Synthesis method of dihydrobenzofuran derivative

Abstract

The invention provides a method for preparing a dihydrobenzofuran derivative, which comprises the following steps: reacting a compound as shown in a formula III with corresponding amine or amine salt to prepare a compound as shown in a formula II, and reacting the compound as shown in the formula II with a methylene transfer reagent to prepare a compound as shown in a formula I. The method has the advantages of few synthesis steps, mild reaction conditions, simple operation and high yield. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly to a method for synthesizing dihydrobenzofuran derivatives. Background Art

[0002] Dihydrobenzofuran derivatives have been proven to have important applications in many biological medicines. Due to the special five-membered oxygen heterocyclic skeleton structure of dihydrobenzofuran, aromatization is likely to occur during the synthesis process, resulting in great challenges in the synthesis of its related derivatives. Currently, with the development of the biological medicine field, the applications of dihydrobenzofuran derivatives are becoming more and more extensive. Therefore, there is a need for effective, shorter routes, cost-effective and suitable for large-scale production methods to prepare dihydrobenzofuran derivatives. Summary of the Invention

[0003] The present invention provides a method for synthesizing a compound represented by formula I, its stereoisomers, tautomers or isotopically labeled compounds:

[0004]

[0005] This method has fewer synthesis steps, mild reaction conditions, simple operation and high total yield of reaction products.

[0006] One aspect of the present invention provides a method for preparing a compound represented by formula II, comprising the following step 1: reacting a compound represented by formula III with a corresponding amine (R-NH2) or amine salt in a protic or aprotic organic solvent or water to prepare a compound represented by formula II,

[0007]

[0008] wherein,

[0009] R is selected from C 1-6 alkyl optionally substituted by phenyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic group, and the phenyl is optionally substituted by 1, 2 or 3 C 1-6 alkoxy groups;

[0010] Y is selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0011] Z 1 、Z 2 and Z 3 each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl each time they appear.

[0012] Another aspect of the present invention provides a method for preparing a compound of formula I, its stereoisomers, tautomers or isotopically labeled compounds, comprising step 1 described above, and the following step 2: reacting a compound of formula II with a methylene transfer reagent in a protic or aprotic organic solvent to prepare a compound of formula I,

[0013]

[0014] wherein R, Y, Z 1 , Z 2 and Z 3 are as defined above.

[0015] Another aspect of the present invention provides a compound of formula II', its stereoisomers, tautomers, isotopically labeled compounds or salts thereof,

[0016]

[0017] wherein,

[0018] R' is selected from C 1-6 alkyl;

[0019] Y' is selected from C 1-6 haloalkyl;

[0020] Z 1 , Z 2 and Z 3 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl each time they appear. Detailed Description

[0021] Definition

[0022] Unless otherwise defined hereinafter, 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. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those techniques that are obvious to one of ordinary skill in the art or substitutions of equivalent techniques. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present invention.

[0023] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6"Alkyl" refers to a linear or branched group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0024] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms, and the terms "C 1-8 haloalkyl", "C 1-6 haloalkyl" and "C 1-4 haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0025] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spiro, fused (condensed) or bridged ring systems (i.e., spiroalkyl, fused (condensed) alkyl and bridged alkyl, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.). In the present invention, the cycloalkyl is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted by an oxo group (i.e., forming C=O). The term "C 3-8 cycloalkyl" refers to a cycloalkyl having 3 to 8 ring-forming carbon atoms, such as C 3-6 cycloalkyl, which can be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or can be a bicyclic alkyl group, such as C 5-8 spiroalkyl, C 5-8 bridged alkyl, C 5-8 fused alkyl, C 5-6 spiroalkyl, C 5-6 bridged alkyl or C 5-6 fused alkyl.

[0026] As used herein, the term "heterocyclic group" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spiro or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms, and one or more (e.g., 1, 2, 3 or 4) heteroatoms, said heteroatoms including but not limited to oxygen, nitrogen and sulfur atoms, and the carbon atoms and heteroatoms on the heterocyclic group are optionally substituted with oxo groups (e.g., to form C=O, S(=O) or S(=O)2), or optionally substituted with one or more (such as 1 to 3) substituents independently selected from halogen and C 1-3 alkyl.

[0027] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

[0028] If a substituent is described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0029] The term "stereoisomer" refers to isomers formed due to at least one asymmetric center. In a compound having one or more (e.g., one, two, three or four) asymmetric centers, it can give rise to a racemic mixture, a single enantiomer, a mixture of diastereomers and individual diastereomers. A particular individual molecule may also exist as a geometric isomer (cis / trans). Similarly, the compounds of the present invention may exist as a mixture of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:

[0030]

[0031] It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0032] A solid line a solid wedge or a dashed wedge Depict the chemical bonds of the compounds of the present invention. Using solid lines to depict the bonds attached to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., a specific enantiomer, a racemic mixture, etc.). Using solid or dashed wedges to depict the bonds attached to an asymmetric carbon atom is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereoisomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

[0033] The term "about" means within ±10% of the stated value, preferably within ±5% of the stated value, more preferably within ±2% of the stated value.

[0034] It should be noted that if there is a difference between the described structure and the name of that structure, the described structure will be given greater weight.

[0035] Preparation method

[0036] In one aspect, the present invention provides a method for preparing a compound of formula II, comprising the following step 1: reacting a compound of formula III with the corresponding amine (R-NH2) or amine salt in a protic or aprotic organic solvent or water to prepare a compound of formula II,

[0037]

[0038] wherein,

[0039] R is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclic group, said phenyl being optionally substituted by 1, 2, or 3 C 1-6 alkoxy groups;

[0040] Y is selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0041] Z 1 、Z 2 and Z 3 each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl each time they appear.

[0042] On the one hand, the present invention provides a method for preparing a compound represented by Formula II, comprising the following Step 1: reacting a compound represented by Formula III with a corresponding amine or amine salt in a protic or aprotic organic solvent or water to prepare a compound represented by Formula II,

[0043]

[0044] wherein,

[0045] R is selected from C 1-6 alkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group;

[0046] Y is selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0047] Z 1 、Z 2 and Z 3 each independently represents H, halogen, C 1-6 alkyl, C 1-6 haloalkyl each time it appears.

[0048] In some embodiments, R is C 1-6 alkyl. In some embodiments, R is methyl or ethyl.

[0049] In some embodiments, R is C 1-6 alkyl substituted with phenyl, and the phenyl is substituted with 1, 2 or 3 C 1-6 alkoxy groups. In some embodiments, R is 2,4-dimethoxybenzyl.

[0050] In some embodiments, R is C 3-8 cycloalkyl. In some embodiments, R is cyclopropyl.

[0051] In some embodiments, Y is C 1-6 haloalkyl. In some embodiments, Y is trifluoromethyl.

[0052] In some embodiments, Y is halogen. In some embodiments, Y is Br.

[0053] In some embodiments, Y is C 1-6 alkyl. In some embodiments, Y is methyl.

[0054] In some embodiments, Z 1 、Z 2 and Z 3 are H.

[0055] In some embodiments, the compound of Formula III is In some embodiments, the compound of formula III is

[0056] In some embodiments, the compound of formula II is In some embodiments, the compound of formula II is In some embodiments, the compound of formula II is

[0057] In some embodiments, the protic or aprotic organic solvent in Step 1 is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. In some embodiments, the protic or aprotic organic solvent in Step 1 is methanol.

[0058] In some embodiments, the reaction temperature in Step 1 is 0 °C to 100 °C, preferably 10 °C to 70 °C, more preferably 10 °C to 50 °C. In some embodiments, the reaction in Step 1 is carried out at about 20 °C.

[0059] In some embodiments, the equivalent ratio of the amine or amine salt in Step 1 to the compound represented by formula III is 1 to 10:1, preferably 1 to 5:1, more preferably 2 to 4:1. In some embodiments, the equivalent ratio of the amine or amine salt in Step 1 to the compound represented by formula III is about 3:1. In some embodiments, the equivalent ratio of the amine or amine salt in Step 1 to the compound represented by formula III is about 2:1.

[0060] In some embodiments, the amine in Step 1 is an alkylamine. In some embodiments, the amine in Step 1 is a C 1-6 alkylamine. In some embodiments, the amine in Step 1 is methylamine.

[0061] In some embodiments, the amine in Step 1 is a C-alkylamine substituted with a phenyl group, and the phenyl group is substituted with 1, 2, or 3 C 1-6 alkoxy groups. In some embodiments, the amine in Step 1 is 2,4-dimethoxybenzylamine. 1-6 In some embodiments, the amine in Step 1 is a cycloalkylamine. In some embodiments, the amine in Step 1 is a C

[0062] cycloalkylamine. In some embodiments, the amine in Step 1 is cyclopropylamine. 3-8 In some embodiments, the amine in Step 1 is a cycloalkylamine. In some embodiments, the amine in Step 1 is a C

[0063] In some embodiments, the amine in Step 1 is provided in the form of an amine solution. In some embodiments, the amine solution is selected from a methanol solution of an amine, an ethanol solution of an amine, an aqueous solution, a tetrahydrofuran solution, etc. For example, when the amine in Step 1 is methylamine, the amine is provided in the form of a methylamine solution, such as a methylamine methanol solution, a methylamine ethanol solution, a methylamine aqueous solution, a methylamine tetrahydrofuran solution, etc.

[0064] In some embodiments, the amine in Step 1 is provided in the form of an amine salt.

[0065] In some embodiments, the amine salt in Step 1 is the hydrochloride, hydrobromide, hydroiodide or sulfate of the amine. For example, when the amine in Step 1 is methylamine, the amine salt is provided in the form of a methylamine salt, such as methylamine hydrochloride, methylamine hydrobromide, methylamine hydroiodide, methylamine sulfate, etc.

[0066] In some embodiments, when the amine in Step 1 is methylamine, it is preferred to use the form of methylamine salt because methylamine solution is a flammable, explosive and regulated product with great potential safety hazards in production, while methylamine salt has stable properties, is cheap and easily available, and is safe for transportation and storage. Therefore, it has the advantage of factory scale-up production.

[0067] In some embodiments, in Step 1, in a protic or aprotic organic solvent, the compound shown in Formula III and the corresponding amine salt react under the action of a base to prepare the compound shown in Formula II.

[0068] In some embodiments, the base in Step 1 is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine and pyridine. In some embodiments, the base in Step 1 is triethylamine.

[0069] In some embodiments, the equivalent ratio of the base in Step 1 to the compound shown in Formula III is 1 to 10:1. In some embodiments, the equivalent ratio of the base in Step 1 to the compound shown in Formula III is 2 to 8:1, preferably 3 to 7:1, preferably 4 to 6:1. In some embodiments, the equivalent ratio of the base in Step 1 to the compound shown in Formula III is 1 to 5:1, such as about 5:1.

[0070] In some embodiments, in Step 1, in a protic or aprotic organic solvent, the compound shown in Formula III and the corresponding amine react under the action of a drying agent to prepare the compound shown in Formula II.

[0071] In some embodiments, the drying agent in Step 1 is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, calcium sulfate and molecular sieve. In some embodiments, the drying agent in Step 1 is anhydrous magnesium sulfate.

[0072] In some embodiments, the equivalent ratio of the desiccant in Step 1 to the compound represented by Formula III is 1 to 10:1, preferably 2 to 8:1. In some embodiments, the equivalent ratio of the desiccant in Step 1 to the compound represented by Formula III is about 6:1.

[0073] Another aspect of the present invention provides a method for preparing a compound represented by Formula I, its stereoisomers, tautomers or isotopically labeled compounds, comprising Step 1 as described in any one of the foregoing, and the following Step 2: reacting a compound represented by Formula II with a methylene transfer reagent in a protic or aprotic organic solvent to prepare a compound represented by Formula I,

[0074]

[0075] wherein R, Y, Z 1 , Z 2 and Z 3 are defined as in any one of the foregoing.

[0076] Another aspect of the present invention provides a method for preparing a compound represented by Formula I, its stereoisomers, tautomers or isotopically labeled compounds, comprising the above Step 2 and optionally Step 1 as described in any one of the foregoing.

[0077] In some embodiments, the compound of Formula II is The compound of Formula I is

[0078] In some embodiments, the compound of Formula II is The compound of Formula I is

[0079] In some embodiments, the compound of Formula II is The compound of Formula I is

[0080] In some embodiments, the compound of Formula II is The compound of Formula I is

[0081] In some embodiments, the reaction temperature of Step 2 is 0 °C to 100 °C, preferably 20 °C to 60 °C.

[0082] In some embodiments, the methylene transfer reagent in Step 2 is selected from dimethylmethylene sulfonium ylide and sulfoxide ylide reagents, preferably trimethylsulfoxonium iodide or trimethylsulfonium iodide.

[0083] In some embodiments, the protic or aprotic organic solvent in step 2 is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0084] In some embodiments, the equivalent ratio of the methylene transfer reagent to the compound represented by formula II in step 2 is 1 to 5:1, preferably 2 to 3:1. In some embodiments, the equivalent ratio of the methylene transfer reagent to the compound represented by formula II in step 2 is about 2.5:1.

[0085] In some embodiments, the reaction in step 2 is carried out under the action of a base. In some embodiments, the base in step 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, NaH, NaHMDS, NaOH, sodium tert-butoxide, potassium tert-butoxide, and pyridine. In some embodiments, the base in step 2 is potassium tert-butoxide.

[0086] In some embodiments, the equivalent ratio of the base in step 2 to the compound represented by formula II is 1 to 5:1, preferably 2 to 4:1, preferably 2 to 3:1. In some embodiments, the equivalent ratio of the base in step 2 to the compound represented by formula II is about 2.5:1. In some embodiments, the equivalent ratio of the base in step 2 to the compound represented by formula II is about 3.5:1.

[0087] In some embodiments, the method for preparing the compound represented by formula I, its stereoisomers, tautomers, or isotope-labeled compounds further includes step 3: resolving the compound of formula I into S and R configurational isomers.

[0088] In some embodiments, this resolution step uses resolution methods known in the art, such as using supercritical fluid chromatography (SFC) technology or chemical resolution methods, etc. In some embodiments, the chemical resolution method is by means of a chemical reaction, that is, using a chiral reagent to convert the two enantiomers of formula I into diastereoisomers, and then separating the two by utilizing the differences in physical and chemical properties between the diastereoisomers.

[0089] In some embodiments, the method for preparing the compound represented by formula I, its stereoisomers, tautomers, or isotope-labeled compounds includes the following steps:

[0090]

[0091] wherein,

[0092] R, Y, Z 1 、Z 2 and Z 3 are as defined in any one of the foregoing.

[0093] In some embodiments, the present invention provides the following synthetic route:

[0094]

[0095] Intermediate

[0096] Another aspect of the present invention provides a compound of formula II, its stereoisomers, tautomers, isotopically labeled compounds or salts thereof,

[0097]

[0098] wherein R, Y, Z 1 , Z 2 and Z 3 are as defined in any one of the foregoing.

[0099] The compound of formula II is an intermediate for preparing the compound of formula I.

[0100] In some embodiments, the compound of formula II is a compound of formula II':

[0101]

[0102] wherein,

[0103] R' is selected from C 1-6 alkyl and C 3-8 cycloalkyl, optionally substituted with phenyl, and the phenyl is substituted with 1, 2 or 3 C 1-6 alkoxy groups;

[0104] Y' is selected from halogen and C 1-6 haloalkyl;

[0105] Z 1 , Z 2 and Z 3 each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl each time it appears.

[0106] In some embodiments, in the compound of formula II',

[0107] R' is selected from C 1-6 alkyl;

[0108] Y' is selected from C 1-6 haloalkyl;

[0109] Z 1 , Z 2 and Z 3Each independently selected from H, halogen, C at each occurrence 1-6 alkyl, C 1-6 haloalkyl.

[0110] In some embodiments, in the compound of formula II’, R’ is methyl.

[0111] In some embodiments, in the compound of formula II’, Y’ is trifluoromethyl.

[0112] In some embodiments, in the compound of formula II’, Z 1 、Z 2 and Z 3 are H.

[0113] In some embodiments, the compound of formula II is In some embodiments, the compound of formula II is In some embodiments, the compound of formula II is In some embodiments, the compound of formula II is

[0114] All the technical features disclosed in this specification, or the steps or reaction conditions in all the methods or processes disclosed, except for the mutually exclusive technical features and / or steps and / or reaction conditions, can be combined in any way.

[0115] Example

[0116] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation to the present invention. For those without specific technical or conditions noted in the examples, the techniques or conditions described in the literature in this field or according to the product specifications are followed. For the reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0117] Example 1: Synthesis of N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0118]

[0119] The first step: Synthesis of intermediate 1-2 (method a)

[0120] Methylamine hydrochloride (1.07 g, 15.78 mmol) and triethylamine (2.66 g, 26.30 mmol, 3.66 mL) were dissolved in 15 mL of methanol. After stirring for 30 minutes, a methanol solution (5 mL) of 2-hydroxy-4-(trifluoromethyl)benzaldehyde (1 g, 5.26 mmol) was added. After addition, the reaction system was reacted at 20 °C for 12 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 1-2 (0.97 g), and the product was used for the next step without further purification. MS (ESI, m / z): 204.1 [M+H] + 。

[0121] Step 2: Synthesis of N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0122] Trimethylsulfoxonium iodide (2.63 g, 11.94 mmol) was dissolved in 10 mL of tetrahydrofuran. Potassium tert-butoxide (1.34 g, 11.94 mmol) was added. After the reaction system was reacted at 20 °C for 30 min, a tetrahydrofuran solution (10 mL) of compound 1-2 (0.97 g, 4.77 mmol) was added dropwise. After addition, the reaction system was stirred at 20 °C for 1 h, then heated to 50 °C and stirred for 3 h. After cooling to room temperature, another equivalent of potassium tert-butoxide (535.24 mg, 4.77 mmol) was added, and the reaction was carried out at 20 °C for 12 h. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure, and was separated and purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 1 (0.9 g, 4.14 mmol, total yield of two steps 78.7%). MS (ESI, m / z): 218.2 [M+H] + 。

[0123] Step 1: Synthesis of Intermediate 1-2 (Method b)

[0124] A methylamine methanol solution (1.63 g, 15.78 mmol, 30% pure) was dissolved in 20 mL of methanol. 2-Hydroxy-4-(trifluoromethyl)benzaldehyde (1 g, 5.26 mmol) and anhydrous magnesium sulfate (3.80 g, 31.56 mmol) were added. After addition, the reaction system was reacted at 20 °C for 12 h, filtered, and concentrated under reduced pressure to obtain compound 1-2 (0.88 g), and the product was used for the next step without further purification. MS (ESI, m / z): 204.1 [M+H] + 。

[0125] Step 2: Synthesis of N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0126] Dissolve trimethylsulfoxonium iodide (2.38 g, 10.83 mmol) in 10 mL of tetrahydrofuran, add potassium tert-butoxide (1.22 g, 10.83 mmol). After the reaction system reacts at 20 °C for 30 min, add dropwise a solution of compound 1-2 (0.88 g, 4.33 mmol) in tetrahydrofuran (10 mL). After addition, the reaction system is stirred at 20 °C for 1 hr, then heated to 50 °C and stirred for 3 hr. Cool to room temperature, add another equivalent of potassium tert-butoxide (486.04 mg, 4.33 mmol). After addition, react at 20 °C for 12 hr. After the reaction is completed, filter and concentrate under reduced pressure, and purify by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 1 (0.8 g, 3.68 mmol, total yield of two steps 70%). MS (ESI, m / z): 218.2 [M+H] + 。

[0127] 1 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 7.6 Hz, 1H), 7.24 (dd, J = 7.8, 1.6 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 4.65–4.56 (m, 1H), 4.53–4.43 (m, 1H), 4.43–4.35 (m, 1H), 2.26 (s, 3H).

[0128] Example 2: Synthesis of ethyl-(6-trifluoromethyl-2,3-dihydrobenzofuran-3-yl)-amine

[0129]

[0130] The first step: Synthesis of intermediate 2-1

[0131] Dissolve ethylamine (1.07 g, 23.67 mmol, purity: 68 - 72% aqueous solution) in 20 mL of methanol, add 2-hydroxy-4-(trifluoromethyl)benzaldehyde (1.5 g, 7.89 mmol), anhydrous magnesium sulfate (4.75 g, 39.45 mmol). After addition, the reaction system reacts at 20 °C for 12 hr, filter, and concentrate under reduced pressure to obtain compound 2-1 (1.7 g). The product is used in the next step without further purification. MS (ESI, m / z): 218.1 [M+H] + 。

[0132] The second step: Synthesis of ethyl-(6-trifluoromethyl-2,3-dihydrobenzofuran-3-yl)-amine

[0133] Dissolve trimethylsulfoxonium iodide (4.31 g, 19.57 mmol) in 20 mL of tetrahydrofuran, add potassium tert-butoxide (2.20 g, 19.57 mmol). After the reaction system reacts at 20 °C for 30 min, add dropwise a solution of compound 2-1 (1.7 g, 7.83 mmol) in tetrahydrofuran (10 mL). After addition, the reaction system is stirred at 20 °C for 1 hr, then heated to 50 °C and stirred for 5 hr. Cool to room temperature, add another equivalent of potassium tert-butoxide (1.72 g, 7.83 mmol). After addition, react at 20 °C for 12 hr. After the reaction is completed, filter and concentrate under reduced pressure, and separate and purify by silica gel column chromatography (DCM:MeOH = 94:6) to obtain compound 2 (1.45 g, 6.27 mmol, total yield of two steps 79.6%). MS (ESI, m / z): 232.1 [M+H] + 。

[0134] 1 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 1H), 7.19–7.14 (m, 1H), 7.06 (s, 1H), 4.61 (dd, J = 9.6, 7.6 Hz, 1H), 4.53–4.48 (m, 1H), 4.44 (dd, J = 9.6, 4.0 Hz, 1H), 2.83–2.72 (m, 1H), 2.71–2.62 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H).

[0135] Example 3: Synthesis of (2,4-dimethoxybenzyl)-(6-trifluoromethyl-2,3-dihydrobenzofuran-3-yl)-amine

[0136]

[0137] First step: Synthesis of intermediate 3-1

[0138] Dissolve 2,4-dimethoxybenzylamine (351.79 mg, 2.10 mmol) in 5 mL of methanol, add 2-hydroxy-4-(trifluoromethyl)benzaldehyde (0.2 g, 1.05 mmol). After addition, the reaction system reacts at 20 °C for 12 hr, and concentrate under reduced pressure to obtain compound 3-1 (0.33 g). The product is used in the next step without further purification. MS (ESI, m / z): 340.1 [M+H] + 。

[0139] Second step: Synthesis of (2,4-dimethoxybenzyl)-(6-trifluoromethyl-2,3-dihydrobenzofuran-3-yl)-amine

[0140] Dissolve trimethylsulfoxonium iodide (535.08 mg, 2.43 mmol) in 10 mL of tetrahydrofuran, add potassium tert-butoxide (272.83 mg, 2.43 mmol). After the reaction system reacts at 20 °C for 30 min, add dropwise a solution of compound 3-1 (0.33 g, 972.57 μmol) in tetrahydrofuran (5 mL). After addition, the reaction system is stirred at 20 °C for 1 hr, then heated to 50 °C and stirred for 5 hr, cooled to room temperature, and add another equivalent of potassium tert-butoxide (109.13 mg, 972.57 μmol). After addition, react at 20 °C for 12 hr. After the reaction is completed, filter and concentrate under reduced pressure, and separate and purify by silica gel column chromatography (PE:EA = 82:18) to obtain compound 3 (0.21 g, 594.34 μmol, total yield of two steps 56.5%). MS (ESI, m / z): 354.1 [M+H] + 。

[0141] 1 H NMR (400 MHz, DMSO) δ 7.54 (d, J = 7.6 Hz, 1H), 7.26–7.23 (m, 1H), 7.23–7.21 (m, 1H), 7.13 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.4, 2.4 Hz, 1H), 4.58 (dd, J = 9.2, 8.0 Hz, 1H), 4.55–4.48 (m, 1H), 4.36 (dd, J = 8.8, 4.0 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.70–3.55 (m, 2H), 2.55 (s, 1H).

[0142] Example 4: Synthesis of (6-bromo-2,3-dihydrobenzofuran-3-yl)methanamine

[0143]

[0144] The first step: Synthesis of intermediate 4-1

[0145] Dissolve methylamine hydrochloride (3.36 g, 49.75 mmol) and triethylamine (5.03 g, 49.75 mmol, 6.91 mL) in 20 mL of methanol. After stirring for 30 minutes, add a solution of 4-bromo-2-hydroxybenzaldehyde (5 g, 5.26 mmol) in methanol (10 mL). After addition, the reaction system reacts at 20 °C for 12 hr. After the reaction is completed, concentrate under reduced pressure, and separate and purify by silica gel column chromatography (DCM:MeOH = 92:8) to obtain compound 4-1 (5 g, yield 93.9%). MS (ESI, m / z): 214.0 [M+H] + 。

[0146] Step 2: Synthesis of (6-bromo-2,3-dihydrobenzofuran-3-yl)-methanamine

[0147] Dissolve trimethylsulfoxonium iodide (12.85 g, 58.40 mmol) in 80 mL of tetrahydrofuran, add potassium tert-butoxide (6.55 g, 58.40 mmol). After the reaction system reacts at 20 °C for 30 min, dropwise add a tetrahydrofuran solution (20 mL) of compound 4-1 (5 g, 23.36 mmol). After addition, the reaction system continues to stir at 20 °C for 1 hr, then is heated to 50 °C and stirred for 5 hr. After cooling to room temperature, add another equivalent of potassium tert-butoxide (5.14 g, 23.36 mmol). After addition, react at 20 °C for 12 hr. After the reaction is completed, filter and concentrate under reduced pressure, and separate and purify by silica gel column chromatography (DCM:MeOH = 94:6) to obtain compound 4 (2.1 g, 9.21 mmol, total yield of two steps 37.0%). MS (ESI, m / z): 228.1 [M+H] + 。

[0148] 1 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 4.56 (dd, J = 9.6, 7.6 Hz, 1H), 4.43 (dd, J = 10.0, 3.6 Hz, 1H), 4.37 (dd, J = 7.6, 3.6 Hz, 1H), 2.43 (s, 3H).

[0149] Example 5: Synthesis of N-cyclopropyl-6-methyl-2,3-dihydrobenzofuran-3-amine

[0150]

[0151] Step 1: Synthesis of intermediate 5-2

[0152] Dissolve cyclopropylamine (1.26 g, 22.03 mmol) and MgSO4 (4.42 g, 36.72 mmol) in MeOH (20 mL). After stirring at 20 °C for 30 min, add 2-hydroxy-4-methylbenzaldehyde (1 g, 7.34 mmol). After addition, the reaction system reacts at 20 °C for 12 hr. After the reaction is completed, filter, and concentrate the filtrate under reduced pressure. Separate and purify by silica gel column chromatography (PE:EA = 85:15) to obtain compound 5-2 (1.1 g, yield 85.5%), MS (ESI, m / z): 176.1 [M+H] + 。

[0153] Step 2: Synthesis of N-cyclopropyl-6-methyl-2,3-dihydrobenzofuran-3-amine

[0154] Dissolve trimethylsulfoxonium iodide (627.96 mg, 2.85 mmol) in 10 mL of tetrahydrofuran, add potassium tert-butoxide (319.80 mg, 2.85 mmol). After the reaction system reacts at 20 °C for 30 min, add dropwise a solution of compound 5-2 (0.2 g, 1.14 mmol) in tetrahydrofuran (5 mL). After addition, the reaction system is continuously stirred at 20 °C for 1 hr, then heated to 50 °C and stirred for 5 hr. Cool to room temperature, add another equivalent of potassium tert-butoxide (127.92 mg, 1.14 mmol). After addition, react at 20 °C for 12 hr. After completion of the reaction, filter and concentrate under reduced pressure, and separate and purify by silica gel column chromatography (DCM:MeOH = 92:8) to obtain compound 5 (0.19 g, 1.00 mmol, total yield of two steps 75.2%). MS (ESI, m / z): 190.1 [M+H] + 。

[0155] 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J = 7.6 Hz, 1H), 6.68–6.63 (m, 1H), 6.61–6.58 (m, 1H), 4.48 (dd, J = 8.8, 7.6 Hz, 1H), 4.41 (dd, J = 8.0, 4.0 Hz, 1H), 4.28 (dd, J = 9.2, 4.4 Hz, 1H), 2.73 (s, 1H), 2.24 (s, 3H), 2.15–2.08 (m, 1H), 0.41–0.34 (m, 2H), 0.27–0.22 (m, 2H).

[0156] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. All the content disclosed in the specification, including the abstract, and all the methods and steps disclosed, can be combined arbitrarily, unless these features and / or steps are mutually exclusive combinations. Each technical feature disclosed in the specification, including the abstract, unless otherwise stated, can be replaced by technical features that achieve the same, equivalent or similar purposes. Therefore, unless otherwise stated, each technical feature disclosed in the present invention is only an example of equivalent or similar technical features in the general series. Those of ordinary skill in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a compound of formula II, comprising the following steps 1: preparing a compound of formula II by reacting a compound of formula III with a corresponding amine or amine salt in a protic or aprotic organic solvent or water, in, R is selected from C optionally substituted by phenyl 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, the phenyl group is optionally substituted by 1, 2 or 3 C 1-6 Alkoxy substitution; Y is selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Z 1 , Z 2 and Z 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

2. The method of claim 1, wherein: R is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group, preferably C 1-6 alkyl; Y is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; Z 1 , Z 2 and Z 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

3. The method according to claim 1 or 2, which satisfies one or more of the following conditions: (1) The protic or aprotic organic solvent in step 1 is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, preferably methanol; (2) The reaction temperature in step 1 is 0°C to 100°C, preferably 10°C to 70°C, preferably 10°C to 50°C; (3) The equivalent ratio of the amine or amine salt in step 1 to the compound represented by formula III is 1 to 10:1, preferably 1 to 5:1, and preferably 2 to 4:1; (4) The amine salt in step 1 is the hydrochloride, hydrobromide, hydroiodide or sulfate of the amine.

4. The method according to any one of claims 1 to 3, wherein: The compound represented by formula III and the corresponding amine salt react under the action of a base to prepare the compound represented by formula II, preferably satisfying one or more of the following conditions: (1) The base in step 1 is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine and pyridine, preferably triethylamine; (2) The equivalent ratio of the base in step 1 to the compound represented by formula III is 1 to 10:1, preferably 1 to 5:

1.

5. The method according to any one of claims 1 to 3, wherein: The compound represented by formula III and the corresponding amine react under the action of a desiccant to prepare the compound represented by formula II, preferably satisfying one or more of the following conditions: (1) The desiccant in step 1 is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, calcium sulfate and molecular sieves; (2) The equivalent ratio of the desiccant in step 1 to the compound represented by formula III is 1 to 10:1, preferably 2 to 8:

1.

6. A method for preparing a compound of formula I, a stereoisomer, a tautomer or an isotope-labeled compound thereof, comprising step 1 according to any one of claims 1 to 5, and step 2: preparing a compound of formula I by reacting a compound of formula II with a methylene transfer reagent in a protic or aprotic organic solvent, in, R, Y, Z 1 , Z 2 and Z 3 As defined in any one of claims 1 to 5.

7. The method of claim 6, wherein step 2 satisfies one or more of the following: (1) The reaction temperature in step 2 is 0°C to 100°C, preferably 20°C to 60°C; (2) the methylene transfer reagent in step 2 is selected from dimethylmethylenesulfonium ylide and sulfoxide ylide reagent, preferably trimethylsulfoxide iodide or trimethylsulfonium iodide; (3) the protic or aprotic organic solvent in step 2 is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; (4) The equivalent ratio of the methylene transfer reagent in step 2 to the compound represented by formula II is 1 to 5:1, preferably 2 to 3:1; (5) The reaction in step 2 is carried out under the action of a base. Preferably, the base in step 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, NaH, NaHMDS, NaOH, sodium tert-butoxide, potassium tert-butoxide and pyridine, and / or the equivalent ratio of the base in step 2 to the compound represented by formula II is 1 to 5:1, preferably 2 to 4:1, and preferably 2 to 3:

1.

8. The method according to claim 6 or 7, further comprising step 3: resolving the compound of formula I into S and R configuration isomers.

9. A compound represented by II', its stereoisomer, tautomer, isotope-labeled compound or salt thereof, in, R' is selected from C optionally substituted by phenyl 1-6 Alkyl and C 3-8 Cycloalkyl, the phenyl group is replaced by 1, 2 or 3 C 1-6 Alkoxy substitution; Y' is selected from halogen and C 1-6 Haloalkyl; Z 1 , Z 2 and Z 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

10. The compound according to claim 9, its stereoisomer, tautomer, isotope-labeled compound or salt thereof, wherein: R' is selected from C 1-6 alkyl; Y' is selected from C 1-6 Haloalkyl; Z 1 , Z 2 and Z 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

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