspiro compound, an intermediate and a preparation method thereof.
Background
Compound 1, chemically known as 4- [7- (6-cyano-5-trifluoromethylpyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl ] -2-fluoro-N-methylbenzamide (aka aparetamide), is a second generation androgen receptor antagonist of intense development, belonging to the thiodiazaspiro class of compounds, for use in non-metastatic castration-resistant prostate cancer.
Apatamide is a derivative of diarylthiohydantoin, consisting of a pyridine ring, a benzene ring, cyclobutane and thiohydantoin ring systems connected together, the synthesis of which is developed mainly around the connection of arylamines and the construction of thiohydantoin ring systems, as shown below.
At present, the synthesis of apatamide generally comprises two types of "[ 3+2] and" [4+1], which are shown in the following table.
Among them, the synthesis route of the "[ 3+2] type" has two main routes: a compound 1 is prepared by the [3+2] cyclization of alpha-aminonitrile and thioisocyanate, such as CN201180009819.9, CN200780019654.7, CN200780020099.X and the synthetic method in China medicine industry journal, 2018, 49(4), and comprises the following specific steps:
the synthesis method uses highly toxic sodium cyanide and adopts a microwave method, thereby increasing the difficulty of industrial scale-up production and being not suitable for industrial production.
The second [3+2] preparation route is the synthesis method disclosed in compounds 1, such as CN201610985993.1, CN201711271655.2, CN201711474542.2, which is prepared by the [3+2] cyclization of α -carbamate with thioisocyanate, and is as follows:
the synthesis method has the advantages that the yield of each step is low, the cost is high, the reaction process and the post-treatment process are complicated, the optimization of intermediate purification in each step is not considered in detail, and the method is not suitable for industrial production and the like; therefore, the reaction process and post-treatment conditions in each step of the [3+2] path need to be further optimized and designed, so as to achieve the purposes of improving efficiency and yield and reducing cost, and meet the requirement of industrial production of the bulk drug.
The [4+1] type preparation method of apatamide is a synthetic method for preparing a compound 1 by performing [4+1] cyclization on alpha-aminoamide and thiocarbonyl compounds, such as CN201580069602.5, and specifically comprises the following steps:
the synthetic route requires the use of stoichiometric amounts of copper salts; and the final step of the [4+1] cyclization needs to use expensive thiocarbonyl compounds, so the cost is high.
Therefore, the synthetic method of apatamide has the advantages of simple process, few working procedures, simple and convenient operation and low production cost, and becomes a problem to be solved by technical personnel in the field.
Disclosure of Invention
Aiming at the problems in the prior art, the main purpose of the application is to provide a novel synthetic method of apatamide, which has the advantages of simple process, simple and convenient operation, mild reaction conditions of each step, no other special equipment requirements and suitability for industrial production.
The first aspect of the application provides a method for preparing a compound 1 shown as the following formula or a pharmaceutically acceptable salt thereof, which is characterized in that a compound 4 and a compound 2 are subjected to coupling reaction under the action of a catalytic amount of copper salt, an acid-binding agent, a ligand and an aprotic polar solvent to generate the compound 1,
wherein X is selected from chlorine, bromine and iodine.
In some embodiments, provided herein is the method for preparing compound 1, wherein the acid scavenger is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and potassium tert-butoxide.
In some embodiments, provided herein is a method of making compound 1, as described above, wherein the ligand is selected from the group consisting of 2-acetylcyclohexanone and tetramethylethylenediamine.
In some embodiments, provided herein is a method of making compound 1, as described above, wherein the aprotic polar solvent is selected from DMF and DMAc.
In some embodiments, provided herein is the above method for preparing compound 1, wherein the coupling reaction is a ullmann coupling reaction.
In some embodiments, the present application provides a method for preparing the above compound 1, wherein the coupling reaction is performed at a temperature of 105-130 ℃; more preferably, the coupling reaction is carried out at a temperature of 105 ℃ and 115 ℃.
In some embodiments, provided herein is a method for preparing compound 1 above, wherein the molar equivalent ratio of compound 4 to compound 2 is 1.0: 1.1 to 2.0; preferably 1.0: 1.5. In some embodiments, the preparation method of the compound 1 provided herein includes a step of purifying a crude product of the compound 1, specifically, washing the crude product of the compound 1, collecting an organic phase, adding anhydrous sodium sulfate, filtering, concentrating, heating to 80 ± 5 ℃, dropwise adding isopropanol, stirring for 2-3 hours, slowly cooling to 5 ± 5 ℃, stirring for 12-15 hours, filtering, and washing a filter cake with 10mL of isopropanol.
In some embodiments, the compound 4 is prepared by the following steps: carrying out cyclization reaction on a compound 7 and a compound 5 in the presence of a solvent and an acid-binding agent to generate a compound 4;
wherein R is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six-membered heteroaryl, said C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six membered heteroaryl are optionally independently selected from halogen, nitro, C2-C4Alkenyl radical, C2-C4Alkynyl and phenyl substituents; preferably, R is methyl or benzyl.
In some embodiments, provided herein is the method for preparing compound 4 above, wherein the solvent for the cyclization reaction is selected from the group consisting of N 'N-dimethylformamide, N' N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, and toluene; dimethyl sulfoxide is preferred.
In some embodiments, the acid scavenger is selected from triethylamine, N' N-diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1, 8-diazabicycloundece-7-ene, and tetramethylethylenediamine; triethylamine is preferred.
In some embodiments, the cyclization reaction is carried out at a temperature of from 70 ℃ to 110 ℃; preferably, the cyclization reaction is carried out at a temperature of 85-95 ℃.
In some embodiments, the compound 7 is prepared by the following steps:
wherein R is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six-membered heteroaryl, said C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six membered heteroaryl are optionally independently selected from halogen, nitro, C2-C4Alkenyl radical, C2-C4Alkynyl and phenyl substituents; by reacting the compounds 8 with acids or capable of hydrolysis in alcoholic mediaThe reagent reaction of the acid is converted into an ester compound 7;
alternatively, compound 8 is converted to compound 7 by carboxylic acid alkylation with a benzyl halide in the presence of an acid-binding agent.
In some embodiments, provided herein are methods of making compound 7 as described above, wherein the acid or reagent capable of hydrolyzing to an acid is selected from concentrated sulfuric acid, POCl3And thionyl chloride; preferably thionyl chloride;
the alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol; preferably methanol;
alternatively, the first and second electrodes may be,
the benzyl halide is selected from benzyl chloride and benzyl bromide;
the acid-binding agent is selected from sodium carbonate, potassium carbonate and cesium carbonate, and potassium carbonate is preferred. The carboxylic acid alkylation reaction is carried out in a suitable solvent selected from the group consisting of: acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, preferably N, N-dimethylformamide and acetonitrile.
In some embodiments, compound 5 is prepared by the following steps:
compound 6 is reacted in the presence of thiophosgene to form compound 5.
In some embodiments, the compound 2 is prepared by the following steps:
the compound 3 reacts with acid or a reagent which can be hydrolyzed into acid in an alcohol medium to be converted into ester, and then the compound 2 is generated through one-pot methylamine hydrolysis reaction.
In some embodiments, the present application provides the above method for preparing compound 2, wherein the acid or the reagent capable of hydrolyzing to an acid is an organic acid, an inorganic acid or a mixture thereof; preferably, it is selected from concentrated sulfuric acid, phosphorus oxychloride and thionyl chloride;
in some embodiments, provided herein is a method for preparing compound 2, wherein the alcoholic medium is selected from methanol, ethanol, isopropanol, and benzyl alcohol.
In a second aspect of the present application, there is provided a compound of the structure shown below,
in some embodiments, the compound 4 is prepared by the above preparation method.
In a third aspect, the present application provides the use of compound 4 as described above for the preparation of compound 1.
The preparation method of the compound 1 provided by the application has the following advantages:
(1) the preparation method provided by the application is a convergent synthesis route, and is more beneficial to improving the reaction yield and reducing side reactions compared with linear synthesis.
(2) In the synthetic method of apatamide disclosed in the prior art, the construction of a thiohydantoin ring system is placed in the later stage of synthesis, but the cyclization effect of [3+2] is not good enough due to the complex substrate system; the intermediate compound 4 is obtained through preferential synthesis, the problem of building the thiohydantoin ring system is creatively solved in the early stage of synthesis, and the problems in the prior art are smoothly solved. The yield of the thiohydantoin ring system constructed in the application is 92%, which is obviously improved compared with the prior art; is beneficial to obtain the final product with high yield.
Detailed Description
The technical solutions of the present application will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art without any inventive work based on the embodiments in the present application are within the scope of protection of the present application.
The examples of the present application do not indicate specific conditions, and the examples are conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Definition of
“C1-C6Alkyl "refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.
“C3-C6Cycloalkyl "refers to a saturated monocyclic, fused, spiro or bridged ring containing the indicated number of carbon atoms. For example: cycloalkyl is a 3 to 6 membered monocyclic group. Including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"heteroaryl" refers to a 5 or 6 membered aromatic ring containing at least one N, O or S heteroatom, for example, pyridinyl, pyrimidinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, thienyl or pyrazinyl.
"halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
"optionally substituted" means that the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.
Instrument for measuring the position of a moving object
The structure of the compound is determined by nuclear magnetic resonance1H) Or Mass Spectrometry (MS).
1H-spectroscopy adopts Bruker superconducting nuclear magnetic resonance spectrometer (instrument model: BRUKERAVANCE400 type nuclear magnetic resonance instrument); the solvent DMSO-d6 is a mixture of DMSO-d6,the temperature is 22 ℃;
LC-MS detection adopts: agilent 6120B Ms liquid chromatography-single four-stage rod, positive ion mode, ESI ionization source and scanning range of 50-3000 m/z
The abbreviations of the reagents referred to in the examples have the following Chinese meanings:
| abbreviations | Name of Chinese | Abbreviations | Name of Chinese |
| SOCl2 | Thionyl chloride | MeOH | Methanol |
| TEA | Triethylamine | DMSO | Dimethyl sulfoxide |
| CuI | Cuprous iodide | K2CO3 | Potassium carbonate |
| TMEDA | Tetramethyl ethylene diamine | DMF | N, N-dimethylformamide |
| equiv | Molar equivalent ratio | DMAc | N, N-dimethyl acetamide |
Example 1A: preparation of Compound 7A (1-Aminocyclobutanecarboxylic acid methyl ester) from Compound 8
Dissolving 1-aminocyclobutanecarboxylic acid (compound 8) (86.86mmol) in methanol (50mL), reducing the temperature to 15 +/-5 ℃ under the protection of nitrogen, slowly dropwise adding thionyl chloride (130.28mmol), controlling the temperature to 15 +/-5 ℃, heating to 25 +/-5 ℃ after dropwise adding is finished, adding 100mL of purified water after the raw materials completely react, dropwise adding a saturated sodium bicarbonate solution to adjust the pH to 8-9, extracting twice by using 100mL of ethyl acetate, collecting an organic phase, adding anhydrous sodium sulfate for drying, concentrating the ethyl acetate until the ethyl acetate is dry to obtain a white solid, and performing forced air drying to obtain 10.56g of compound 7A with the yield of 94%.
LC-MS：[M+H]+＝130
1H NMR(400MHz,CDCl3)δ3.76(s,3H),2.58-2.53(m,2H),2.04-1.91(m,4H).
Example 1B: preparation of Compound 7B (benzyl 1-aminocyclobutane-1-carboxylate) from Compound 8
Dissolving 1-aminocyclobutanecarboxylic acid (compound 8) (86.86mmol) in acetonitrile (50mL), adding potassium carbonate (173.72mmol) under nitrogen protection, heating to 60 +/-5 ℃, slowly adding benzyl chloride (95.55mmol) dropwise, controlling the temperature to be 60 +/-5 ℃, after the raw materials completely react, adding 150mL of purified water dropwise, filtering to obtain a white solid, and drying by air blowing to obtain 15.15g of compound 7B with the yield of 85%.
LC-MS：[M+H]+＝206.
1H NMR(400MHz,CDCl3):δ7.40-7.20(m,5H),δ5.20(s,2H)2.56-2.46(m,2H),2.11-2.01(m,2H),2.00-1.90(m,2H).
Example 2: preparation of Compound 5 (5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine) from Compound 6
Dissolving 5-amino-3-trifluoromethyl-2-cyanopyridine (compound 6) (0.53mol) in 0.5L acetone, dropwise adding thiophosgene (0.64mol), reacting at room temperature for 1-3 h, then carrying out reduced pressure distillation to remove most of the solvent, adding 1.0L n-hexane and 50g neutral alumina into the residue, heating to 40 +/-5 ℃, stirring for 1 hour, filtering and concentrating to obtain 105g of compound 5, namely a white solid with the yield of 86%.
1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝2.2Hz,1H),8.57(d,J＝2.3Hz,1H).
Example 3: preparation of Compound 2A (N-methyl-4-bromo-2-fluorobenzamide) from Compound 3A
Dissolving 4-bromo-2-fluorobenzoic acid (compound 3A) (45.66mmol) in methanol (30mL), slowly dropwise adding 27.40mmol of thionyl chloride under the protection of nitrogen, controlling the temperature to be 15 +/-5 ℃, heating to be 45 +/-5 ℃ after dropwise adding is finished, slowly cooling to be 25 +/-5 ℃ after raw materials are completely reacted, slowly dropwise adding 0.32mol (25-30%) of methylamine water solution (25-30%), after dropwise adding is finished, keeping the temperature to be 25 +/-5 ℃, continuously reacting for 2 hours, controlling the temperature to be 25 +/-5 ℃, slowly dropwise adding 150mL of purified water, and continuously stirring for two hours after dropwise adding is finished; filtering, collecting filter cakes, blowing and drying the filter cakes at 50 +/-5 ℃, and collecting to obtain 10.38g of the compound 2A with the yield of 98%.
LC-MS：m/z＝231.9[M+1]+、233.9[M+3]+
1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.64-7.52(m,2H),7.46(d,J＝8.3Hz,1H),2.80(d,J＝4.8Hz,3H).
Example 4A: preparation of Compound 4 from Compound 7A and Compound 5
Under nitrogen protection, compound 7A (38.71mmol), DMSO (15mL) and triethylamine (77.42mmol) were added to a reaction flask, the temperature was raised to 90. + -. 5 ℃ and compound 5(77.42mmol) was added and stirred for 16 hours. Concentrating the reaction solution to dryness, heating to 80 +/-5 ℃, slowly adding n-heptane (50mL) dropwise, stirring for 2 hours, slowly cooling to room temperature, stirring for 12 hours, filtering, leaching the filter cake twice by using 10mL of n-heptane, and drying the material in vacuum at 45 +/-5 ℃ for 16 hours to obtain 11.68g of compound 4 with the yield of 92%.
Example 4B: preparation of Compound 4 from Compound 7B and Compound 5
Under nitrogen protection, compound 7B (38.71mmol), DMSO (20mL) and triethylamine (77.42mmol) were added to a reaction flask, the temperature was raised to 90. + -. 5 ℃ and compound 5(77.42mmol) was added and stirred for 16 hours. Concentrating the reaction solution to dryness, heating to 80 +/-5 ℃, slowly adding n-heptane (50mL) dropwise, stirring for 2 hours, slowly cooling to room temperature, stirring for 12 hours, filtering, leaching the filter cake twice by using 10mL of n-heptane, and drying the material in vacuum at 45 +/-5 ℃ for 16 hours to obtain 10.92g of compound 4 with the yield of 86%.
[M+H+]＝327.05。
1H-NMR(400Hz,CDCl3)：δ11.26(s,1H),δ9.10(s,1H),δ8.65(s,1H),δ2.61–2.54(m,2H),δ2.49–2.41(m,2H),δ1.99–1.81(m,2H).
Example 5: preparation of Compound 1 from Compound 4 and Compound 2A
Mixing compound 4(15.32mmol), compound 2A (22.98mmol) and K2CO3(45.96mmol), CuI (0.77mmol) and tetramethylethylenediamine (7.66mmol) are added into 30mL DMF, the mixture is cooled to room temperature after reacting for 6h at 110 +/-5 ℃ under the protection of nitrogen, 7.5mL of concentrated ammonia water is added and stirred for half an hour, 50mL of purified water is added, 50mL of ethyl acetate is added, extraction is carried out for three times, and organic phases are combined. And adding 10mL of purified water to wash the organic phase twice, collecting the organic phase, adding anhydrous sodium sulfate into the organic phase, filtering, concentrating the filtrate to be dry, heating to 80 +/-5 ℃, slowly dropwise adding isopropanol (50mL), stirring for 2 hours, slowly cooling to 5 +/-5 ℃, stirring for 12 hours, filtering, leaching the filter cake twice by using 10mL of isopropanol, and drying the material in vacuum at 45 +/-5 ℃ for 16 hours to obtain 6.42g of compound 1 with the yield of 87%.
LC-MS：m/z＝478.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝2.0Hz,1H),8.77(d,J＝2.0Hz,1H),8.54–8.39(m,1H),7.92(t,J＝8.0Hz,1H),7.50(dd,J＝10.5,1.8Hz,1H),7.43(dd,J＝8.1,1.8Hz,1H),2.89(d,J＝4.6Hz,3H),2.78–2.66(m,2H),2.64–2.49(m,2H),2.11–1.98(m,1H),1.72–1.55(m,1H).
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications and equivalents of the present invention, which are made by the present specification or directly/indirectly applied to other related technical fields under the inventive concept of the present invention, are included in the scope of the present invention.
Claims (11)
1. A method for preparing a compound 1 or a pharmaceutically acceptable salt thereof is characterized in that a compound 4 and a compound 2 are subjected to coupling reaction under the action of a catalytic amount of copper salt, an acid-binding agent, a ligand and an aprotic polar solvent to generate the compound 1,
wherein X is selected from chlorine, bromine and iodine.
2. The process according to claim 1, wherein the acid scavenger is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide;
the ligand is selected from 2-acetyl cyclohexanone and tetramethyl ethylene diamine;
the aprotic polar solvent is selected from DMF and DMAc;
the coupling reaction is carried out at a temperature of 105-130 ℃; preferably, the coupling reaction is carried out at a temperature of 105-115 ℃;
the molar equivalent ratio of compound 4 to compound 2 is 1.0: 1.1 to 2.0; preferably 1.0: 1.5.
3. The preparation method according to claim 1, wherein said compound 4 is prepared by a method comprising the steps of: carrying out cyclization reaction on a compound 7 and a compound 5 in the presence of a solvent and an acid-binding agent to generate a compound 4;
wherein R is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six-membered heteroaryl, said C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl and six membered heteroaryl are optionally independently selected from halogen, nitro, C2-C4Alkenyl radical, C2-C4Alkynyl and phenyl substituents; preferably, R is methyl or benzyl.
4. The production process according to claim 3, wherein the solvent for the cyclization reaction is selected from the group consisting of N 'N-dimethylformamide, N' N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone and toluene; preferably dimethyl sulfoxide;
the acid-binding agent is selected from triethylamine, N' N-diisopropylethylamine, triethylene diamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1, 8-diazabicycloundecen-7-ene and tetramethylethylenediamine; preferably triethylamine;
the cyclization reaction is carried out at the temperature of 70-110 ℃; preferably, the cyclization reaction is carried out at a temperature of 85-95 ℃.
5. The method according to claim 3, wherein the compound 7 is produced by a method comprising the steps of,
reacting the compound 8 with an acid or a reagent capable of being hydrolyzed into an acid in an alcohol medium to convert the compound into an ester compound 7; alternatively, the first and second electrodes may be,
and (3) carrying out carboxylic acid alkylation reaction on the compound 8 and benzyl halide in the presence of an acid binding agent to convert the compound into a compound 7.
6. The process according to claim 5, wherein the acid or the reagent capable of hydrolyzing into an acid is selected from the group consisting of concentrated sulfuric acid, POCl3And thionyl chloride; preferably thionyl chloride;
the alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol; preferably methanol;
alternatively, the first and second electrodes may be,
the benzyl halide is selected from benzyl chloride and benzyl bromide;
the acid-binding agent is selected from sodium carbonate, potassium carbonate and cesium carbonate, and potassium carbonate is preferred;
the carboxylic acid alkylation reaction is carried out in a suitable solvent selected from the group consisting of: acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide; preference is given to N, N-dimethylformamide and acetonitrile.
7. The method of claim 3, wherein Compound 5 is prepared by a process comprising:
compound 6 is reacted in the presence of thiophosgene to form compound 5.
8. The method of claim 1, wherein Compound 2 is prepared by a process comprising:
the compound 3 reacts with acid or a reagent which can be hydrolyzed into acid in an alcohol medium to be converted into ester, and then the compound 2 is generated through one-pot methylamine hydrolysis reaction.
9. The method according to claim 8, wherein the acid or the agent capable of hydrolyzing into an acid is an organic acid, an inorganic acid, or a mixture thereof; preferably, it is selected from concentrated sulfuric acid, phosphorus oxychloride and thionyl chloride;
the alcoholic medium is selected from methanol, ethanol, isopropanol and benzyl alcohol.
10. A compound represented by the following formula, having the structure shown in the following formula,
11. use of a compound according to claim 10 in the preparation of compound 1.
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